The influence of innate immunity, adaptive immunity and diet on intestinal microbiota following Trichuris muris infection

Background Trichuris trichiura (whipworm) affects nearly 500 million people globally, causing chronic intestinal inflammation and contributing to malnutrition, growth stunting, and impaired cognitive development especially in children living in low-resource settings. While host immune responses are central to parasite clearance, growing evidence suggests that diet and the gut microbiota may modulate both infection susceptibility and treatment outcomes. However, the mechanisms by which diet influences helminth expulsion, particularly in the context of immune deficiency, remain poorly defined. Methods We used a Trichuris muris infection model to investigate how host immune competence and diet influence worm burden, parasite-specific humoral responses and the gut microbiome. Wild-type (WT), RAG2-deficient (lacking adaptive immunity), and RAG2/γc-deficient (lacking both adaptive and innate lymphoid immunity) mice received either a standard normal diet (ND) or high-fat diet (HFD) and infected with a low dose of T. muris . Worm burdens, parasite specific serum IgG1 and IgG2a/c responses were measured together with profiling of the intestinal microbiota using 16S rRNA gene sequencing and shotgun metagenomics Results Infection of WT mice on a ND with a low dose infection resulted in a chronic infection. Antibody analysis showed a strong parasite-specific IgG2a/c response, consistent with Th1-biased immunity during chronic infection. Notably, WT mice fed a high fat diet (HFD) achieved near-complete parasite clearance, accompanied by elevated IgG1 and reduced IgG2a/c titres, suggesting a diet-induced skewing toward a protective Th2-type response. RAG2-deficient mice and RAG2/γc-deficient mice on a normal diet (ND) also maintained a low dose chronic infection, aligned with the role of immune responses in clearance: no parasite-specific antibodies were detected in either strain as expected. However, RAG2-deficient mice and RAG2/γc-deficient mice fed a HFD exhibited reduced parasite numbers but not complete worm loss as seen in WT mice suggesting a second mechanism of effect. Microbiota composition clustered primarily by genotype and diet, with infection status exerting a more subtle influence. HFD-fed mice exhibited enrichment of several taxa with known roles in mucosal immunity and metabolic regulation, including Bacteroides , Parabacteroides , Faecalibacterium , Blautia , and Lactococcus . Conclusion Diet and host immune competence jointly influence susceptibility to helminth infection and the composition and function of the gut microbiota. A HFD shapes the gut toward a state of resilience, characterized by enhanced Th2-biased immune responses and enrichment of epithelial barrier-supportive microbial taxa. This milieu promotes resistance to T. muris infection, even in partially immunocompromised hosts. These findings underscore the importance of diet in modulating host–microbiota–parasite interactions and highlight the potential for diet or microbiome-based strategies to enhance resistance against intestinal helminths,pending studies that directly test microbiome causality.