Shealy, N. | Search bioRxiv

bioRxiv2025

Short-term alterations in dietary amino acids override host genetic susceptibility and reveal mechanisms of Salmonella Typhimurium small intestine colonization

In addition to individual genetics, environmental factors (e.g., dietary changes) may influence host susceptibility to gastrointestinal infection through unknown mechanisms. Herein, we developed a model in which CBA/J mice, a genetically resistant strain that tolerates intestinal colonization by the enteric pathogen Salmonella Typhimurium (S. Tm), rapidly succumb to infection after exposure to a diet rich in L-amino acids (AA). In mice, S. Tm-gastroenteritis is restricted to the large intestine (cecum), limiting their use to understand S. Tm small intestine (ileum) colonization, a feature of human Salmonellosis. Surprisingly, CBA mice fed AA diet developed ileitis with enhanced S. Tm ileal colonization. Using germ-free mice and ileal-fecal slurry transplant, we found diet-mediated S. Tm ileal expansion to be microbiota-dependent. Mechanistically, S. Tm relied on Fructosyl-asparagine utilization to expand in the ileum during infection. We demonstrate how AA diet overrides host genetics by altering the gut microbiotas ability to prevent S. Tm ileal colonization.

microbiology↗

bioRxiv2023

Turicibacterales protect mice from severe Citrobacter rodentium infection

One of the major contributors to child mortality in the world is diarrheal diseases, with an estimated 800,000 deaths per year. Many pathogens are causative agents of these illnesses, including the enteropathogenic (EPEC) or enterohemorrhagic (EHEC) forms of Escherichia coli. These bacteria are characterized by their ability to cause attaching and effacing lesions in the gut mucosa. Although much has been learned about the pathogenicity of these organisms and the immune response against them, the role of the intestinal microbiota during these infections is not well characterized. Infection of mice with E. coli requires pre-treatment with antibiotics in most mouse models, which hinders the study of the microbiota in an undisturbed environment. Using Citrobacter rodentium as a murine model for attaching and effacing bacteria, we show that C57BL/6 mice deficient in granzyme B expression are highly susceptible to severe disease caused by C. rodentium infection. Although a previous publication from our group shows that granzyme B-deficient CD4+ T cells are partially responsible for this phenotype, in this report we present data demonstrating that the microbiota, in particular members of the order Turicibacterales, have an important role in conferring resistance. Mice deficient in Turicibacter sanguinis have increased susceptibility to severe disease. However, when these mice are co-housed with resistant mice, or colonized with T. sanguinis, susceptibility to severe infection is reduced. These results clearly suggest a critical role for this commensal in the protection against entero-pathogens.

microbiology↗