Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans

Abstract

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.

FIGURE 1.

Illustration of the marked phylogenic differences in microbiota composition between AAs (n = 12) and NAs (n = 12) detected by 16S-rRNA-based taxonomic pyrosequencing. Nonmetric multidimensional scaling shows strong clustering (multivariate ANOVA: P < 0.01) according to ethnic group. AA, African American; NA, native African; rRNA, ribosomal RNA.

FIGURE 2.

Composition was dominated by Bacteroides in the 12 AAs, which indicated that they belonged to enterotype 1, and was dominated by Prevotella in the 12 NAs, which categorized them as enterotype 2 (10). AA, African American; NA, native African.

FIGURE 3.

Illustration of the similarities and differences in fecal microbial taxa between AAs and NAs. The solid circle encloses the taxa that were detected in NA and the dotted circle those identified in AA. The overlap between the 2 circles contains taxa common to both populations. Much of the shared taxa were significantly (independent Kruskal-Wallis tests) more enriched in one group than in the other, indicated by the boxed text in AAs on the left and underlined text in NAs on the right. AA, African American; NA, native African.

FIGURE 4.

Summary of the differences in mean (±SE) group concentrations of the major short-chain fatty acids in fecal samples. Concentrations were significantly greater in NAs (n = 12) than in AAs (n = 12): Mann-Whitney U test for acetate (P = 0.001), propionate (P = 0.003), and butyrate (P = 0.049). AA, African American; NA, native African.

FIGURE 5.

The abundance of total bacteria correlated significantly (Spearman's test) with the concentrations of acetate (□, dashed and dotted line; r² = 0.38, P = 0.033), propionate (▴, dashed line; r² = 0.33, P = 0.039), and butyrate (×, continuous line; r² = 0.37, P = 0.042) in fecal samples from African Americans and native Africans (n = 24).

FIGURE 6.

Contents of major bile acids in feces were significantly lower in NAs (n = 12) than in AAs (n = 12): Mann-Whitney U test for CA (P = 0.027), CDCA (P = 0.016), DCA (P = 0.043), and LCA (P = 0.031). *P < 0.05 compared with AA. AA, African American; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; NA, native African.

FIGURE 7.

The abundance of 7α-dehydroxylating bacteria, estimated from detection of their functional genes by polymerase chain reaction, correlated significantly with the concentration of secondary bile acids in fecal samples (n = 24). r² = 0.65, P = 0.001 (Spearman's test).