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The impact of bariatric surgery on colorectal cancer risk

Open AccessPublished:October 27, 2022DOI:https://doi.org/10.1016/j.soard.2022.10.016

      Highlights

      • Cohort and biomarker studies suggest an increased risk of colorectal cancer following bariatric surgery.
      • Microbial alterations reported after Roux-en-Y gastric bypass are similar to those observed in patients with colorectal cancer.
      • Higher serum concentrations of bile acids and lower levels of butyrate following bariatric surgery could contribute to an increased risk of colorectal cancer.

      Abstract

      Obesity is considered a risk factor for different types of cancer, including colorectal cancer (CRC). Bariatric surgery has been associated with improvements in obesity-related co-morbidities and reductions in overall cancer risk. However, given the contradictory outcomes of several cohort studies, the impact of bariatric surgery on CRC risk appears controversial. Furthermore, measurement of CRC biomarkers following Roux-en-Y gastric bypass (RYGB) has revealed hyperproliferation and increased pro-inflammatory gene expression in the rectal mucosa. The proposed mechanisms leading to increased CRC risk are alterations of the gut microbiota and exposure of the colorectum to high concentrations of bile acids, both of which are caused by RYGB-induced anatomical rearrangements. Studies in animals and humans have highlighted the similarities between RYGB-induced microbial profiles and the gut microbiota documented in CRC. Microbial alterations common to post-RYGB cases and CRC include the enrichment of pro-inflammatory microbes and reduction in butyrate-producing bacteria. Lower concentrations of butyrate following RYGB may also contribute to an increased risk of CRC, given the anti-inflammatory and anticarcinogenic properties of this molecule. Laparoscopic sleeve gastrectomy appears to have a more moderate impact than RYGB; however, relatively few animal and human studies have investigated its effects on CRC risk. Moreover, evidence regarding the impact of anastomosis gastric bypass on one is even more limited. Therefore, further studies are required to establish whether the potential increase in CRC risk is restricted to RYGB or may also be associated with other bariatric procedures.

      Keywords

      Obesity (defined as body mass index [BMI] over 30 kg/m2) is rising dramatically worldwide [
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      GBD 2015 Obesity Collaborators
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      ]. The prevalence of obesity doubled between 1980 and 2015 in more than 70 countries and increased in most other countries. In 2015, about 12% of the world’s adult population was obese, and by 2030, the prevalence of obesity is expected to increase to 42% [
      GBD 2015 Obesity Collaborators
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      ]. Obesity has become a severe public health issue due to its associated morbidity and mortality [
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      Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.
      ]. Excess body weight has been correlated with type II diabetes, cardiovascular diseases, nonalcoholic fatty liver disease, and several cancers [
      • Guh D.P.
      • Zhang W.
      • Bansback N.
      • Amarsi Z.
      • Birmingham C.L.
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      Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.
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      Therapeutic options for obesity include medical treatment and bariatric surgery. Surgical treatment is a valid option for patients who have failed to lose weight or maintain long-term weight loss despite appropriate nonsurgical treatment. Bariatric surgery should be considered for patients with a BMI equal to or over 40 kg/m2 or with a BMI between 35.0 and 39.9 kg/m2 and associated co-morbidities that are expected to improve with weight loss [
      • Di Lorenzo N.
      • Antoniou S.A.
      • Batterham R.L.
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      Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery: update 2020 endorsed by IFSO-EC, EASO and ESPCOP.
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      • Fried M.
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      International Federation for surgery of obesity and metabolic Disorders-European Chapter (IFSO-EC); European Association for the Study of Obesity (EASO); European Association for the Study of Obesity Obesity Management Task Force (EASO OMTF). Interdisciplinary European guidelines on metabolic and bariatric surgery.
      ]. In the last decades, the demand for bariatric surgery has increased significantly in many countries and is expected to increase further, given the increasing prevalence of obesity. According to global reports conducted by the International Federation for the Surgery of Obesity and Metabolic Disorders, the total number of bariatric surgery procedures performed worldwide increased from 146,301 in 2003 to 696,191 in 2018 [
      • Buchwald H.
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      • Angrisani L.
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      • Ramos A.
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      • Kow L.
      Bariatric surgery survey 2018: similarities and disparities among the 5 IFSO chapters.
      ]. Several studies have proven the superiority of bariatric surgery over nonsurgical treatment in promoting long-term weight loss, as well as resolving or improving type II diabetes, reducing the incidence of adverse cardiovascular events, and lowering the mortality rate [
      • Sheng B.
      • Truong K.
      • Spitler H.
      • Zhang L.
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      • Chen L.
      The long-term effects of bariatric surgery on type 2 diabetes remission, microvascular and macrovascular complications, and mortality: a systematic review and meta-analysis.
      ,
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      • Braunwald E.
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      Bariatric surgery: a systematic review and meta-analysis.
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      • Briel M.
      • Bhatt D.L.
      • et al.
      Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials.
      ,
      • Buchwald H.
      • Estok R.
      • Fahrbach K.
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      Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis.
      ,
      • Sutanto A.
      • Wungu C.D.K.
      • Susilo H.
      • Sutanto H.
      Reduction of major adverse cardiovascular events (MACE) after bariatric surgery in patients with obesity and cardiovascular diseases: a systematic review and meta-analysis.
      ].
      Both weight loss–dependent and weight loss–independent mechanisms associated with bariatric procedures have been proposed to be involved in reduced cancer incidence and improved prognosis. These mechanisms include decreases in systemic inflammation and oxidative stress as well as changes in gastrointestinal hormones and alterations in the gut microbiota and metabolism of fat, glucose, and bile [
      • Castagneto-Gissey L.
      • Casella-Mariolo J.
      • Casella G.
      • Mingrone G.
      Obesity surgery and cancer: what are the Unanswered questions?.
      ,
      • Ashrafian H.
      • Ahmed K.
      • Rowland S.P.
      • et al.
      Metabolic surgery and cancer: protective effects of bariatric procedures.
      ]. The protective effects of bariatric surgery in relation to cancer risk and development are most evident for obesity-associated malignancies such as hormone-related and gastrointestinal tumors [
      • Schauer D.P.
      • Feigelson H.S.
      • Koebnick C.
      • et al.
      Bariatric surgery and the risk of cancer in a large multisite cohort.
      ,
      • Tao W.
      • Santoni G.
      • von Euler-Chelpin M.
      • et al.
      Cancer risk after bariatric surgery in a cohort study from the five Nordic countries.
      ,
      • Wiggins T.
      • Antonowicz S.S.
      • Markar S.R.
      Cancer risk following bariatric surgery-systematic review and meta-analysis of national population-based cohort studies.
      ]. In contrast, the effect of bariatric surgery on colorectal cancer (CRC) is uncertain and controversial, given that some studies report an increase in risk [
      • Afshar S.
      • Kelly S.B.
      • Seymour K.
      • Lara J.
      • Woodcock S.
      • Mathers J.C.
      The effects of bariatric surgery on colorectal cancer risk: systematic review and meta-analysis.
      ,
      • Ciccioriccio M.C.
      • Iossa A.
      • Boru C.E.
      • et al.
      CRIC-ABS 2020 GROUP. Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey.
      ], while others document a reduction in risk for this cancer [
      • Mackenzie H.
      • Markar S.R.
      • Askari A.
      • et al.
      Obesity surgery and risk of cancer.
      ,
      • Derogar M.
      • Hull M.A.
      • Kant P.
      • Östlund M.
      • Lu Y.
      • Lagergren J.
      Increased risk of colorectal cancer after obesity surgery.
      ].
      CRC is the third most commonly diagnosed cancer and the second leading cause of cancer deaths, with an estimated number of 1.9 million new cases and around 935,000 deaths worldwide in 2020 [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. CRC is a multifactorial disease resulting from genetic, environmental, and lifestyle factors and is associated with several risk factors that cannot be modified. These include age, personal history of inflammatory bowel disease, and familial history of CRC. Additional risk factors are related to lifestyle, such as obesity, sedentary life, unhealthy nutritional habits, alcohol consumption, and smoking [
      • Mármol I.
      • Sánchez-de-Diego C.
      • Pradilla Dieste A.
      • Cerrada E.
      • Rodriguez Yoldi M.J.
      Colorectal carcinoma: a general overview and future perspectives in colorectal cancer.
      ,
      • Dai Z.
      • Xu Y.C.
      • Niu L.
      Obesity and colorectal cancer risk: a meta-analysis of cohort studies.
      ,
      • Schwingshackl L.
      • Schwedhelm C.
      • Hoffmann G.
      • et al.
      Food groups and risk of colorectal cancer.
      ,
      • McNabb S.
      • Harrison T.A.
      • Albanes D.
      • et al.
      Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.
      ,
      • Liang P.S.
      • Chen T.Y.
      • Giovannucci E.
      Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis.
      ].
      Since obesity is a risk factor for CRC, weight loss achieved with bariatric surgery is expected to reduce the risk of this cancer. However, several studies have yielded conflicting results, reflecting the complex and controversial nature of this association [
      • Afshar S.
      • Kelly S.B.
      • Seymour K.
      • Lara J.
      • Woodcock S.
      • Mathers J.C.
      The effects of bariatric surgery on colorectal cancer risk: systematic review and meta-analysis.
      ,
      • Ciccioriccio M.C.
      • Iossa A.
      • Boru C.E.
      • et al.
      CRIC-ABS 2020 GROUP. Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey.
      ,
      • Mackenzie H.
      • Markar S.R.
      • Askari A.
      • et al.
      Obesity surgery and risk of cancer.
      ,
      • Derogar M.
      • Hull M.A.
      • Kant P.
      • Östlund M.
      • Lu Y.
      • Lagergren J.
      Increased risk of colorectal cancer after obesity surgery.
      ]. Therefore, in this review, we aimed to evaluate whether bariatric surgery leads to an increased risk of CRC and to investigate the mechanisms that may be involved.

      Materials and methods

      A literature search using PubMed was conducted to identify articles relevant to the review topic. Search terms used were “colorectal cancer,” “bariatric surgery” or “Roux-en-Y gastric bypass” or “sleeve gastrectomy,” “colorectal cancer risk,” “biomarkers of colorectal cancer,” “gut microbiota” or “microbiome,” “bile acid metabolism,” “short-chain fatty acids,” “butyrate.” Additional articles were identified from the references of the included studies.
      Case reports, comments, and non-English publications were excluded from the review. In total, 95 papers (published between 1984 and 2021) were included in the review; of these, 66 were research articles, 27 were literature reviews, 1 was a systematic review, and 1 was a meta-analysis.

      Bariatric procedures

      Bariatric procedures are classified into 3 main groups according to their mechanism of action in promoting weight loss. Malabsorptive bariatric surgery limits the absorption of nutrients by bypassing part of the small intestine to some degree [
      • Fried M.
      • Yumuk V.
      • Oppert J.M.
      • et al.
      International Federation for surgery of obesity and metabolic Disorders-European Chapter (IFSO-EC); European Association for the Study of Obesity (EASO); European Association for the Study of Obesity Obesity Management Task Force (EASO OMTF). Interdisciplinary European guidelines on metabolic and bariatric surgery.
      ]. In restrictive procedures, the size of the stomach is considerably reduced in order to induce an early sense of satiety in patients during food intake [
      • Wolfe B.M.
      • Kvach E.
      • Eckel R.H.
      Treatment of obesity: weight loss and bariatric surgery.
      ,
      • Phillips B.T.
      • Shikora S.A.
      The history of metabolic and bariatric surgery: development of standards for patient safety and efficacy.
      ]. A further major category of bariatric procedures combines malabsorptive and restrictive components; these techniques involve significant reduction of available gastric capacity in conjunction with the bypassing of a section of the proximal small intestine [
      • Aarts E.O.
      • Mahawar K.
      From the knife to the endoscope-a history of bariatric surgery.
      ].
      Laparoscopic sleeve gastrectomy (LSG), a restrictive procedure, is currently the most commonly performed bariatric technique worldwide [
      • Welbourn R.
      • Hollyman M.
      • Kinsman R.
      • et al.
      Bariatric surgery worldwide: baseline demographic description and one-year outcomes from the fourth IFSO global registry report 2018.
      ]. LSG involves the transection and removal of the greater curvature portion of the stomach, leaving only a narrow tube along the lesser curvature. The popularity of this procedure is likely due to its promotion of significant weight loss and improvement in metabolic conditions, alongside a reduced risk of complications, compared with malabsorptive procedures [
      • Phillips B.T.
      • Shikora S.A.
      The history of metabolic and bariatric surgery: development of standards for patient safety and efficacy.
      ].
      Roux-en-Y gastric bypass (RYGB), currently the second most common bariatric technique, is a combined restrictive and malabsorptive procedure [
      • Welbourn R.
      • Hollyman M.
      • Kinsman R.
      • et al.
      Bariatric surgery worldwide: baseline demographic description and one-year outcomes from the fourth IFSO global registry report 2018.
      ]. This involves the creation of a gastric pouch from the upper stomach that is then anastomosed to the jejunum, forming the Roux or alimentary limb through which ingested nutrients flow. Anastomosis of the biliopancreatic limb with the jejunum allows the interaction of bile acids (BAs) and pancreatic secretions with nutrients in the common limb [
      • Pucci A.
      • Batterham R.L.
      Mechanisms underlying the weight loss effects of RYGB and SG: similar, yet different.
      ]. One anastomosis gastric bypass (OAGB) is a variation of gastric bypass, consisting of a single anastomosis of the gastric pouch to a loop of jejunum 150–200 cm from the ligament of Treitz [
      • Wiggins T.
      • Majid M.S.
      • Agrawal S.
      From the knife to the endoscope-a history of bariatric surgery.
      ,
      • Robert M.
      • Espalieu P.
      • Pelascini E.
      • et al.
      Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass for obesity (YOMEGA): a multicentre, randomised, open-label, non-inferiority trial.
      ].

      CRC risk after bariatric surgery

      Although bariatric surgery has proven to reduce overall cancer incidence, cohort studies have reported conflicting results on the impact of bariatric surgery on CRC. For instance, in 2010, Ostlund et al. conducted a population-based cohort study of bariatric surgery patients to test whether the risk of obesity-related cancer decreased with time after obesity surgery. The results of the study showed that CRC risk gradually and significantly increased with follow-up time after bariatric surgery. Patients followed up for more than 10 years showed a 2-fold increased risk. Such increases were not observed for the other main obesity-related malignancies, including breast, prostate, and endometrial cancer [
      • Ostlund M.P.
      • Lu Y.
      • Lagergren J.
      Risk of obesity-related cancer after obesity surgery in a population-based cohort study.
      ].
      Another population-based study, conducted by Derogar et al., identified an increased risk of CRC in patients with obesity undergoing surgery. An overall standardized incidence ratio (SIR) of 1.60 for CRC was reported for the obese surgery cohort, increasing to 2.00 after 10 years. In contrast, the SIR in the obese no-surgery cohort was 1.26, remaining stable over time [
      • Derogar M.
      • Hull M.A.
      • Kant P.
      • Östlund M.
      • Lu Y.
      • Lagergren J.
      Increased risk of colorectal cancer after obesity surgery.
      ]. This increased risk of CRC more than 10 years after surgery is consistent with the long natural history of colorectal carcinogenesis, from normal mucosa to malignant lesions. In both studies, bariatric surgeries consisted of restrictive procedures such as vertical banded gastroplasty and adjustable gastric banding, as well as malabsorptive procedures such as gastric bypass [
      • Derogar M.
      • Hull M.A.
      • Kant P.
      • Östlund M.
      • Lu Y.
      • Lagergren J.
      Increased risk of colorectal cancer after obesity surgery.
      ,
      • Ostlund M.P.
      • Lu Y.
      • Lagergren J.
      Risk of obesity-related cancer after obesity surgery in a population-based cohort study.
      ].
      In addition, a large cohort study performed by Mackenzie et al. revealed an association between higher CRC risk and RYGB, although this association was not reported for sleeve gastrectomy or gastric banding [
      • Mackenzie H.
      • Markar S.R.
      • Askari A.
      • et al.
      Obesity surgery and risk of cancer.
      ].
      Likewise, a cohort study conducted across 5 Nordic countries demonstrated a higher risk of colon cancer in individuals who had undergone bariatric surgery, increasing further after ≥ 10 years. In contrast, the risk of rectal cancer was not significantly increased following bariatric surgery, although it appeared to increase with longer follow-up periods [
      • Tao W.
      • Artama M.
      • von Euler-Chelpin M.
      • et al.
      Colon and rectal cancer risk after bariatric surgery in a multicountry Nordic cohort study.
      ].
      These findings are in parallel with the results of a retrospective study conducted by Hussan et al., who examined the risk of colorectal polyp formation following RYGB. To focus on the long-term impact of RYGB, the authors compared colonoscopies performed 5 years or more after surgery with presurgery colonoscopies. Results revealed a higher percentage of serrated polyps (precursors of CRC) 5 years or more after surgery, suggesting an increased risk of precancerous lesion formation following RYGB [
      • Hussan H.
      • Drosdak A.
      • Le Roux M.
      • et al.
      The long-term impact of roux-en-Y gastric bypass on colorectal polyp formation and relation to weight loss outcomes.
      ].
      The impact of bariatric surgery is not limited to the incidence of CRC but also appears to affect prognosis. In 2016, a cohort study conducted by Tao et al. revealed that patients with CRC who had previously undergone bariatric surgery experienced higher mortality rates and a poorer prognosis than patients with CRC with obesity who had not undergone such surgery. When analyzed separately, the mortality rate was increased more than three-fold in patients with rectal cancer, while no statistically significant increase in mortality rate was found in patients with colon cancer [
      • Tao W.
      • Konings P.
      • Hull M.A.
      • Adami H.O.
      • Mattsson F.
      • Lagergren J.
      Colorectal cancer prognosis following obesity surgery in a population-based cohort study.
      ].
      The negative impact of bariatric surgery found in these studies conflicted with the results of a meta-analysis conducted by Afshar et al. This revealed bariatric surgery to be associated with a 27% lower risk of CRC, although few studies were included in this meta-analysis, and follow-up was limited. Thus, lower CRC risk may have been related to weight loss alone [
      • Afshar S.
      • Kelly S.B.
      • Seymour K.
      • Lara J.
      • Woodcock S.
      • Mathers J.C.
      The effects of bariatric surgery on colorectal cancer risk: systematic review and meta-analysis.
      ]. Similarly, an English retrospective observational study found that obesity surgery was not associated with a higher incidence of CRC. However, the limitations of this study included follow-up period (3 years) and a small obese surgery cohort, compared with the obese no-surgery population [
      • Aravani A.
      • Downing A.
      • Thomas J.D.
      • Lagergren J.
      • Morris E.J.A.
      • Hull M.A.
      Obesity surgery and risk of colorectal and other obesity-related cancers: an english population-based cohort study.
      ]. In addition, a nationwide survey of CRC incidence following LSG or RYGB (conducted in Italy by the Italian Society of Obesity Surgery) revealed a low incidence of CRC (0.10%) 10 years after surgery. While this suggested that bariatric surgery had little impact on CRC development, the absence of no-surgery patients with obesity control group and the small number of cases observed (22 CRC cases in 20,571 bariatric patients) meant that the evidence was relatively weak, especially in terms of comparison of LSG and RYGB [
      • Ciccioriccio M.C.
      • Iossa A.
      • Boru C.E.
      • et al.
      CRIC-ABS 2020 GROUP. Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey.
      ].
      The characteristics and findings of the investigations into CRC risk following bariatric surgery are summarized in Table 1. Their contradictory outcomes highlight the need to delve deeper into the mechanisms underlying this association.
      Table 1Studies on CRC risk following bariatric surgery included in the review
      AuthorYearsParticipantsType of bariatric surgeryFindingsFollow-up
      Ostlund et al. [
      • Ostlund M.P.
      • Lu Y.
      • Lagergren J.
      Risk of obesity-related cancer after obesity surgery in a population-based cohort study.
      ]
      1980–2006• Obesity surgery cohort: 13,123• Gastric banding

      • Vertical banding gastroplasty

      • Gastric bypass
      • SIR: 1.52 (95% CI: 1.06−2.11)

      • SIR ≥10 yr: 2.14 (95% CI: 1.33–3.22)
      • Mean follow-up: 9 yr
      Derogar et al. [
      • Derogar M.
      • Hull M.A.
      • Kant P.
      • Östlund M.
      • Lu Y.
      • Lagergren J.
      Increased risk of colorectal cancer after obesity surgery.
      ]
      1980–2009• Obesity surgery cohort: 15,095

      • Obesity no-surgery cohort: 62,016
      • Vertical banded gastroplasty

      • Adjustable gastric banding

      • Roux-en-Y gastric bypass
      • SIR obesity surgery cohort: 1.60 (95% CI: 1.25–2.02)

      • SIR obesity surgery cohort ≥10 yr: 2.00 (95% CI: 1.48–2.64).

      • SIR obesity no-surgery cohort: 1.26 (95% CI: 1.14–1.40)

      • SIR obese no-surgery cohort ≥10 yr: 1.27 (95% CI: 1.03–1.53)
      • Median follow-up: 10 yr (range: 1–30 yr)
      Mackenzie et al. [
      • Mackenzie H.
      • Markar S.R.
      • Askari A.
      • et al.
      Obesity surgery and risk of cancer.
      ]
      1997–2012• Obesity surgery cohort: 8794

      • Obesity no-surgery cohort: 8794
      • Gastric bypass (56.6%)

      • Gastric banding (33.6%)

      • Sleeve gastrectomy (9.8%)
      • OR (bariatric surgery): 2.19 (95% CI: 1.21–3.96)

      • OR (gastric bypass): 2.63 (95% CI: 1.17–5.95)
      • Median follow up: 55 mo
      Tao W et al. [
      • Tao W.
      • Artama M.
      • von Euler-Chelpin M.
      • et al.
      Colon and rectal cancer risk after bariatric surgery in a multicountry Nordic cohort study.
      ]
      1980–2015• Obesity surgery cohort: 49,931

      • Obesity no-surgery cohort: 492,427
      • Gastric bypass (72.5%)

      • Restrictive surgery (9.6%)

      • Other (17.9%).
      • Colon cancer:

      - SIR obesity surgery cohort: 1.56 (95% CI: 1.28–1.88)

      - SIR obesity surgery cohort >10–14 yr: 2.07 (95% CI: 1.36–3.01)

      • Rectal cancer:

      - SIR obesity surgery cohort: 1.14 (95% CI: 0.83–1.52)

      - SIR obesity surgery cohort ≥20 yr: 1.62 (95% CI: 0.78–2.98)
      • N.A.
      Hussan et al. [
      • Hussan H.
      • Drosdak A.
      • Le Roux M.
      • et al.
      The long-term impact of roux-en-Y gastric bypass on colorectal polyp formation and relation to weight loss outcomes.
      ]
      1994–2018• Presurgery cohort: 106

      • Postsurgery cohort: 86
      • Roux-en-Y gastric bypass• Higher percentage of serrated polyps ≥5 yr post-RYGB compared with pre-RYGB (8.7% vs. 2.1%, P = .04; RR: 4.22 (95% CI: 0.97–18.4)• Median follow-up: 9.4 yr
      Tao W et al. [
      • Tao W.
      • Konings P.
      • Hull M.A.
      • Adami H.O.
      • Mattsson F.
      • Lagergren J.
      Colorectal cancer prognosis following obesity surgery in a population-based cohort study.
      ]
      1980–2012• Obesity surgery cohort: 131

      • Obesity no-surgery cohort: 1332
      • Gastric bypass (26%)

      • Gastric banding (33%)

      • Vertical banded gastroplasty (36%)

      • Malabsorptive surgery (5%)
      • Colorectal cancer mortality rate: disease-specific HR: 1.50 (95% CI: 1.00–2.19)

      • Colon cancer mortality rate: disease-specific HR: 1.10 (95% CI: 0.67–1.70)

      • Rectal cancer mortality rate: (disease-specific HR: 3.70 (95% CI: 2.00–6.90)
      • Median follow-up for obesity surgery cohort: 3.7 yr

      • Median follow-up for obesity no-surgery cohort: 4.3 yr
      Aravani et al. [
      • Aravani A.
      • Downing A.
      • Thomas J.D.
      • Lagergren J.
      • Morris E.J.A.
      • Hull M.A.
      Obesity surgery and risk of colorectal and other obesity-related cancers: an english population-based cohort study.
      ]
      1997–2013• Obesity surgery cohort: 39,747

      • Obesity no-surgery cohort: 962,860
      • Restrictive surgery (52%)

      • Restrictive and malabsorptive surgery (48%)
      • SIR obesity surgery cohort: 1.26 (95% CI: 0.92–1.71)

      • SIR obesity no-surgery cohort: 1.12 (95% CI: 1.08–1.16)
      • Median follow up for obesity surgery cohort: 3 yr

      • Median follow up for obesity no-surgery cohort: 2.5 yr
      Ciccioriccio et al. [
      • Ciccioriccio M.C.
      • Iossa A.
      • Boru C.E.
      • et al.
      CRIC-ABS 2020 GROUP. Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey.
      ]
      2010–2015• Bariatric surgery patients: 20,571• Sleeve gastrectomy (70%)

      • Gastric bypass (30%)
      • Sleeve gastrectomy:

      - SIR (male gender): 0.5 (CI: 0.2–0.72)

      - SIR (female gender): 0.6 (CI: 0.3–0.76)

      • Gastric bypass:

      - SIR (male gender): 1.07 (CI: 0.91–1.2)

      - SIR (female gender): 0.8 (CI: 0.32–0.94)
      • Follow up: equally distributed between 5 and 10 yr
      SIR: standardized incidence ratios; 95% CI, 95% confidence interval; OR: odds ratio; RR: relative risk; HR: hazard ratio; N.A.: not available.

      Biomarkers of CRC

      A number of studies have investigated changes in CRC biomarkers following bariatric surgery. A study carried out by Sainsbury et al. in 2008 investigated mucosal biomarkers—considered indicators of future CRC risk [
      • Lipkin M.
      Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects.
      ,
      • Wong W.M.
      • Mandir N.
      • Goodlad R.A.
      • et al.
      Histogenesis of human colorectal adenomas and hyperplastic polyps: the role of cell proliferation and crypt fission.
      ]—in normal-weight individuals (n = 21) and patients with obesity undergoing RYGB (n = 24) [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]. Mucosal biomarkers of proliferation such as rectal epithelial cell mitosis, crypt area, and crypt branching were quantified by carrying out whole crypt microdissection; apoptosis was also evaluated by immunohistochemical staining for neo-cytokeratin 18. Before surgery, patients with obesity exhibited higher levels of rectal epithelial cell proliferation than normal-weight individuals, consistent with the link between obesity and CRC risk. Six months after RYGB, analysis of the same patients revealed a two-fold increase in the number of mitoses per crypt, compared with presurgery values. This further increase in rectal epithelial cell mitosis post-RYGB was accompanied by a decrease in the number of apoptotic cells. Systemic and mucosal markers of inflammation were also analyzed, including serum levels of C-reactive protein (CRP), cytokines, and mucosal pro-inflammatory gene expression. As expected, serum levels of CRP, interleukin (IL) 6, tumor necrosis factor α (TNFα), and macrophage migration inhibitory factor (MIF) were higher in patients with obesity than in normal-weight controls. After surgery, the patients with obesity had lower levels of CRP and IL-6 but significantly increased levels of TNFα and MIF, both of which are implicated in colorectal mucosal inflammation and carcinogenesis [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Gordon-Weeks A.N.
      • Lim S.Y.
      • Yuzhalin A.E.
      • Jones K.
      • Muschel R.
      Macrophage migration inhibitory factor: a key cytokine and therapeutic target in colon cancer.
      ,
      • De Simone V.
      • Franzè E.
      • Ronchetti G.
      • et al.
      Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.
      ]. Furthermore, the expression of pro-inflammatory genes cyclooxygenase-1 (COX-1) and COX-2 increased significantly following RYGB surgery [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]. COX-2, in particular, is known to be overexpressed in CRC and appears to play a major role in its development and progression [
      • Negi R.R.
      • Rana S.V.
      • Gupta V.
      • et al.
      Over-expression of cyclooxygenase-2 in colorectal cancer patients.
      ,
      • Liu Y.
      • Sun H.
      • Hu M.
      • et al.
      The role of cyclooxygenase-2 in colorectal carcinogenesis.
      ].
      Interestingly, these mucosal biomarkers were quantified in the same group of patients (n = 19) 3 years after RYGB to determine their long-term persistence. Rectal epithelial cell mitosis and crypt size remained abnormally increased 3 years after RYGB, compared with preoperative values. COX-1 and COX-2 messenger RNA (mRNA) levels also remained elevated, similar to the values observed 6 months post-RYGB. A remarkable outcome of the study was the marked upregulation of MIF in the rectal mucosa 3 years after surgery. The authors observed a 40.5-fold increase in mucosal MIF mRNA levels compared with pre-RYGB values, as well as higher MIF protein levels in colorectal epithelial cells. However, serum MIF was reduced, compared with levels observed 6 months after surgery, indicating that MIF upregulation was a local pro-inflammatory phenomenon rather than a systemic response [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ].
      A similar study conducted by Afshar et al. investigated the impact of RYGB on biomarkers of CRC risk. This study included 22 post-RYGB patients and 20 normal-weight controls. Notably, in this case, the results revealed lower rectal crypt cell proliferation and reduced systemic and mucosal markers of inflammation 6 months after RYGB [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]. However, the contrasting outcomes of the 2 studies may have been due to the different characteristics of the populations and differences in the surgical procedures [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]. For example, the decreased levels of inflammatory markers identified by Afshar et al. may have been due to the lower mean BMI of patients in this study, compared with the patients studied by Sainsbury et al. Furthermore, a remarkable difference between the 2 investigations was the length of the bypassed tract: the biliopancreatic limb was 150 cm long in the study of Sainsbury et al., whereas it was 60–75 cm long in the study of Afshar et al. It has been suggested, therefore, that the length of the biliopancreatic limb may be a key factor in the hyperproliferation and inflammation of the rectal mucosa [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]. This is supported by the results of a study conducted by Appleton et al. on patients with obesity who had undergone jejunoileal bypass (JIB). In these patients, the bypassing of a long portion of the small intestine led to a marked and persistent increase in rectal crypt cell proliferation [
      • Appleton G.V.
      • Wheeler E.E.
      • Al-Mufti R.
      • Challacombe D.N.
      • Williamson R.C.
      Rectal hyperplasia after jejunoileal bypass for morbid obesity.
      ].
      According to this hypothesis, these effects should not occur after restrictive bariatric procedures, where intestinal flow remains largely unaltered. Kant et al. tested this assumption by comparing mucosal biomarkers of CRC risk in patients undergoing LSG (n = 21) and normal-weight controls (n = 20). Unlike the results observed following RYGB, there was no significant change in rectal epithelial cell proliferation 6 months after LSG. Furthermore, mucosal MIF mRNA levels increased by 39% following LSG, but there were no changes in the expression of TNFα, IL-1, IL-6, COX-1, or COX-2 over the same period [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ].
      Levels of serum biomarkers and expression of pro-inflammatory genes prior to bariatric surgery, 6 months after RYGB, 3 years after RYGB, and 6 months after LSG (reported by different authors) are summarized in Table 2.
      Table 2Biomarkers of colorectal cancer
      BiomarkersPre-surgery [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ,
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      6 mo post-RYGB [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]
      3 yr post-RYGB [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      6 mo post-LSG [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Serum CRPHigher levels in patients with obesity, compared with normal-weight controls [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ,
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      • Significant reduction due to RYGB-induced weight loss [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]

      • 71% decrease following RYGB-induced weight loss [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]
      Lower levels than at 6 mo postsurgery due to further weight loss [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      Significant reduction due to LSG-induced weight loss [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Serum IL-6Higher levels in patients with obesity, compared with normal-weight controls [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Significant reduction due to RYGB-induced weight loss [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]
      Lower levels than at 6 mo postsurgery due to further weight loss [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      No significant change, compared to presurgery values [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Serum TNFαHigher levels in patients with obesity, compared with normal-weight controls [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Increased levels, compared with presurgery values [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]
      Levels similar to presurgery values [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      No significant change, compared to presurgery values [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Serum MIFHigher levels in patients with obesity, compared with normal-weight controls [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ,
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      Increased levels, compared with presurgery values [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]
      Lower levels than presurgery and 6 mo post-RYGB values [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      N.A.
      Mucosal MIF mRNA levelsSimilar levels in patients with obesity and normal-weight controls [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      No significant change, compared to presurgery values [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]
      Significantly increased levels, compared with presurgery values [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      Significantly increased levels, compared with presurgery values [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      COX-1 mRNA levelsSimilar levels in patients with obesity and normal-weight controls [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      • Significantly increased levels, compared with presurgery values [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]

      • Significantly decreased levels, compared with presurgery values [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]
      Significantly increased levels, compared with presurgery values [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      No significant change, compared to presurgery values [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      COX-2 mRNA levelsSimilar levels in patients with obesity and normal-weight controls [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      • Significantly increased levels, compared with presurgery values [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]

      • No significant change, compared to presurgery values [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]
      Significantly increased levels, compared with presurgery values [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      No significant change, compared to presurgery values [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      IL-6 mRNA levelsSimilar levels in patients with obesity and normal-weight controls [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      • Significantly increased levels, compared with presurgery values [
      • Sainsbury A.
      • Goodlad R.A.
      • Perry S.L.
      • Pollard S.G.
      • Robins G.G.
      • Hull M.A.
      Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.
      ]

      • No significant change, compared to presurgery values [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ]
      Slightly elevated levels, compared with presurgery values (not significant) [
      • Kant P.
      • Sainsbury A.
      • Reed K.R.
      • et al.
      Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
      ]
      No significant change, compared to presurgery values [
      • Kant P.
      • Perry S.L.
      • Dexter S.P.
      • Race A.D.
      • Loadman P.M.
      • Hull M.A.
      Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass.
      ]
      Levels of serum biomarkers and pro-inflammatory gene expression prior to bariatric surgery, 6 months after RYGB, 3 years after RYGB, and 6 months after LSG.
      RYGB: Roux-en-Y gastric bypass; LSG: laparoscopic sleeve gastrectomy; CRP: C-reactive protein; IL-6: interleukin-6; TNFα: tumor necrosis factor α; MIF: macrophage migration inhibitory factor; COX-1: cyclooxygenase-1; COX-2: cyclooxygenase-2; NA: Not available; mRNA, messenger RNA.
      The mechanisms leading to hyperproliferation of the rectal mucosa following RYGB and malabsorptive procedures (but not LSG) are still unclear. Nonetheless, several possible pro-carcinogenic pathways have been proposed, as outlined below.

      Alteration of gut microbiota

      Alteration of the gut microbiota has been suggested to be one of the main potential mechanisms linking bariatric surgery to an increased risk of CRC. This hypothesis arises from the intriguing finding that some of the gut bacteria found to be increased after bariatric surgery have been associated with CRC due to their pro-carcinogenic properties.
      Bariatric surgery (especially RYGB and malabsorptive procedures) induces major anatomical rearrangements in the gastrointestinal tract, altering nutrient transit and affecting gut physiology. Malabsorption, changes in the metabolism of BAs, alteration of pH, and modulation of enteric and adipose hormones all affect the composition of the gut microbiota [
      • Aron-Wisnewsky J.
      • Doré J.
      • Clement K.
      The importance of the gut microbiota after bariatric surgery.
      ,
      • Anhê F.F.
      • Varin T.V.
      • Schertzer J.D.
      • Marette A.
      The gut microbiota as a mediator of metabolic benefits after bariatric surgery.
      ,
      • Ulker İ.
      • Yildiran H.
      The effects of bariatric surgery on gut microbiota in patients with obesity: a review of the literature.
      ]. Accordingly, changes in the gut microbiota following RYGB have been widely demonstrated. The most commonly reported alterations in post-RYGB patients are a marked increase in the phylum Fusobacteria, higher levels of the class Gammaproteobacteria and the genera Bacteroides and Escherichia, and a decrease in the abundance of the phylum Firmicutes [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Furet J.P.
      • Kong L.C.
      • Tap J.
      • et al.
      Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers.
      ,
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ,
      • Kong L.C.
      • Tap J.
      • Aron-Wisnewsky J.
      • et al.
      Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes.
      ].
      The impact of LSG on gut microbiota composition has also been investigated. Three studies on human patients found that LSG led to changes in the fecal microbial community similar to those observed after RYGB; however, the alterations were more moderate than those seen following RYGB, demonstrating the lower impact of LSG [
      • Damms-Machado A.
      • Mitra S.
      • Schollenberger A.E.
      • et al.
      Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption.
      ,
      • Tabasi M.
      • Eybpoosh S.
      • Siadat S.D.
      • Elyasinia F.
      • Soroush A.
      • Bouzari S.
      Modulation of the gut microbiota and serum biomarkers after laparoscopic sleeve gastrectomy: a 1-Year follow-up study.
      ,
      • Farin W.
      • Oñate F.P.
      • Plassais J.
      • et al.
      Impact of laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy on gut microbiota: a metagenomic comparative analysis.
      ]. These 2 bariatric procedures were further compared in terms of microbiota alteration by Shao et al. in a rat model. Analysis revealed a striking shift in the gut microbiota following RYGB. However, while RYGB was associated with a significantly higher proportion of Proteobacteria, the post-LSG microbiota was comparable to that of sham-operated rats [
      • Shao Y.
      • Ding R.
      • Xu B.
      • et al.
      Alterations of gut microbiota after roux-en-Y gastric bypass and sleeve gastrectomy in Sprague-Dawley rats.
      ].
      Overall, these findings imply that bariatric surgery results in procedure-dependent alterations in gut microbiota. In comparison with LSG, RYGB results in greater modification of the gastrointestinal tract and intestinal environment, resulting in more severe and profound effects on microbiota composition [
      • Shao Y.
      • Ding R.
      • Xu B.
      • et al.
      Alterations of gut microbiota after roux-en-Y gastric bypass and sleeve gastrectomy in Sprague-Dawley rats.
      ,
      • Ciobârcă D.
      • Cătoi A.F.
      • Copăescu C.
      • Miere D.
      • Crișan G.
      Bariatric surgery in obesity: effects on gut microbiota and micronutrient status.
      ]. This may be due to the effect of the shortened small intestine in RYGB, as increased oxygen concentration in the normally anaerobic distal lumen favors the presence of facultative anaerobes (such as Gammaproteobacteria) over obligate anaerobes (e.g., Firmicutes) [
      • Anhê F.F.
      • Varin T.V.
      • Schertzer J.D.
      • Marette A.
      The gut microbiota as a mediator of metabolic benefits after bariatric surgery.
      ,
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ]. Furthermore, the bypassing of the upper small intestine in this procedure might result in the relocation of some of the typical small intestine microbiota, such as Enterobacteriaceae, to the large intestine [
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ].
      Another important modification related to RYGB is the reduction in stomach size and subsequent alteration in pH. Indeed, reduced gastric volume is associated with significantly decreased acid secretion in the gastric pouch, leading to higher pH levels [
      • Smith C.D.
      • Herkes S.B.
      • Behrns K.E.
      • Fairbanks V.F.
      • Kelly K.A.
      • Sarr M.G.
      Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity.
      ]. Evidence regarding the effect of LSG on gastric acid secretion is somewhat limited. However, it has been hypothesized that the anatomical rearrangements associated with this bariatric procedure could also contribute to reduced gastric acid secretion, albeit to a lesser extent than RYGB, as some acid-producing cells are still present [
      • Steenackers N.
      • Vanuytsel T.
      • Augustijns P.
      • et al.
      Adaptations in gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass.
      ]. Increasing the pH in the gastrointestinal tract induces major changes in gut bacterial populations since it produces a more favorable environment for Bacteroides and inhibits the growth of butyrate-producing bacteria [
      • Anhê F.F.
      • Varin T.V.
      • Schertzer J.D.
      • Marette A.
      The gut microbiota as a mediator of metabolic benefits after bariatric surgery.
      ,
      • Ciobârcă D.
      • Cătoi A.F.
      • Copăescu C.
      • Miere D.
      • Crișan G.
      Bariatric surgery in obesity: effects on gut microbiota and micronutrient status.
      ]. This evidence is confirmed by the study of Walker et al. who tested, in vitro, the response of microbial communities to pH increase and found higher levels of the genus Bacteroides and a decrease of Roseburia spp. and Faecalibacterium prausnitzii abundance [
      • Walker A.W.
      • Duncan S.H.
      • McWilliam Leitch E.C.
      • Child M.W.
      • Flint H.J.
      pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon.
      ]. Roseburia spp. and F. prausnitzii are considered the main butyrate-producing bacteria in the human gut [
      • Pryde S.E.
      • Duncan S.H.
      • Hold G.L.
      • Stewart C.S.
      • Flint H.J.
      The microbiology of butyrate formation in the human colon.
      ] and appear to have a protective role because of the beneficial and anti-inflammatory effects of butyrate [
      • Miquel S.
      • Martín R.
      • Rossi O.
      • et al.
      Faecalibacterium prausnitzii and human intestinal health.
      ,
      • Tamanai-Shacoori Z.
      • Smida I.
      • Bousarghin L.
      • et al.
      Roseburia spp.: a marker of health?.
      ]. Decreased levels of both bacterial groups (belonging to the Firmicutes phylum) have been observed in postsurgery patients. [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ,
      • Farin W.
      • Oñate F.P.
      • Plassais J.
      • et al.
      Impact of laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy on gut microbiota: a metagenomic comparative analysis.
      ].
      An indirect effect of RYGB is altered microbial catabolism, which produces changes in metabolite levels. Gastric acid secretion, which normally ensures the activation of proteolytic enzymes and protein digestion, is reduced after RYGB [
      • Smith C.D.
      • Herkes S.B.
      • Behrns K.E.
      • Fairbanks V.F.
      • Kelly K.A.
      • Sarr M.G.
      Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity.
      ]. As a consequence, more incompletely digested proteins reach the colon, leading to increased microbial protein catabolism. This, in turn, results in elevated production of toxic polyamines such as putrescine [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Li J.V.
      • Ashrafian H.
      • Bueter M.
      • et al.
      Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk.
      ]. Fecal water from post-RYGB rats has been observed to be highly cytotoxic, likely correlating with a postoperative increase in the levels of fecal putrescine, given the deleterious effects of this polyamine on cell survival [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Li J.V.
      • Reshat R.
      • Wu Q.
      • et al.
      Experimental bariatric surgery in rats generates a cytotoxic chemical environment in the gut contents.
      ]. Importantly, it has been reported that the levels of putrescine and other polyamines are elevated in patients with cancer and are correlated with tumor stage and progression [
      • Weiss T.S.
      • Bernhardt G.
      • Buschauer A.
      • et al.
      Polyamine levels of human colorectal adenocarcinomas are correlated with tumor stage and grade.
      ,
      • Novita Sari I.
      • Setiawan T.
      • Seock Kim K.
      • Toni Wijaya Y.
      • Won Cho K.
      • Young Kwon H.
      Metabolism and function of polyamines in cancer progression.
      ]. Relevant to this finding, putrescine appears capable of stimulating cell proliferation in a dose-dependent manner. Furthermore, the accumulation of putrescine has been associated with colon inflammation, high levels of pro-inflammatory cytokines, and increased gut permeability [
      • Farriol M.
      • Segovia-Silvestre T.
      • Castellanos J.M.
      • Venereo Y.
      • Orta X.
      Role of putrescine in cell proliferation in a colon carcinoma cell line.
      ,
      • Grosheva I.
      • Zheng D.
      • Levy M.
      • et al.
      High-throughput Screen identifies host and microbiota Regulators of intestinal barrier function.
      ].
      Various human studies have reported, in the gut, the increased presence of oral microbes including Streptococcus spp., Veillonella spp., and Fusobacterium nucleatum following RYGB [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ,
      • Farin W.
      • Oñate F.P.
      • Plassais J.
      • et al.
      Impact of laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy on gut microbiota: a metagenomic comparative analysis.
      ]. Intestinal colonization by the oral microbiota could be related to increased pH and decreased acid secretion, which reduce the efficiency of the gastric barrier, facilitating the orofecal transit of bacteria [
      • Anhê F.F.
      • Varin T.V.
      • Schertzer J.D.
      • Marette A.
      The gut microbiota as a mediator of metabolic benefits after bariatric surgery.
      ,
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ].
      Interestingly, there are several similarities between the fecal microbial profiles observed following bariatric surgery (particularly RYGB) and those of patients diagnosed with CRC. Indeed, several studies have analyzed and compared gut microbiota composition in patients with CRC and healthy individuals, revealing enrichment of the phylum Fusobacteria and the genera Bacteroides and Escherichia in the CRC group [
      • Sobhani I.
      • Tap J.
      • Roudot-Thoraval F.
      • et al.
      Microbial dysbiosis in colorectal cancer (CRC) patients.
      ,
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ,
      • Ma Y.
      • Zhang Y.
      • Xiang J.
      • et al.
      Metagenome analysis of intestinal bacteria in healthy people, patients with inflammatory bowel disease and colorectal cancer.
      ,
      • Kostic A.D.
      • Gevers D.
      • Pedamallu C.S.
      • et al.
      Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]. Furthermore, the results of these studies indicate significantly decreased abundance of the butyrate-producing genera Faecalibacterium and Roseburia in patients with cancer, compared with controls [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]. Zhu et al. found similar results using a murine model of CRC, observing increases in Proteobacteria, Fusobacterium, and Bacteroides populations and significant reductions in Roseburia and Eubacterium abundance [
      • Zhu Q.
      • Jin Z.
      • Wu W.
      • et al.
      Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer.
      ]. Therefore, the microbial dysbiosis associated with CRC leads to both enrichment of pro-inflammatory microbes and depletion of butyrate-producing bacteria, resembling the effects of RYGB [
      • Zackular J.P.
      • Baxter N.T.
      • Iverson K.D.
      • et al.
      The gut microbiome modulates colon tumorigenesis.
      ,
      • Saus E.
      • Iraola-Guzmán S.
      • Willis J.R.
      • Brunet-Vega A.
      • Gabaldón T.
      Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential.
      ].
      Alteration of microbiota composition is emerging as a major factor associated with inflammation and tumorigenesis that appears to modulate CRC risk and development [
      • Sobhani I.
      • Tap J.
      • Roudot-Thoraval F.
      • et al.
      Microbial dysbiosis in colorectal cancer (CRC) patients.
      ]. Zackular et al. used a murine model of inflammation-associated CRC to determine the role of gut microbiota in the development of CRC. This study demonstrated that microbial alterations contribute to CRC through the initiation of inflammation and have a causal role in exacerbating tumor formation [
      • Zackular J.P.
      • Baxter N.T.
      • Iverson K.D.
      • et al.
      The gut microbiome modulates colon tumorigenesis.
      ]. The authors hypothesized that enrichment of the genus Bacteroides, observed in the fecal samples of their murine model and in patients with CRC [
      • Sobhani I.
      • Tap J.
      • Roudot-Thoraval F.
      • et al.
      Microbial dysbiosis in colorectal cancer (CRC) patients.
      ,
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ], may contribute to tumorigenesis [
      • Zackular J.P.
      • Baxter N.T.
      • Iverson K.D.
      • et al.
      The gut microbiome modulates colon tumorigenesis.
      ]. In support of this hypothesis, Wu et al. found a positive correlation between Bacteroides abundance and tumor stage in patients with cancer [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ]. Furthermore, according to a study conducted by Sobhani et al., Bacteroides populations were linked with high proportions of pro-inflammatory IL-17-producing cells in tumor samples and normal mucosa in patients with CRC [
      • Sobhani I.
      • Tap J.
      • Roudot-Thoraval F.
      • et al.
      Microbial dysbiosis in colorectal cancer (CRC) patients.
      ]. Escherichia coli, a member of the Gammaproteobacteria class, is also enriched in post-RYGB patients [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Furet J.P.
      • Kong L.C.
      • Tap J.
      • et al.
      Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers.
      ] and has been found to be associated with colorectal carcinogenesis. Interestingly, the intestinal mucosa of patients with more advanced colorectal neoplasia is reportedly colonized by pathogenic and virulent E. coli strains with genotoxic properties [
      • Kohoutova D.
      • Smajs D.
      • Moravkova P.
      • et al.
      Escherichia coli strains of phylogenetic group B2 and D and bacteriocin production are associated with advanced colorectal neoplasia.
      ,
      • Bonnet M.
      • Buc E.
      • Sauvanet P.
      • et al.
      Colonization of the human gut by E. coli and colorectal cancer risk.
      ].
      Several studies have focused on the colorectal carcinogenic effects and tumor-promoting mechanisms of F. nucleatum, a pro-inflammatory bacterium. The increased presence of F. nucleatum in stool samples represents a further microbial alteration common to bariatric and CRC patients [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ]. F. nucleatum has also been detected in premalignant colorectal lesions, suggesting its involvement in neoplastic initiation and the early stages of tumorigenesis [
      • Kostic A.D.
      • Chun E.
      • Robertson L.
      • et al.
      Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment.
      ,
      • Ito M.
      • Kanno S.
      • Nosho K.
      • et al.
      Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway.
      ]. Moreover, increased abundance of this species in patients with CRC has been associated with shorter survival time [
      • Flanagan L.
      • Schmid J.
      • Ebert M.
      • et al.
      Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome.
      ].
      The similarity of the microbial changes observed in postbariatric patients and patients with CRC (Table 3) is striking. Such changes highlight a potential mechanism by which the alteration of gut microbiota associated with bariatric surgery could lead to an increased risk of CRC.
      Table 3Microbial alterations following bariatric surgery and in colorectal cancer reported in studies conducted on murine models and human patients
      TaxaAlterations following bariatric surgeryAlterations in colorectal cancer
      Bacteroidetes

      Damms-Machado et al., Tabasi et al. [
      • Damms-Machado A.
      • Mitra S.
      • Schollenberger A.E.
      • et al.
      Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption.
      ,
      • Tabasi M.
      • Eybpoosh S.
      • Siadat S.D.
      • Elyasinia F.
      • Soroush A.
      • Bouzari S.
      Modulation of the gut microbiota and serum biomarkers after laparoscopic sleeve gastrectomy: a 1-Year follow-up study.
      ]
      -
      Bacteroides

      Furet et al., Shao et al., Kong et al. [
      • Furet J.P.
      • Kong L.C.
      • Tap J.
      • et al.
      Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers.
      ,
      • Kong L.C.
      • Tap J.
      • Aron-Wisnewsky J.
      • et al.
      Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes.
      ,
      • Shao Y.
      • Ding R.
      • Xu B.
      • et al.
      Alterations of gut microbiota after roux-en-Y gastric bypass and sleeve gastrectomy in Sprague-Dawley rats.
      ]


      Sobhani et al., Wu et al., Zhu et al., Zackular et al. [
      • Sobhani I.
      • Tap J.
      • Roudot-Thoraval F.
      • et al.
      Microbial dysbiosis in colorectal cancer (CRC) patients.
      ,
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ,
      • Zhu Q.
      • Jin Z.
      • Wu W.
      • et al.
      Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer.
      ,
      • Zackular J.P.
      • Baxter N.T.
      • Iverson K.D.
      • et al.
      The gut microbiome modulates colon tumorigenesis.
      ]
      Fusobacteria

      Palleja et al., Zhang et al., Graessler et al. [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ]


      Wu et al., Kostic et al., He et al. [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Kostic A.D.
      • Gevers D.
      • Pedamallu C.S.
      • et al.
      Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]
      Fusobacterium-

      Wu et al., Wang et al., Zhu et al. [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ,
      • Zhu Q.
      • Jin Z.
      • Wu W.
      • et al.
      Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer.
      ]
      Fusobacterium nucleatum

      Palleja et al. [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ]


      Wu et al., Flanagan et al. [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Flanagan L.
      • Schmid J.
      • Ebert M.
      • et al.
      Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome.
      ]
      Proteobacteria

      Palleja et al., Tremaroli et al., Zhang et al., Graessler et al., Shao et al., Li et al. [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ,
      • Shao Y.
      • Ding R.
      • Xu B.
      • et al.
      Alterations of gut microbiota after roux-en-Y gastric bypass and sleeve gastrectomy in Sprague-Dawley rats.
      ,
      • Li J.V.
      • Ashrafian H.
      • Bueter M.
      • et al.
      Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk.
      ]


      Wang et al., Zhu et al., He et al. [
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ,
      • Zhu Q.
      • Jin Z.
      • Wu W.
      • et al.
      Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer.
      ]
      Gammaproteobacteria

      Tremaroli et al., Zhang et al., Shao et al. [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ,
      • Shao Y.
      • Ding R.
      • Xu B.
      • et al.
      Alterations of gut microbiota after roux-en-Y gastric bypass and sleeve gastrectomy in Sprague-Dawley rats.
      ]


      He et al. [
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]
      Escherichia

      Tremaroli et al., Kong et al. [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Kong L.C.
      • Tap J.
      • Aron-Wisnewsky J.
      • et al.
      Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes.
      ]


      Wu et al., Wang et al. [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ]
      Escherichia coli

      Palleja et al., Furet et al., Graessler et al. [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Furet J.P.
      • Kong L.C.
      • Tap J.
      • et al.
      Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ]


      Ma et al., He et al. [
      • Ma Y.
      • Zhang Y.
      • Xiang J.
      • et al.
      Metagenome analysis of intestinal bacteria in healthy people, patients with inflammatory bowel disease and colorectal cancer.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]
      Firmicutes

      Tremaroli et al., Zhang et al., Graessler et al., Damms-Machado et al., Tabasi et al., Li et al. [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • et al.
      Human gut microbiota in obesity and after gastric bypass.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ,
      • Damms-Machado A.
      • Mitra S.
      • Schollenberger A.E.
      • et al.
      Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption.
      ,
      • Tabasi M.
      • Eybpoosh S.
      • Siadat S.D.
      • Elyasinia F.
      • Soroush A.
      • Bouzari S.
      Modulation of the gut microbiota and serum biomarkers after laparoscopic sleeve gastrectomy: a 1-Year follow-up study.
      ,
      • Li J.V.
      • Ashrafian H.
      • Bueter M.
      • et al.
      Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk.
      ]


      Kostic et al., He et al. [
      • Kostic A.D.
      • Gevers D.
      • Pedamallu C.S.
      • et al.
      Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]
      Roseburia spp.

      Tremaroli et al. [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ]


      Wu et al., Wang et al., Zhu et al. [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • Wang T.
      • Cai G.
      • Qiu Y.
      • et al.
      Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.
      ,
      • Zhu Q.
      • Jin Z.
      • Wu W.
      • et al.
      Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer.
      ]
      Faecalibacterium prausnitzii

      Palleja et al., Graessler et al. [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ]


      Wu et al., He et al. [
      • Wu N.
      • Yang X.
      • Zhang R.
      • et al.
      Dysbiosis signature of fecal microbiota in colorectal cancer patients.
      ,
      • He T.
      • Cheng X.
      • Xing C.
      The gut microbial diversity of colon cancer patients and the clinical significance.
      ]

      BA exposure

      BAs are metabolites of the gastrointestinal tract that facilitate the absorption of dietary lipids and fat-soluble molecules. They also play a role in the control of glucose homeostasis and regulation of energy metabolism [
      • Ulker İ.
      • Yildiran H.
      The effects of bariatric surgery on gut microbiota in patients with obesity: a review of the literature.
      ,
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Ajouz H.
      • Mukherji D.
      • Shamseddine A.
      Secondary bile acids: an underrecognized cause of colon cancer.
      ]. Primary BAs are synthesized in the liver and stored in the gallbladder before secretion into the intestinal lumen; here, they are converted into secondary BAs by 7α-dehydroxylating bacteria [
      • Anhê F.F.
      • Varin T.V.
      • Schertzer J.D.
      • Marette A.
      The gut microbiota as a mediator of metabolic benefits after bariatric surgery.
      ]. The circulation of enterohepatic bile is affected by the altered gastrointestinal anatomy associated with RYGB and malabsorptive bariatric surgery [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Patti M.E.
      • Houten S.M.
      • Bianco A.C.
      • et al.
      Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism.
      ]. In RYGB, bile secretion into the biliopancreatic limb and nutrient flow in the alimentary limb are uncoupled, coming together only in the distal gut. Consequently, the distal gut is exposed to high levels of nutrients and BAs [
      • Anhê F.F.
      • Varin T.V.
      • Schertzer J.D.
      • Marette A.
      The gut microbiota as a mediator of metabolic benefits after bariatric surgery.
      ,
      • Ulker İ.
      • Yildiran H.
      The effects of bariatric surgery on gut microbiota in patients with obesity: a review of the literature.
      ]. Accordingly, several human studies have detected a significant increase in serum primary and secondary BAs following RYGB and malabsorptive procedures [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Patti M.E.
      • Houten S.M.
      • Bianco A.C.
      • et al.
      Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism.
      ,
      • Cole A.J.
      • Teigen L.M.
      • Jahansouz C.
      • Earthman C.P.
      • Sibley S.D.
      The influence of bariatric surgery on serum bile acids in humans and potential metabolic and hormonal implications: a systematic review.
      ,
      • Nakatani H.
      • Kasama K.
      • Oshiro T.
      • Watanabe M.
      • Hirose H.
      • Itoh H.
      Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery.
      ].
      Remarkably, high concentrations of BAs (especially deoxycholic acid) correlate significantly with hyperproliferation of the colonic mucosa, considered an early step in colorectal carcinogenesis [
      • Ochsenkühn T.
      • Bayerdörffer E.
      • Meining A.
      • et al.
      Colonic mucosal proliferation is related to serum deoxycholic acid levels.
      ]. It has been suggested that longer bypass limbs might be associated with higher levels of BAs in the gut lumen, inducing a hyperproliferative state in the colorectal mucosa [
      • Afshar S.
      • Malcomson F.
      • Kelly S.B.
      • Seymour K.
      • Woodcock S.
      • Mathers J.C.
      Biomarkers of colorectal cancer risk decrease 6 months after roux-en-Y gastric bypass surgery.
      ,
      • Steinbach G.
      • Lupton J.
      • Reddy B.S.
      • Kral J.G.
      • Holt P.R.
      Effect of calcium supplementation on rectal epithelial hyperproliferation in intestinal bypass subjects.
      ]. Consistent with this hypothesis, marked increases in BA levels have been noted following JIB, which involves bypassing an extensive portion of the intestine [
      • Steinbach G.
      • Lupton J.
      • Reddy B.S.
      • Kral J.G.
      • Holt P.R.
      Effect of calcium supplementation on rectal epithelial hyperproliferation in intestinal bypass subjects.
      ]. Increased crypt cell proliferation rates and expansion of the proliferative zone in patients and murine models following JIB may therefore be due to chronic exposure of the colonic mucosa to high concentrations of BAs [
      • Appleton G.V.
      • Wheeler E.E.
      • Al-Mufti R.
      • Challacombe D.N.
      • Williamson R.C.
      Rectal hyperplasia after jejunoileal bypass for morbid obesity.
      ,
      • Steinbach G.
      • Lupton J.
      • Reddy B.S.
      • Kral J.G.
      • Holt P.R.
      Effect of calcium supplementation on rectal epithelial hyperproliferation in intestinal bypass subjects.
      ,
      • Bristol J.B.
      • Wells M.
      • Williamson R.C.
      Adaptation to jejunoileal bypass promotes experimental colorectal carcinogenesis.
      ]. The correlation between elevated BA levels and increased colorectal proliferation applies to both RYGB and malabsorptive procedures as all of these techniques involve the bypassing of intestinal segments and subsequent alterations in BA flow.
      Repeated and prolonged exposure of the intestinal tract to high concentrations of BAs appears to be an important etiologic factor in colorectal carcinogenesis and development [
      • Ajouz H.
      • Mukherji D.
      • Shamseddine A.
      Secondary bile acids: an underrecognized cause of colon cancer.
      ,
      • Bernstein H.
      • Bernstein C.
      • Payne C.M.
      • Dvorak K.
      Bile acids as endogenous etiologic agents in gastrointestinal cancer.
      ]. Serum and fecal levels of secondary BAs are elevated in patients diagnosed with CRC and at-risk individuals, compared with healthy controls [
      • Jia W.
      • Xie G.
      • Jia W.
      Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.
      ,
      • Ocvirk S.
      • O'Keefe S.J.
      Influence of bile acids on colorectal cancer risk: potential mechanisms mediated by diet - gut microbiota interactions.
      ]. Furthermore, cholecystectomy has been associated with increased risk of colon cancer because of the resultant constant flow of bile and enhanced exposure of the colonic mucosa to BAs [
      • Shao T.
      • Yang Y.X.
      Cholecystectomy and the risk of colorectal cancer.
      ,
      • Lagergren J.
      • Ye W.
      • Ekbom A.
      Intestinal cancer after cholecystectomy: is bile involved in carcinogenesis?.
      ,
      • Kim S.B.
      • Kim K.O.
      • Kim T.N.
      Prevalence and risk factors of gastric and colorectal cancer after cholecystectomy.
      ]. Collectively, these data highlight how altered BA concentrations can influence CRC risk.
      BAs promote CRC initiation and progression by damaging the colonic epithelium, inducing oxidative stress and inflammation and activating specific signaling pathways [
      • Jia W.
      • Xie G.
      • Jia W.
      Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.
      ,
      • Nguyen T.T.
      • Ung T.T.
      • Kim N.H.
      • Jung Y.D.
      Role of bile acids in colon carcinogenesis.
      ]. Such pathways include nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling, which is involved in genome instability and mutation. In addition, activation of epidermal growth factor receptor is associated with cell proliferation, while the MAPK pathway enhances the invasiveness and angiogenic activity of cancer cells [
      • Nguyen T.T.
      • Ung T.T.
      • Kim N.H.
      • Jung Y.D.
      Role of bile acids in colon carcinogenesis.
      ]. However, one of the most important cytotoxic effects of BAs is the increased production of reactive oxygen and nitrogen species, which can induce oxidative stress, DNA damage, and apoptosis [
      • Ajouz H.
      • Mukherji D.
      • Shamseddine A.
      Secondary bile acids: an underrecognized cause of colon cancer.
      ,
      • Bernstein H.
      • Bernstein C.
      • Payne C.M.
      • Dvorak K.
      Bile acids as endogenous etiologic agents in gastrointestinal cancer.
      ,
      • Bernstein H.
      • Bernstein C.
      • Payne C.M.
      • Dvorakova K.
      • Garewal H.
      Bile acids as carcinogens in human gastrointestinal cancers.
      ]. In addition, long-term exposure to high levels of BAs appears to select cells that are resistant to BA-induced apoptosis. Reduced apoptotic capability may lead to an increased rate of mutation and, thus, predispose to tumor development [
      • Bernstein H.
      • Bernstein C.
      • Payne C.M.
      • Dvorak K.
      Bile acids as endogenous etiologic agents in gastrointestinal cancer.
      ,
      • Bernstein H.
      • Bernstein C.
      • Payne C.M.
      • Dvorakova K.
      • Garewal H.
      Bile acids as carcinogens in human gastrointestinal cancers.
      ]. The multiple mechanisms through which BAs promote colorectal carcinogenesis and development are illustrated in Figure 1.
      Figure thumbnail gr1
      Fig. 1Effects of bile acids (BAs) associated with colorectal carcinogenesis and development.
      The influence of BAs on CRC risk is intimately linked with the gut microbiota since the latter allows the conversion of primary BAs to secondary BAs, known for their tumor-promoting properties. On the other hand, excess BAs induce these changes in the microbiota, favoring the enrichment of 7α-dehydroxylating bacteria [
      • Ocvirk S.
      • O'Keefe S.J.
      Influence of bile acids on colorectal cancer risk: potential mechanisms mediated by diet - gut microbiota interactions.
      ].

      Short-chain fatty acids

      Short-chain fatty acids (SCFAs) derive from microbial fermentation of dietary fiber. These molecules provide energy sources for the intestinal epithelium and are involved in the regulation of gut physiology and immune homeostasis [
      • Walker A.W.
      • Duncan S.H.
      • McWilliam Leitch E.C.
      • Child M.W.
      • Flint H.J.
      pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon.
      ,
      • Tamanai-Shacoori Z.
      • Smida I.
      • Bousarghin L.
      • et al.
      Roseburia spp.: a marker of health?.
      ]. In particular, butyrate is known for its protective and beneficial effects, playing a major role in maintaining the health and integrity of the colonic mucosa [
      • Miquel S.
      • Martín R.
      • Rossi O.
      • et al.
      Faecalibacterium prausnitzii and human intestinal health.
      ,
      • Li J.V.
      • Reshat R.
      • Wu Q.
      • et al.
      Experimental bariatric surgery in rats generates a cytotoxic chemical environment in the gut contents.
      ]. Numerous studies have reported significantly reduced levels of SCFAs (acetate, propionate, and butyrate) following bariatric surgery [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Farup P.G.
      • Valeur J.
      Changes in faecal short-chain fatty acids after weight-loss interventions in subjects with morbid obesity.
      ,
      • Juárez-Fernández M.
      • Román-Sagüillo S.
      • Porras D.
      • et al.
      Long-term effects of bariatric surgery on gut microbiota composition and faecal metabolome related to obesity remission.
      ,
      • Yu D.
      • Shu X.O.
      • Howard E.F.
      • Long J.
      • English W.J.
      • Flynn C.R.
      Fecal metagenomics and metabolomics reveal gut microbial changes after bariatric surgery.
      ], while butyrate concentrations have been demonstrated to be lower in the presence of a more alkaline pH in vitro [
      • Walker A.W.
      • Duncan S.H.
      • McWilliam Leitch E.C.
      • Child M.W.
      • Flint H.J.
      pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon.
      ]. Therefore, the observation of lower SCFA levels after bariatric surgery is consistent with decreased acid production in these patients [
      • Smith C.D.
      • Herkes S.B.
      • Behrns K.E.
      • Fairbanks V.F.
      • Kelly K.A.
      • Sarr M.G.
      Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity.
      ]. Furthermore, the abundance of butyrate-producing bacteria F. prausnitzii and Roseburia spp. has been shown to decrease following bariatric procedures, profoundly affecting butyrate levels [
      • Palleja A.
      • Kashani A.
      • Allin K.H.
      • et al.
      Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota.
      ,
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • et al.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      ,
      • Farin W.
      • Oñate F.P.
      • Plassais J.
      • et al.
      Impact of laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy on gut microbiota: a metagenomic comparative analysis.
      ].
      Dolara et al. demonstrated that higher concentrations of SCFAs are significantly associated with lower rates of colonic mucosal proliferation, highlighting their protective role against CRC [
      • Dolara P.
      • Caderni G.
      • Salvadori M.
      • et al.
      Fecal levels of short-chain fatty acids and bile acids as determinants of colonic mucosal cell proliferation in humans.
      ]. This role was further confirmed by the finding of reduced concentrations of SCFAs in fecal water extracts from patients with CRC, compared with healthy controls [
      • Monleón D.
      • Morales J.M.
      • Barrasa A.
      • López J.A.
      • Vázquez C.
      • Celda B.
      Metabolite profiling of fecal water extracts from human colorectal cancer.
      ]. Furthermore, there is increasing evidence for the anticarcinogenic properties and anti-inflammatory effects of butyrate on the colonic mucosa. Segain et al. showed that butyrate decreases TNF production and pro-inflammatory cytokine mRNA expression by inhibiting NF-kB activation, resulting in reduced inflammatory responses [
      • Segain J.P.
      • Raingeard de la Blétière D.
      • Bourreille A.
      • et al.
      Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.
      ]. In addition, SCFAs upregulate the function of colonic regulatory T cells, which play a role in intestinal homeostasis and gut inflammation [
      • Smith P.M.
      • Howitt M.R.
      • Panikov N.
      • et al.
      The microbial metabolites, short-chain fatty acids, regulate colonic treg cell homeostasis.
      ]. Notably, treatment of colonocytes with butyrate and antioxidants appears to reduce the genotoxicity and DNA damage induced by BAs [
      • Rosignoli P.
      • Fabiani R.
      • De Bartolomeo A.
      • Fuccelli R.
      • Pelli M.A.
      • Morozzi G.
      Genotoxic effect of bile acids on human normal and tumour colon cells and protection by dietary antioxidants and butyrate.
      ].
      The anticarcinogenic role of butyrate results from its ability to induce apoptosis and growth inhibition in CRC cells [
      • Ruemmele F.M.
      • Schwartz S.
      • Seidman E.G.
      • Dionne S.
      • Levy E.
      • Lentze M.J.
      Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway.
      ,
      • Hague A.
      • Elder D.J.
      • Hicks D.J.
      • Paraskeva C.
      Apoptosis in colorectal tumour cells: induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate.
      ,
      • Hague A.
      • Manning A.M.
      • Hanlon K.A.
      • Huschtscha L.I.
      • Hart D.
      • Paraskeva C.
      Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large-bowel cancer.
      ]. Induction of apoptosis by butyrate in CRC cell lines seems to occur through upregulation of the proapoptotic protein Bak and reduction of the levels of antiapoptotic Bcl-xL [
      • Ruemmele F.M.
      • Schwartz S.
      • Seidman E.G.
      • Dionne S.
      • Levy E.
      • Lentze M.J.
      Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway.
      ]. In addition, according to a study by Hague et al., apoptosis may result from the inhibition of histone deacetylase (HDAC) and subsequent changes in chromatin structure, leading to altered gene expression [
      • Hague A.
      • Elder D.J.
      • Hicks D.J.
      • Paraskeva C.
      Apoptosis in colorectal tumour cells: induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate.
      ]. Inhibition of HDAC by butyrate was also observed by Donohoe et al., albeit in this case related to the inhibition of CRC cell proliferation. Interestingly, this SCFA exerted opposing effects on the colonic mucosa, stimulating the proliferation of normal colonocytes and inhibiting the growth of cancerous colonocytes [
      • Donohoe D.R.
      • Collins L.B.
      • Wali A.
      • Bigler R.
      • Sun W.
      • Bultman S.J.
      The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation.
      ]. This differential impact was suggested to be related to the Warburg effect, whereby cancer cells preferentially metabolize glucose anaerobically [
      • Liberti M.V.
      • Locasale J.W.
      The Warburg effect: how Does it Benefit cancer cells?.
      ]. Thus, while normal colorectal cells use butyrate as an energy source for proliferation, cancerous cells instead rely on glucose as their primary energy source, leading to the accumulation of butyrate. At high concentrations, unmetabolized butyrate enters cell nuclei and functions as an HDAC inhibitor, leading to the altered expression of genes relating to cellular proliferation, differentiation, and apoptosis [
      • Donohoe D.R.
      • Collins L.B.
      • Wali A.
      • Bigler R.
      • Sun W.
      • Bultman S.J.
      The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation.
      ]. In addition, Bordonaro et al. showed that butyrate downregulates the Wnt signaling pathway, commonly activated in CRC, unveiling another mechanism underlying the beneficial effects of this molecule [
      • Bordonaro M.
      • Lazarova D.L.
      • Sartorelli A.C.
      Butyrate and Wnt signaling: a possible solution to the puzzle of dietary fiber and colon cancer risk?.
      ].
      Collectively, the evidence suggests that butyrate exerts protective, anticarcinogenic effects via multiple mechanisms (Fig. 2). Thus, the decreased levels of SCFAs reported following bariatric surgery [
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • et al.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.
      ,
      • Farup P.G.
      • Valeur J.
      Changes in faecal short-chain fatty acids after weight-loss interventions in subjects with morbid obesity.
      ,
      • Juárez-Fernández M.
      • Román-Sagüillo S.
      • Porras D.
      • et al.
      Long-term effects of bariatric surgery on gut microbiota composition and faecal metabolome related to obesity remission.
      ,
      • Yu D.
      • Shu X.O.
      • Howard E.F.
      • Long J.
      • English W.J.
      • Flynn C.R.
      Fecal metagenomics and metabolomics reveal gut microbial changes after bariatric surgery.
      ] may contribute to an increased risk of CRC.
      Figure thumbnail gr2
      Fig. 2Protective and beneficial effects of butyrate against colorectal cancer.

      Strengths and limitations

      The conflicting results produced by several cohort studies call into question the association between CRC risk and bariatric surgery. This review aimed to clarify the current understanding of the topic by summarizing the available data and proposing potential mechanisms.
      However, this study presents some limitations, such as the lack of evidence regarding CRC risk following restrictive procedures. Indeed, most of the data included in the review focus on the impact of RYGB, while only a few studies have examined the effects of other bariatric procedures. Thus, no conclusions on the potential correlation between restrictive bariatric surgery and increased risk of CRC can be drawn.
      Another limitation is the inclusion of studies conducted using murine models; their findings, although interesting and relevant to the topic, need to be validated by human studies.

      Conclusions and future perspectives

      Cohort studies have reported contradictory findings regarding the impact of bariatric surgery on CRC risk. However, analysis of CRC biomarkers in the rectal mucosa revealed hyperproliferation and inflammation following RYGB. Multiple mechanisms related to malabsorption and post-RYGB anatomical modifications could predispose to an increased risk of CRC. In particular, alterations in the gut microbiota may play a key role in CRC initiation and development. Significantly, similarities in the gut microbiota of post-RYGB and cancer patients have been described. Other mechanisms potentially contributing to CRC carcinogenesis include exposure of the colorectal mucosa to increased concentrations of BAs and reduced levels of SCFAs, both reported following RYGB. In conclusion, evidence from cohort and mechanistic studies suggests a potential association between RYGB and increased risk of CRC.
      Future research is required to establish whether bariatric surgery induces a procedure-dependent increase in CRC risk. The necessity for further research is highlighted by the limited data currently available regarding the effects of other types of bariatric surgery on CRC. Furthermore, as LSG is currently the most commonly performed bariatric procedure [
      • Angrisani L.
      • Santonicola A.
      • Iovino P.
      • Ramos A.
      • Shikora S.
      • Kow L.
      Bariatric surgery survey 2018: similarities and disparities among the 5 IFSO chapters.
      ], large cohort studies to evaluate the potential association of this technique with the long-term risk of CRC are essential. Long-term analysis of CRC biomarkers following LSG in larger cohorts of patients should also be carried out to determine the impact of this procedure on the colorectal mucosa. In addition, OAGB, the third most common bariatric procedure, is increasing in popularity worldwide, highlighting the need to investigate its effects [
      • Angrisani L.
      • Santonicola A.
      • Iovino P.
      • Ramos A.
      • Shikora S.
      • Kow L.
      Bariatric surgery survey 2018: similarities and disparities among the 5 IFSO chapters.
      ].
      Alteration of microbial profiles in the gut has so far mainly been analyzed in the context of RYGB. However, the gut microbiota should also be characterized after other commonly performed bariatric procedures, given its potential role in colorectal carcinogenesis. Comparative analysis of microbial alterations in postbariatric and CRC patients could represent an important step toward determining the mechanisms involved in the association between bariatric surgery and CRC.

      Disclosures

      The authors have no commercial associations that might be a conflict of interest in relation to this article.

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