A High-Salt Diet Promotes Colitis by Remodeling the Gut Microbiota Toward a Virulent, Osmotolerant State
Excessive salt intake perturbs the gut microbiota and is implicated in the rising prevalence of chronic inflammatory diseases. The precise effects of high-salt diets (HSDs) on the luminal electrolyte profile, the gut microbiome, and subsequent susceptibility to intestinal inflammation, however, remain poorly defined. Here, leveraging a treatment-naïve cohort, we show that patients with Crohn's disease (CD) exhibit a distinct fecal electrolyte profile characterized by elevated Na+ and reduced K+, that correlates with gut and systemic inflammation markers. By systematically profiling halophilic/halotolerant microbial groups and their associated functional genes, we found that the gut microbiome of CD patients is characterized by a parallel enrichment of halophilic archaea, salt-stress response genes, and halotolerant opportunistic pathogens, as demonstrated through integrated metagenomic and culture-based analyses. Using in vivo fecal microbiota transplantation and mono-strain inoculation, we demonstrate that a high Na+ luminal environment drives microbial adaptation toward salt tolerance, amplifies virulence at both the community and single-strain levels, and ultimately exacerbates colitis. Collectively, our findings elucidate a mechanism by which HSDs exacerbate intestinal colitis through microbiome community restructuring and identify the gut microbiota as a promising therapeutic target for mitigating salt-associated chronic inflammatory diseases.