Rates of colon cancer are much higher in African Americans (65:100,000) than in rural South Africans (<5:100,000). The higher rates are associated with higher animal protein and fat and lower fiber consumption, higher colonic secondary bile acids, lower colonic short chain fatty acid quantities and higher mucosal proliferative biomarkers of cancer risk in otherwise healthy middle aged volunteers. Here we investigate further the role of fat and fiber in this association. We performed two-week food exchanges in subjects from the same populations, where African Americans were fed a high-fiber, lowfat African-style diet, and rural Africans a high-fat low-fiber western-style diet under close supervision. In comparison to their usual diets, the food changes resulted in remarkable reciprocal changes in mucosal biomarkers of cancer risk and in aspects of the microbiota and metabolome known to affect cancer risk, best illustrated by increased saccharolytic fermentation and butyrogenesis and suppressed secondary bile acid synthesis in the African Americans.

Background: Epidemiologic studies have suggested that most cases of sporadic colon cancer can be attributed to diet. The recognition that colonic microbiota have a major influence on colonic health suggests that they might mediate colonic carcinogenesis. Objective: To examine the hypothesis that the influence of diet on colon cancer risk is mediated by the microbiota through their metabolites, we measured differences in colonic microbes and their metabolites in African Americans with a high risk and in rural native Africans with a low risk of colon cancer. Design: Fresh fecal samples were collected from 12 healthy African Americans aged 50-65 y and from 12 age-and sex-matched native Africans. Microbiomes were analyzed with 16S ribosomal RNA gene pyrosequencing together with quantitative polymerase chain reaction of the major fermentative, butyrate-producing, and bile acid-deconjugating bacteria. Fecal short-chain fatty acids were measured by gas chromatography and bile acids by liquid chromatography-mass spectrometry. Results: Microbial composition was fundamentally different, with a predominance of Prevotella in native Africans (enterotype 2) and of Bacteroides in African Americans (enterotype 1). Total bacteria and major butyrate-producing groups were significantly more abundant in fecal samples from native Africans. Microbial genes encoding for secondary bile acid production were more abundant in African Americans, whereas those encoding for methanogenesis and hydrogen sulfide production were higher in native Africans. Fecal secondary bile acid concentrations were higher in African Americans, whereas short-chain fatty acids were higher in native Africans. Conclusion: Our results support the hypothesis that colon cancer risk is influenced by the balance between microbial production of health-promoting metabolites such as butyrate and potentially carcinogenic metabolites such as secondary bile acids.Am J Clin Nutr 2013;98:111-20.

It is estimated that most colon cancers can be attributed to dietary causes. We have hypothesized that diet influences the health of the colonic mucosa through interaction with the microbiota and that it is the milieu interior that regulates mucosal proliferation and therefore cancer risk. To validate this further, we compared colonic contents from healthy 50- to 65-y-old people from populations with high and low risk, specifically low risk Native Africans (cancer incidence <1:100,000; n = 17), high risk African Americans (risk 65:100,000; n = 17), and Caucasian Americans (risk 50:100,000; n = 18). Americans typically consume a high-animal protein and -fat diet, whereas Africans consume a staple diet of maize meal, rich in resistant starch and low in animal products. Following overnight fasting, rapid colonic evacuation was performed with 2 L polyethylene glycol. Total colonic evacuants were analyzed for SCFA, vitamins, nitrogen, and minerals. Total SCFA and butyrate were significantly higher in Native Africans than in both American groups. Colonic folate and biotin content, measured by Lactobacillus rhamnoses and Lactobacillus plantarum ATCC 8014 bioassay, respectively, exceeded normal daily dietary intakes. Compared with Africans, calcium and iron contents were significantly higher in Caucasian Americans and zinc content was significantly higher in African Americans, but nitrogen content did not differ among the 3 groups. In conclusion, the results support our hypothesis that the microbiota mediates the effect diet has on colon cancer risk by their generation of butyrate, folate, and biotin, molecules known to play a key role in the regulation of epithelial proliferation.

Background: The vitamin D receptor (VDR) and pregnane X receptor (PXR) are nuclear hormone receptors of the NR1I subfamily that show contrasting patterns of cross-species variation. VDR and PXR are thought to have arisen from duplication of an ancestral gene, evident now as a single gene in the genome of the chordate invertebrate Ciona intestinalis (sea squirt). VDR genes have been detected in a wide range of vertebrates including jawless fish. To date, PXR genes have not been found in cartilaginous fish. In this study, the ligand selectivities of VDRs were compared in detail across a range of vertebrate species and compared with those of the Ciona VDR/PXR. In addition, several assays were used to search for evidence of PXR-mediated hepatic effects in three model non-mammalian species: sea lamprey (Petromyzon marinus), zebrafish (Danio rerio), and African clawed frog (Xenopus laevis).

We propose that the influence of diet on colon cancer risk is mediated by the microbiota. To investigate how dietary fat influences risk, we compared the colonic contents of 12 adult high-risk African Americans (AAs) and 10 Caucasian Americans (CAs) who consumed a high-fat diet (123 ± 11 g/d and 129 ± 17 g/d, respectively) to 13 native Africans (NAs) who subsisted on a low-fat (38 ± 3.0 g/d) diet, all aged 50-60 yr. The colonic bile acids were measured by LC-MS and the short-chain fatty acids (SCFAs) by GC. The chief secondary colonic bile acids, deoxycholic acid and lithocholic acid, were correlated with fat intake and similar between AAs and CAs, but 3-4 times higher than in AAs (p < 0.05). The major SCFAs were lower in AAs (p < 0.001) and CAs (p < 0.001) compared to AAs, but conversely, the branched chain fatty acids (BFCA) were higher. Our results suggest that the higher risk of colon cancer in Americans may be partly explained by their high-fat and high-protein, low complex carbohydrate diet, which produces colonic residues that promote microbes to produce potentially carcinogenic secondary bile acids and less antineoplastic SCFAs. The role of BCFA in colonic carcinogenesis deserves further study.

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AIM:To determine tolerance to fiber supplementation of semi-elemental tube feeds in critically ill patients and measure its effect on colonic microbiota and fermentation.

Summary Reduced susceptibility to sporadic colorectal cancer in native Africans (NA) is correlated with low consumption of animal products and greater microbial production of colonic methane. In this context, two hydrogenotrophic microbial groups are of interest, methanogenic Archaea (MA) utilizing H2 to produce methane and sulfate‐reducing bacteria (SRB) generating hydrogen sulfide, which has been linked with chronic inflammatory disorders of the colon. In the present study, stool samples from NA, consuming a diet high in resistant starch and low in animal products, and from African Americans (AA) and European Americans (EA), both consuming a typical Western diet, were examined for genetic diversity and structure of Archaea, MA and SRB communities. In general, a greater proportion of NA than AA and EA harboured the full range of targeted hydrogenotrophic groups. Terminal restriction fragment length polymorphism analysis of 16S rRNA genes and specific functional genes, combined with multivariate statistical analyses, revealed that NA harboured more diverse and different Archaea and MA populations than AA and EA. Also, NA harboured significantly distinct SRB populations compared with AA and EA. Taken together, these data are consistent with diet selecting for distinct hydrogenotrophic microbiota.