A High-Salt Diet Promotes Colitis by Remodeling the Gut Microbiota Toward a Virulent, Osmotolerant State

Background Excessive dietary salt disrupts the gut microbiota and is increasingly recognized as a contributor to the rising prevalence of chronic inflammatory diseases. In Crohn’s disease (CD), Western dietary patterns and gut microbiome dysbiosis are well‑established drivers of disease incidence. Identifying modifiable dietary factors, such as high salt intake, is therefore critical for developing improved preventive and therapeutic strategies. However, 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. Results Using a treatment‑naïve cohort, we show that CD patients exhibit a distinct fecal electrolyte profile characterized by elevated Na⁺ and reduced K⁺, which correlates with markers of both gut and systemic inflammation. Relative and absolute quantification further reveal increased abundance of the halophilic archaeon Halorubrum and a corresponding decrease in Methanobrevibacter . Systematic profiling of salt‑stress associated functional genes, including those involved in K⁺ transport, compatible solute transport and biosynthesis, revealed that the CD gut microbiome is enriched with salt stress response genes. A similar enrichment trend was observed in industrialized populations compared to the Hadza hunter‑gatherer communities. Phylogenetic and growth assays demonstrated that these genetic determinants are more prevalent in opportunistic pathogens, which consequently exhibit greater resistance to growth inhibition under high Na⁺ conditions. Indeed, using high‑salt selective media, we isolated salt‑tolerant opportunistic pathogens from colonic biopsies of CD patients. Through in vivo fecal microbiota transplantation, we demonstrate that a high‑Na⁺ adapted microbial community exacerbates colitis. Salt tolerance and its associated pathogenicity vary across strains. The E. coli CD09 isolate from CD patients exhibited greater salt tolerance than the model strain E. coli MG1655, and mice inoculated with CD09 developed more severe colitis. Conclusions Collectively, our findings elucidate a mechanism by which HSDs exacerbate intestinal colitis through restructuring of the gut microbial community. 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. Thus, the gut microbiota represents a promising therapeutic target for preventing and mitigating salt‑associated chronic inflammatory diseases.