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Gut microbiota, inflammatory bowel disease and colorectal cancer - is there a link?

Gut microbiota, inflammatory bowel disease and colorectal cancer - is there a link?. Jakub Fichna Department of Biochemistry Medical University of Lodz , Lodz , Poland. The importance of microbiota in human health , 2018. Colorectal cancer.

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Gut microbiota, inflammatory bowel disease and colorectal cancer - is there a link?

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  1. Gut microbiota, inflammatory bowel disease and colorectal cancer - is there a link? Jakub Fichna Department of BiochemistryMedical University of Lodz, Lodz, Poland The importance of microbiota in human health, 2018

  2. Colorectalcancer The importance of microbiota in human health, 2018

  3. Colorectal cancer More prevalent in men than women Moreprevalent in patients >40 y.o. Most prevalent in patients ~70 y.o. 90% cases - adenocarcinomas The importance of microbiota in human health, 2018

  4. Colorectal cancer The importance of microbiota in human health, 2018

  5. Colorectal cancer Risk factors: genetics inflammation, IBD environmental pollution The importance of microbiota in human health, 2018

  6. Colorectal cancer Risk factors: genetics inflammation, IBD environmental pollution microbiota-relatedfactors The importance of microbiota in human health, 2018

  7. Microbiota in colorectal cancer The importance of microbiota in human health, 2018

  8. Microbiota in colorectal cancer Significantlydifferent: (A) The microbiota of healthy controls, individuals with polyps and individualswith cancer (C) The microbiotafromindividuals with distaland proximal cancers (D) The faecal microbiota ofboth cancer and control individualswas different from the mucosalmicrobiota Flemer et al., 2017 The importance of microbiota in human health, 2018

  9. Hypothesis models The importance of microbiota in human health, 2018

  10. Hypothesis models No. 1 The driver–passenger model: driver bacteria (cause DNAdamage in epithelial cells whichmay start theprogression of CRC) passenger bacteria (favored by tumor environment, dominate inthe tumor site later). • Time-dependent changes in microbiota • Challenge for furtherstudies Gao et al., 2017 The importance of microbiota in human health, 2018

  11. Hypothesis models No. 2 The keystonemodel: Keystonepathogen • Iferased / not present, no CRC possible Gao et al., 2017 The importance of microbiota in human health, 2018

  12. Hypothesis models No. 3 Garrett’smodels: 1. the specific microorganism, 2. the microbial community, 3. the sequential collaboration by the single andcommunity Gao et al., 2017 The importance of microbiota in human health, 2018

  13. Whichmicrobiota? The importance of microbiota in human health, 2018

  14. Whichmicrobiota? • 1. Fusobacteriumnucleatum • the Gram-negative, anaerobic commensal • pro-inflammatory role of Fn in the intestine • associated with human IBD Tilg et al., 2018 The importance of microbiota in human health, 2018

  15. Whichmicrobiota? • 1. Fusobacteriumnucleatum • Fn detected in CRC tissue in 76(13%) of 598 cases, and was inversely associated with the densityof CD3+ T cells supporting the idea that disease mechanismsinvolve regulation of immune responses(Mima et al., 2015) • Infection of CRC cells with Fn increasestheir proliferation rate, invasive activity, and potential to inducexenograft tumors in mice(Yang et al., 2017) • Fn, through FadA adhesion,bind to E-cadherin thereby activatingthe b-catenin signaling pathway resultingin induction of oncogenic and inflammatoryresponses(Rubinstein et al., 2013) Tilg et al., 2018 The importance of microbiota in human health, 2018

  16. Whichmicrobiota? • 2. E. coli • gut commensals • certain strains acquired the abilityto promote intestinalinflammationand to produce toxins such as colibactinwith oncogenic potential • the evidence mainly based on preclinical investigations Tilg et al., 2018 The importance of microbiota in human health, 2018

  17. Whichmicrobiota? • 2. E. coli • Mucosa-associated E. coli significantly more prevalentin CRC tissue and correlate with tumor stage and prognosis • Colonization of a colon cancer-associated E. coli straininto ApcMin/+ mice resulted in a marked increase in number ofpolyps • Cultured mammalianepithelial cells exposed to E. coli exhibited a transientDNA damage response with impaired DNA repair and an increasein gene mutation frequency Tilg et al., 2018 The importance of microbiota in human health, 2018

  18. Whichmicrobiota? • 3. Others • OtherBacteroides spp. (e.g., B. dorei, B. vulgatus,B. massilensis) • Parvimonas, Bilophilawadsworthia, and Alistipesspp. Tilg et al., 2018 The importance of microbiota in human health, 2018

  19. Whichmicrobiota? Zou et al., 2018 The importance of microbiota in human health, 2018

  20. Mechanisms of action The importance of microbiota in human health, 2018

  21. Mechanisms of action Zou et al., 2018 The importance of microbiota in human health, 2018

  22. Mechanisms of action Zou et al., 2018 The importance of microbiota in human health, 2018

  23. Mechanisms of action + inflammasomesensing throughNOD-like receptors (NLRs) Tilg et al., 2018; Zou et al., 2018 The importance of microbiota in human health, 2018

  24. The ButyrateParadox Tilg et al., 2018; Zou et al., 2018 The importance of microbiota in human health, 2018

  25. The ButyrateParadox Bacterial metabolites, including the short-chainfatty acid (SCFA)butyrate, emerged as regulators of immune responses. Several bacteria have been identifiedas potentialbutyrate producers, among them Fn. Although most studies suggest that butyrate suppresses bothinflammation and carcinogenesis in the colon, some studies revealedopposite results (the butyrate paradox). Tilg et al., 2018; Zou et al., 2018 The importance of microbiota in human health, 2018

  26. The ButyrateParadox Bacterial metabolites, including the short-chainfatty acid (SCFA)butyrate, emerged as regulators of immune responses. Several bacteria have been identifiedas potentialbutyrate producers, among them Fn. Although most studies suggest that butyrate suppresses bothinflammation and carcinogenesis in the colon, some studies revealedopposite results (the butyrate paradox). Tilg et al., 2018; Zou et al., 2018 The importance of microbiota in human health, 2018

  27. The ButyrateParadox Zou et al., 2018 The importance of microbiota in human health, 2018

  28. Diet vs. Microbiota vs. CRC The importance of microbiota in human health, 2018

  29. Diet vs. Microbiota vs. CRC • Yazici et al., 2017: • Expansion of sulfidogenic bacteria (e.g. Bilophilawadsworthia) found in African American CRC subjects. • Linked to certain dietary habits such as consumptionof fat and red meat intake. • Hydrogen sulfideis genotoxic and triggersinflammation and hyperproliferation. • Devkota et al., 2012: • In an experimentalapproach, diet-induced overgrowth of B. wadsworthiapromotedinflammation in genetically susceptible mice The importance of microbiota in human health, 2018

  30. Diet vs. Microbiota vs. CRC • Emulsifiers: • Lead to gut microbiota alterations andfavor inflammatory and malignant intestinal diseases in mice(Chassaing et al., 2015; Viennois et al., 2017) • Fibre: • The intestinal microbiota exhibita high diversity in cultures that eat less-processed high-fibre diets(De Filippo et al., 2010; Schnorr et al., 2014) The importance of microbiota in human health, 2018

  31. Diet vs. Microbiota vs. CRC • Exposure to antibiotics earlyin life is associated with an increased risk for colorectal adenomaat the age of 60which suggeststhat • a dysbiotic microbiota is acquired and sustained over alonger period of time Cao et al., 2017; Gensollen et al., 2016 The importance of microbiota in human health, 2018

  32. Microbiota in CRC screening The importance of microbiota in human health, 2018

  33. Microbiota in CRC screening • Bowel Cancer Screening inNorway (BCSN) trial aims to discover gut microbiota biomarkers for colorectal cancerscreening. • Project Aims • 1. Identify associations between the gut microbiota and cancer precursors/early cancer in a Norwegianscreening population • 2. Evaluate how the microbiota are modified by removal of adenomas • 3. Assess interactions between cancer precursors/early cancer, lifestyle and the gut microbiota. The importance of microbiota in human health, 2018

  34. Microbiota in CRC screening • Bowel Cancer Screening inNorway (BCSN) trial aims to discover gut microbiota biomarkers for colorectal cancerscreening. • Project Aims • 1. Identify associations between the gut microbiota and cancer precursors/early cancer in a Norwegianscreening population • 2. Evaluate how the microbiota are modified by removal of adenomas • 3. Assess interactions between cancer precursors/early cancer, lifestyle and the gut microbiota. The importance of microbiota in human health, 2018

  35. Questions? Comments? The importance of microbiota in human health, 2018

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