Impact of fiber supplementation on the butyrate synthesis of the intestinal microbiota and how it affects the risk for colorectal cancer.

• Applicant: Dr. Sören Ocvirk, Ph.D.
• Subject Area: Nutritional Sciences ; Gastroenterology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 338582098

• Final Report Year: 2023

Final Report Abstract

Colorectal cancer (CRC) risk is largely driven by environmental factors, in particular diet. Western dietary patterns rich in fat and low in fiber promote CRC risk through their effects on gut microbial cometabolism. Dietary fiber is fermented to short-chain fatty acids (SCFA) by the gut microbiota, including tumorsuppressive butyrate. In addition, host-derived bile acids are transformed by gut bacteria to secondary bile acids that show tumor-promoting activity. Here, we investigate how these reciprocal effects on CRC risk are affected by fiber supplementation in germfree mice colonized with human gut microbiota associated with high CRC risk. Fecal microbiota transfer using feces from healthy individuals of a high-risk cohort for CRC (Alaska Native, n=4) to germfree wildtype mice was performed. All mice received a standard diet (SD) or high-fat diet (HFD) with/without dietary fiber supplementation (FIB), and were treated with AOM/DSS to induce colonic tumorigenesis. CRC-associated mucosal markers and colon histopathology were assessed using qPCR and immunofluorescence imaging. Colonic microbiota composition was analyzed using 16S rRNA gene sequencing and fecal microbial metabolites (SCFA, bile acids) were quantified by GC-FID or LC-MS/MS, respectively. Fiber supplementation led to significantly lower tumor numbers in the colon of mice colonized with human ‘high CRC risk microbiota’ compared with the respective SD or HFD without fiber. Mice receiving fiber supplementation had higher colon lengths, lower mesenteric lymph node weights (HFD+FIB) or less Ki67+ cells per colonic crypt (SD+FIB), respectively. Fiber supplementation resulted in moderately altered SCFA levels in the intestinal lumen of mice, but reduced cecal bile acid levels, in particular of primary bile acids. For both diet groups, SD and HFD, fiber supplementation promoted a separate compositional clustering of the colonic microbiota, higher levels of SCFA-producing bacteria and lower abundance of bacteria associated with colonic inflammation. Fiber-associated alterations of the colonic microbiota were more distinct under HFD conditions. However, human fecal donor-dependent effects on microbiota susceptibility to fiber-linked modulation were demonstrated at microbiota compositional and colonic gene expression level of CRC-associated genes. In conclusion, fiber supplementation reduces experimental colonic tumorigenesis under human ‘high CRC risk microbiota’ conditions. The tumorsuppressive effects are specific for the individual fecal microbiota donor, supporting the need of targeted approaches for fiber supplementation to reduce CRC risk.

Publications

• Differences in Fecal Gut Microbiota, Short-Chain Fatty Acids and Bile Acids Link Colorectal Cancer Risk to Dietary Changes Associated with Urbanization Among Zimbabweans. Nutrition and Cancer, 71(8), 1313-1324.
  Katsidzira, L.; Ocvirk, S.; Wilson, A.; Li, J.; Mahachi, C. B.; Soni, D.; DeLany, J.; Nicholson, J. K.; Zoetendal, E. G. & O.’Keefe, S. J. D.
  
• Fiber, Fat, and Colorectal Cancer: New Insight into Modifiable Dietary Risk Factors. Current Gastroenterology Reports, 21(11).
  Ocvirk, Soeren; Wilson, Annette S.; Appolonia, Corynn N.; Thomas, Timothy K. & O.’Keefe, Stephen J. D.
  
• A prospective cohort analysis of gut microbial co-metabolism in Alaska Native and rural African people at high and low risk of colorectal cancer. The American Journal of Clinical Nutrition, 111(2), 406-419.
  Ocvirk, Soeren; Wilson, Annette S.; Posma, Joram M.; Li, Jia V.; Koller, Kathryn R.; Day, Gretchen M.; Flanagan, Christie A.; Otto, Jill Evon; Sacco, Pam E.; Sacco, Frank D.; Sapp, Flora R.; Wilson, Amy S.; Newton, Keith; Brouard, Faye; DeLany, James P.; Behnning, Marissa; Appolonia, Corynn N.; Soni, Devavrata; Bhatti, Faheem ... & O.’Keefe, Stephen JD
  
• 801 DIETARY FIBER SUPPRESSES COLONIC TUMORIGENESIS IN GNOTOBIOTIC MICE COLONIZED WITH HUMAN FECAL MICROBIOTA FROM A COHORT AT HIGH RISK OF COLON CANCER. Gastroenterology, 160(6), S-165.
  Kuhls, Stephanie; Schumacher, Fabian; Blaut, Michael; Koller, Kathryn R.; Sapp, Flora; Thomas, Timothy; Wilson, Annette; O.'Keefe, Stephen J. & Ocvirk, Soren
  
• Dietary fat, bile acid metabolism and colorectal cancer. Seminars in Cancer Biology, 73, 347-355.
  Ocvirk, Soeren & O.’Keefe, Stephen J.D.
  
• Su528 INVESTIGATION OF THE TUMOR-PROMOTING ACTIVITY OF DEOXYCHOLIC ACID IN GNOTOBIOTIC MICE USING A SIMPLIFIED MICROBIAL CONSORTIUM. Gastroenterology, 160(6), S-727-S-728.
  Osswald, Annika; Schumacher, Fabian; Wolf, Patricia G.; Schmidt, Sabine; Dittberner, Nicole; Ridlon, Jason M. & Ocvirk, Soren
  
• Bile acids, bile pigments and colorectal cancer risk. Current Opinion in Gastroenterology, 38(2), 173-178.
  Kuhls, Stephanie; Osswald, Annika & Ocvirk, Soeren
  
• Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer. Cold Spring Harbor Laboratory.
  Wortmann, Esther; Osswald, Annika; Wylensek, David; Kuhls, Stephanie; Coleman, Olivia I.; Ducarmon, Quinten; Liang, Wei; Treichel, Nicole; Schumacher, Fabian; Volet, Colin; Matysik, Silke; Kleigrewe, Karin; Gigl, Michael; Rohn, Sascha; Kleuser, Burkhard; Liebisch, Gerhard; Schnieke, Angelika; Bernier-Latmani, Rizlan; Zeller, Georg ... & Clavel, Thomas