Association of Intestinal Barrier Damage and Mucosal Microbiota Dysbiosis with the TLR4/NF-κB Pathway in High-Salt Diet-Induced Hypertensive Rats
Abstract
Background: A high-salt diet is a major risk factor for hypertension, but the role of the intestinal mucosal microbiota and the dysfunction of the intestinal barrier remain to be explored. Methods: Wistar rats were fed a normal diet (OF) and a high-salt diet (HSF) for 33 days to establish hypertension. Serum NO and TNF-α levels were quantified by enzyme-linked immunosorbent assay (ELISA). Histopathological changes in the intestine and vasculature were evaluated by hematoxylin and eosin (HE) staining. Immunofluorescence staining was employed to further assess intestinal barrier damage by detecting the expression levels of the tight junction proteins Claudin-1, Occludin, and ZO-1. Results: Mucosal microbiota was analyzed via 16S rRNA sequencing. TLR4/NF-κB pathway activation was analyzed by RT-qPCR and Western blot (WB). HSF rats developed hypertension with significant intestinal barrier damage, characterized by villus autolysis and reduced Claudin-1 and ZO-1 expression. High-salt intake significantly inhibited the growth of beneficial bacteria including Brevibacterium sp. RHS-str. 520 and Levilactobacillus brevis, while promoting harmful species such as Streptococcus mitis and Nodosilinea nodulosa. Correlation analyses showed that the species-level key differential bacteria including Levilactobacillus brevis and Eubacterium tenue were negatively correlated with both intestinal TNF-α protein expression and blood TNF-α levels. Mechanistically, a high-salt diet activated the intestinal TLR4/NF-κB pathway, upregulating TLR4, MyD88, p-P65, and TNF-α protein expression (p < 0.05). Conclusions: Collectively, these findings suggest that a high-salt diet may affect the intestinal mucosal microbiota, trigger TLR4-mediated intestinal inflammation, and impair the mucosal barrier, ultimately driving hypertension via an intestinal mucosal barrier–inflammation–blood pressure axis.