Background: Disease resistance phenotypes are associated with immune regulatory functions and immune tolerance and have implications for both the livestock industry and human health. Microbiota plays an essential role in regulating immunity and autoimmunity in the host organism, but the influence of host-microbiota interactions on disease resistance phenotypes remains unclear. Here, multiomics analysis was performed to identify potential regulatory mechanisms of disease resistance at both the microbiome and host levels in two pig breeds. Results: Acute colitis models were established in Min pigs and Yorkshire pigs, and control and diseased individuals were compared. Compared with Yorkshire pigs under the same nutritional and management conditions, Min pigs exhibited strong disease resistance, as indicated by a low disease activity index (DAI) and a low histological activity index (HAI). Microbiota sequencing analysis showed that potentially harmful microbes Desulfovibrio, Bacteroides and Streptococcus were enriched in diseased individuals of the two breeds. Notably, potentially beneficial microbes, such as Lactobacillus, Clostridia and Eubacterium, and several genera belonging to Ruminococcaceae and Christensenellaceae were enriched in diseased Min pigs and were found to be positively associated with the microbial metabolites related to intestinal barrier function. Specifically, the concentrations of indole derivatives and short-chain fatty acids were increased in diseased Min pigs, suggesting beneficial action in protecting intestinal barrier. In addition, lower concentrations of bile acid metabolites and short-chain fatty acids were observed in diseased Yorkshire pigs, which were associated with increased potentially harmful microbes, such as Bilophila and Alistipes. Concerning enrichment of the immune response, the increase in CD4⁺ T cells in the lamina propria improved supervision of the host immunity response in diseased Min pigs, contributing to the maintenance of Th2-type immune superiority and immune tolerance patterns and control of excessive inflammation with the help of potentially beneficial microbes. In diseased Yorkshire pigs, more terms belonging to biological processes of immunity were enriched, including Toll-like receptors signalling, NF-κB signalling and Th1 and Th17-type immune responses, along with the increases of potentially harmful microbes and damaged intestinal barrier. Conclusions: Cumulatively, the results for the two pig breeds highlight that host-microbiota crosstalk promotes a disease resistance phenotype in three ways: by maintaining partial PRR nonactivation, maintaining Th2-type immune superiority and immunological tolerance patterns and recovering gut barrier function to protect against colonic diseases.

Supplementation with short-chain fatty acids (SCFAs) is a potential therapeutic approach for inflammatory bowel disease (IBD). However, the therapeutic effects and mechanisms of action of isobutyrate in IBD remain unclear. Clinical data indicate that the fecal levels of isobutyrate are markedly lower in patients with Crohn’s disease than in healthy controls. Compared with healthy mice and healthy pigs, mice and pigs with colitis presented significantly lower isobutyrate levels. Furthermore, the level of isobutyrate in pigs was significantly negatively correlated with the disease activity index. We speculate that isobutyrate may play a crucial role in regulating host gut homeostasis. We established a model of dextran sulfate sodium-induced colitis in pigs, which have gastrointestinal structure and function similar to those of humans; we performed multiomic analysis to investigate the therapeutic effects and potential mechanisms of isobutyrate on IBD at both the animal and cellular levels and validated the results. Phenotypically, isobutyrate can significantly alleviate diarrhea, bloody stools, weight loss, and colon shortening caused by colitis in pigs. Mechanistically, isobutyrate can increase the relative abundance of Lactobacillus reuteri , thereby increasing the production of indole-3-lactic acid, regulating aryl hydrocarbon receptor expression and downstream signaling pathways, and regulating Foxp3 ⁺ CD4 ⁺ T cell recruitment to alleviate colitis. Isobutyrate can directly activate G protein-coupled receptor 109A, promote the expression of Claudin-1, and improve intestinal barrier function. In addition, isobutyrate can increase the production of intestinal SCFAs and 3-hydroxybutyric acid and inhibit the TLR4/MyD88/NF-κB signaling pathway to suppress intestinal inflammation. In conclusion, our findings demonstrate that isobutyrate confers resistance to IBD through host–microbiota interactions, providing a theoretical basis for the use of isobutyrate in alleviating colitis.

Ulcerative colitis (UC) is often accompanied by intestinal inflammation and disruption of intestinal epithelial structures, which are closely associated with changes in the intestinal microbiota. We previously revealed that Min pigs, a native Chinese breed, are more resistant to dextran sulfate sodium (DSS)-induced colitis than commercial Yorkshire pigs. Characterizing the microbiota in Min pigs would allow identification of the core microbes that confer colitis resistance. By analyzing the microbiota linked to the disease course in Min and Yorkshire pigs, we observed that Bacillus spp. were enriched in Min pigs and positively correlated with pathogen resistance. Using targeted screening, we identified and validated Bacillus siamensis MZ16 from Min pigs as a bacterial species with biofilm formation ability, superior salt and pH tolerance, and antimicrobial characteristics. Subsequently, we administered B. siamensis MZ16 to conventional or microbiota-deficient BALB/c mice with DSS-induced colitis to assess its efficacy in alleviating colitis. B. siamensis MZ16 partially counteracted DSS-induced colitis in conventional mice, but it did not mitigate DSS-induced colitis in microbiota-deficient mice. Further analysis revealed that B. siamensis MZ16 administration improved intestinal ecology and integrity and immunological barrier function in mice. Compared to the DSS-treated mice, mice preadministered B. siamensis MZ16 exhibited improved relative abundance of potentially beneficial microbes ( Lactobacillus , Bacillus , Christensenellaceae R7 , Ruminococcus , Clostridium , and Eubacterium ), reduced relative abundance of pathogenic microbes ( Escherichia-Shigella ), and maintained colonic OCLN and ZO-1 levels and IgA and SIgA levels. Furthermore, B. siamensis MZ16 reduced proinflammatory cytokine levels by reversing NF-κB and MAPK pathway activation in the DSS group. Overall, B. siamensis MZ16 from Min pigs had beneficial effects on a colitis mouse model by enhancing intestinal barrier functions and reducing inflammation in a gut microbiota-dependent manner.