Cooperation between host immunity and the gut bacteria is essential for helminth-evoked suppression of colitis

Abstract

Background Studies on the inhibition of inflammation by infection with helminth parasites have, until recently, overlooked a key determinant of health: the gut microbiota. Infection with helminths evokes changes in the composition of their host’s microbiota: one outcome of which is an altered metabolome (e.g., levels of short-chain fatty acids (SCFAs)) in the gut lumen. The functional implications of helminth-evoked changes in the enteric microbiome (composition and metabolites) are poorly understood and are explored with respect to controlling enteric inflammation. Methods Antibiotic-treated wild-type, germ-free (GF) and free fatty-acid receptor-2 (ffar2) deficient mice were infected with the tapeworm Hymenolepis diminuta, then challenged with DNBS-colitis and disease severity and gut expression of the il-10 receptor-α and SCFA receptors/transporters assessed 3 days later. Gut bacteria composition was assessed by 16 s rRNA sequencing and SCFAs were measured. Other studies assessed the ability of feces or a bacteria-free fecal filtrate from H. diminuta-infected mice to inhibit colitis. Results Protection against disease by infection with H. diminuta was abrogated by antibiotic treatment and was not observed in GF-mice. Bacterial community profiling revealed an increase in variants belonging to the families Lachnospiraceae and Clostridium cluster XIVa in mice 8 days post-infection with H. diminuta, and the transfer of feces from these mice suppressed DNBS-colitis in GF-mice. Mice treated with a bacteria-free filtrate of feces from H. diminuta-infected mice were protected from DNBS-colitis. Metabolomic analysis revealed increased acetate and butyrate (both or which can reduce colitis) in feces from H. diminuta-infected mice, but not from antibiotic-treated H. diminuta-infected mice. H. diminuta-induced protection against DNBS-colitis was not observed in ffar2−/− mice. Immunologically, anti-il-10 antibodies inhibited the anti-colitic effect of H. diminuta-infection. Analyses of epithelial cell lines, colonoids, and colon segments uncovered reciprocity between butyrate and il-10 in the induction of the il-10-receptor and butyrate transporters. Conclusion Having defined a feed-forward signaling loop between il-10 and butyrate following infection with H. diminuta, this study identifies the gut microbiome as a critical component of the anti-colitic effect of this helminth therapy. We suggest that any intention-to-treat with helminth therapy should be based on the characterization of the patient’s immunological and microbiological response to the helminth.

Helminth Therapy for Immune-Mediated Inflammatory Diseases: Current and Future Perspectives

“… 80 Acetate and butyrate produced by the altered gut microbiota can exert anti-inflammatory effects to protect against colitis. 81 These results show that helminth therapy is a potential therapeutic direction for IBD.…”

Gut Bacterial Composition and Functional Potential of Tibetan Pigs Under Semi-Grazing

“…In addition, gut microbiome was recognized as an acquired bacterial defense system ( Ross et al, 2019 ). The interactions between gut microbiota and host immunity exerted effective suppressions of helminth-evoked colitis ( Shute et al, 2021 ). Recent research suggested that adjustment of intestinal microbiota could improve efficacies of treatments of colorectal cancer ( Si et al, 2021 ).…”

Infection with intestinal helminth (Hymenolepis diminuta) impacts exploratory behavior and cognitive processes in rats by changing the central level of neurotransmitters

“…In addition, recent studies [51] indicates the link between host immunity, the gut bacteria and helminth-evoked suppression of colitis in mice model. Authors speculate that reduced efficacy of helminth therapy could be enhanced by combination with a probiotic matched to compensate for dysbiosis in a particular individual.…”