Small Intestinal Levels of the Branched Short-Chain Fatty Acid Isovalerate Are Elevated during Infection with Heligmosomoides polygyrus and Can Promote Helminth Fecundity

Abstract

Heligmosomoides polygyrus is a helminth which naturally infects mice and is widely used as a laboratory model of chronic small intestinal helminth infection. While it is known that infection with H. polygyrus alters the composition of the host’s bacterial microbiota, the functional implications of this alteration are unclear. We investigated the impact of H. polygyrus infection on short-chain fatty acid (SCFA) levels in the mouse intestine and sera. We found that helminth infection resulted in significantly upregulated levels of the branched SCFA isovaleric acid, exclusively in the proximal small intestine, which is the site of H. polygyrus colonization. We next set out to test the hypothesis that elevating local levels of isovaleric acid was a strategy used by H. polygyrus to promote its own fitness within the mammalian host. To test this, we supplemented the drinking water of mice with isovalerate during H. polygyrus infection and examined whether this affected helminth fecundity or chronicity. We did not find that isovaleric acid supplementation affected helminth chronicity, however, we found that it did promote helminth fecundity, as measured by helminth egg output in the feces of mice. Through antibiotic-treatment of helminth-infected mice, we found that the bacterial microbiota was required in order to support elevated levels of isovaleric acid in the proximal small intestine during helminth infection. Overall, our data reveal that during H. polygyrus infection there is a microbiota-dependent localized increase in the production of isovaleric acid in the proximal small intestine and this supports helminth fecundity in the murine host.

Th2 and metabolic responses to nematodes are independent of prolonged host microbiota abrogation

“…To expand on this, here we focused on applying a prolonged antibiotic treatment regimen over a total of 14 weeks in order to delineate what effects temporary abrogation of the host microbiota has on the development, maintenance and functionality of effector and memory Th2 responses following primary H. polygyrus infection, drug cure and challenge infection. In accordance with other studies, 2,24 we could confirm that prolonged administration of a cocktail of antibiotics in the drinking water is an effective strategy to temporarily remove the intestinal microbiota of mice, evidenced by the lack of detectable total Eubacteria DNA in faecal samples of Abx treated mice. Commensal bacteria have been shown to benefit the survival and persistence of several intestinal nematode species 5,25–27 .…”

Maternal‐driven immune education in offspring

“…Notably, infections with macroparasites such as Heligmosomoides polygyrus have been reported to enhance production of SCFA through microbial modification. 57,58 Conversely, some research suggested that infection with influenza virus can reduce intestinal SCFA production, leading to increased susceptibility to pneumococcal superinfection in the lungs. 59 Undoubtedly, maternal infection can induce changes in microbiota composition, impacting microbiota-derived metabolites.…”

“…Beyond dietary factors, infections also play a crucial role in shaping SCFA production by microbiota. Notably, infections with macroparasites such as Heligmosomoides polygyrus have been reported to enhance production of SCFA through microbial modification 57,58 . Conversely, some research suggested that infection with influenza virus can reduce intestinal SCFA production, leading to increased susceptibility to pneumococcal superinfection in the lungs 59 .…”

Helminth-host-environment interactions: Looking down from the tip of the iceberg

“…The predicted pup stomach metabolome had upregulated SCFA production as well as essential and branched-chain amino acids and vitamins, all of which may provide nutritional or developmental benefits for the uninfected pup (Haque et al 2021). Kennedy et al (2021) found that the higher concentrations of isovaleric acid in the proximal small intestine of H. polygyrus- infected mice was dependent on the presence of bacteria. Furthermore, they identified a benefit to the parasite, as addition of isovaleric acid to the drinking water increased worm fecundity.…”