Race‐dependent Association of Sulfidogenic Bacteria with Colorectal Cancer

Abstract

In the US, there is a higher incidence of colorectal cancer (CRC) in African Americans (AAs) compared to non‐Hispanic whites (NHWs). Recent evidence links consumption of a diet high in animal protein and fat as an environmental risk factor for CRC development, and the intestinal microbiota modulates the tumor promoting or protective effects of diet. Hydrogen sulfide, produced by resident sulfidogenic bacteria, triggers pro‐inflammatory pathways and hyper‐proliferation, and is genotoxic. We hypothesized that sulfidogenic bacterial abundance in colonic mucosa may be an environmental CRC risk factor that distinguishes AA and NHWs, and may be correlated with differences in dietary composition. Colonic biopsies from uninvolved or healthy mucosa from CRC cases and controls were collected from five medical centers through the Chicago Colorectal Cancer Consortium. Using quantitative PCR, sulfidogenic bacterial abundance was measured in uninvolved colonic mucosa of 97 AA and 56 NHW CRC cases, and 100 AA and 76 NHW controls. In addition, 16S rRNA sequencing was performed in AA cases and AA controls. A Block Brief 2000 Food Frequency Questionnaire was collected from a subset of subjects of 50 AA and 31 NHW CRC cases and 30 AA and 24 NHW controls. Differences were examined among bacterial targets, race, disease status, and dietary intake. AAs harbored a greater abundance (p<0.001) of sulfidogenic bacteria compared to NHWs regardless of disease status, including the functional gene for H2S production in sulfate reducing bacteria, dissimilatory sulfate reductase (pan‐dsrA), as well as Bilophila wadsworthia‐specific dsrA, and 16S rRNA genes for Desulfobacter spp., Desulfovibrio spp., and Desulfotomaculum spp. Bilophila wadsworthia‐specific dsrA was significantly more abundant in AA cases compared to AA controls (p<0.001). Linear discriminant analysis of 16S rRNA gene sequences highlighted the sulfidogenic Bilophila, Lactococcus, Odoribacter, Porphyromonas and Pyramidobacter genera as significant in AA cases. Fat intake and daily servings of meat were significantly higher (p<0.01) in AAs compared with NHWs, and dietary fat intake correlated positively with pan‐dsrA abundance (p=0.011). Additionally, intake of dairy and calcium was lower (p<0.001) in AA, and servings of dairy correlated negatively with pan‐dsrA abundance (p=0.007). Together, these results implicate sulfidogenic bacteria as an environmental risk factor contributing to CRC development in AAs.Support or Funding InformationThis work was supported by grants from the National Cancer Institute (U01 CA153060 and P30 CA023074, NAE; RO1 CA204808, HRG, EM, LTH; RO1 CA141057, BJ) and the American Cancer Society Illinois Division (223187, XL). PGW was supported by a predoctoral fellowship from Mayo Clinic and University of Illinois Alliance for Technology‐Based Healthcare. CY was supported by a training grant from National Institute of Health (5T32DK007788‐15). GJA was supported by a Cancer Biology Training Grant (T32CA009213).