Enterohepatic Helicobacter (EHH) species differ in their effects on colonic inflammation and colitis-associated colon tumorigenesis in mice

Abstract

Abstract Enterohepatic Helicobacter (EHH) species are gram-negative bacteria that colonize the colons and sometimes the biliary tracts of humans, primates, rodents, and other mammals. Though ~20% of the human population may be infected, EHH species are poorly studied in humans. H. hepaticus is known for causing colitis in mice with severe immunologic abnormalities; however, virtually nothing is known about the influence of EHH species on colitis in wild-type mice, which are more relevant to humans. Dextran sulfate sodium (DSS) treatment and DSS plus azoxymethane (AOM ) are widely used as mouse models of ulcerative colitis and colitis-associated colon cancer. We hypothesized that specific EHH species would alter the course of DSS-induced colitis and colitis-associated colon tumorigenesis in mice. We infected C57BL/6 mice with human- and rodent-associated EHH species +/− DSS, or +/− DSS/AOM and measured the effects on pathology and inflammation markers. We found that H. cinaedi, H. pullorum, H. fennelliae exacerbate DSS-induced colitis and delay recovery, whereas H. hepaticus reduced the effect of DSS-induced colitis severity. H. hepaticus also prevented tumor development in the AOM/DSS colon cancer model. We measured the proinflammatory and the anti-inflammatory cytokines in serum and colon homogenates and found that cytokine induction varied among the EHH species. Therefore, EHH species alter susceptibility to DSS-induced colitis and DSS-AOM colon cancer. These results suggest that EHH species could increase or decrease the risk of inflammatory bowel disease or colorectal cancer in humans, making it important to identify the infecting species.