Published online Aug 28, 2020. doi: 10.3748/wjg.v26.i32.4763
Peer-review started: March 20, 2020
First decision: April 8, 2020
Revised: July 16, 2020
Accepted: August 12, 2020
Article in press: August 12, 2020
Published online: August 28, 2020
Enterohepatic Helicobacter (EHH) species can infect humans and many animal species. Some of these species are known to cause disease in animals, while others have been described as commensal. In humans, epidemiological evidence suggests that EHH species are associated with inflammatory bowel disease (IBD), but the specific species involved and mechanisms of action are unknown. New treatments being tested for IBD include natural compounds and microRNA (miRNA)-based therapies. MiRNA is also being investigated as a diagnostic tool.
Given the limitations of performing IBD research in humans, an animal model of EHH-mediated pathology is needed. Such a model should reflect the biological changes seen during human IBD. Helicobacter muridarum (H. muridarum) has been referred to as a commensal in mice, yet we previously determined that H. muridarum worsens colitis resulting from dextran sodium sulfate (DSS). This suggested that EHH species could represent environmental factors that cause or worsen IBD in genetically susceptible individuals. It is also important to determine whether phytochemicals being investigated as IBD treatments are influenced by infection with EHH species because there are no commercially available tests for EHH infection in humans.
We sought to determine how the immune and miRNA profiles of H. muridarum-infected wild-type mice compared with DSS-treated mice and with published immune and miRNA profiles of IBD patients. We also determined whether efficacy of a broccoli-derived anti-inflammatory compound, indole-3-carbinol (I3C), was reduced by H. muridarum infection.
We measured changes in body weight, stool consistency, and stool blood following H. muridarum infection, DSS treatment, and/or I3C treatment. We then measured cytokine responses in the colon and plasma and histopathological changes in the colon. MiRNA changes and T cell population changes were measured in mesenteric lymph nodes.
While H. muridarum infection alone did not cause clinical symptoms, it did cause colonic inflammation and induced proinflammatory cytokines. As expected, H. muridarum worsened colitis caused by DSS treatment, but it did not prevent amelioration of colitis by I3C treatment. Both the miRNA changes and cytokine responses to H. muridarum infection were similar to those seen in human IBD and due to DSS treatment. Changes in cytokines and miRNA were consistent with a Th17 response.
H. muridarum causes subclinical colitis that increases vulnerability to DSS treatment. Since I3C is an aryl hydrocarbon receptor agonist, the efficacy of I3C in the presence of H. muridarum suggests that H. muridarum does not influence the aryl hydrocarbon receptor agonist pathway. The strong similarities between cytokine and miRNA profiles induced by DSS and those induced by H. muridarum suggest that similar mechanisms could be at play and that the mouse model is suitable for studying host interactions with EHH species.
This research supports the hypothesis that EHH species could contribute to human IBD by exacerbating the response to other inflammatory stimuli. More research is needed on the prevalence of EHH species in humans and the mechanisms underlying EHH-mediated colonic damage.