40 The gut microbiota modifies host-parasite interactions
Authors: Li Robert W , Liu Fang , Solano-Aguilar Gloria , Urban Joseph F 
Published: September 2024

Abstract
It is well documented that parasitic infections induce a profound change in the structure and function of host gut microbiota, likely due to infection-associated perturbations in the gut microenvironment. However, the mechanisms remain largely unknown. Here we aim to understand how the gut microbiota is modified by host-parasite relationships or vice versa using an integrated multi-omics analysis in a swine-Ascaris infection model. Female pigs (n = 30; 6 to 8 mo of age) were randomly divided into three groups (n = 10 per group). One group served as normal uninfected controls (NU); the remaining 20 pigs were inoculated per os with ~10,000 infective A. suum eggs; and the infection was allowed to progress for 35 d post-inoculation (dpi). At 21 dpi, one of the infected groups (IP) was treated with a single daily dose of an anthelmintic drug, Panacur, for three consecutive days while the other infected pigs remained untreated (IU). At necropsy, intestine tissue, serum and fecal samples were collected for untargeted metabolome analysis using UPLC-MS/MS and the fecal microbiota was characterized using full-length 16S rRNA gene-based sequencing with DADA2. Fecal and serum metabolites were categorized for their origin using MetOrigin. An integrated multi-omics analysis was performed using DIABLO algorithms and NetCoMi networking tools. Our results showed that A. suum worms were well developed in pigs from the IU group, which harbored a significantly reduced microbiota alpha diversity (Simpson, P &lt; 0.005) compared with NU. The infection altered the abundance of at least 17 bacterial species/strains, including multiple butyrate-producing Clostridium spp., such as C. butyricum. The infection also dysregulated 51 fecal metabolites, including microbiota-derived metabolites such as glutaric acid and p-Cresol sulfate, and succinate of mixed origin. Moreover, the anthelmintic treatment was efficacious and eliminated all worms from the gut. Nevertheless, 11 pathways of both host and microbiota origin were significantly enriched in the gut of pigs from the IP group, including peptidoglycan biosynthesis, histidine metabolism (in both feces and serum), and primary bile acid biosynthesis, suggesting the infection-induced alterations may not be transient. In conclusion, the host microbiota modified swine-Ascaris interactions via three different mechanisms. First, microbiota-derived metabolites directly regulate host gene expression, which in turn affects host physiology and immune responses. Second, plasticity of the gut microbiota allows the exploitation of the niche differentiated upon infection, resulting in blossom of certain strains in the gut of post-treated animals. Lastly, the host microbiota is likely one of the key determinants of parasite gut microbiota, indirectly exerting its effect on parasite physiology and nutrition. Further studies aiming to understand reciprocal yet complex relations between the gut microbiota, the host, and parasites (including parasite gut microbiota) will be conducive to the design of next-generation functional anthelmintics.