Dietary Bacteriophage Administration Alleviates Enterotoxigenic Escherichia coli-Induced Diarrhea and Intestinal Impairment through Regulating Intestinal Inflammation and Gut Microbiota in a Newly Weaned Mouse Model

This study aimed to investigate the effects of dietary bacteriophage administration on diarrhea and intestinal impairment induced by enterotoxigenic <i>Escherichia coli</i> (ETEC) in a newly weaned mouse model. Forty-four newly weaned C57BL/6 mice were divided into four treatment groups, where they were provided either the control diet or the bacteriophage-supplemented diet, with or without ETEC infection. The results show that the bacteriophage administration resulted in increased body weight, decreased diarrhea score, and improved jejunal histopathology in ETEC-infected mice. The bacteriophage administration enhanced the intestinal barrier function of the ETEC-infected mice, as indicated by the reduced serum DAO level and the increased expression of Claudin-1, Occludin, and ZO-1 at both the mRNA and protein levels in the jejunum. Also, the bacteriophage administration resulted in a decrease in serum TNF-α and IL-1β levels, a down-regulation of <i>TNF-α</i> and <i>IL-6</i> mRNA levels in the jejunum, and the inhibition of jejunal TLR-4/NF-κB pathway activation induced by ETEC infection. Moreover, the bacteriophage administration increased the levels of acetic acid, propionic acid, butyric acid, and total short-chain fatty acids in the caecum content. The bacteriophage administration increased the Shannon index, increased the abundance of <i>Bacteroidota</i> and <i>Muribaculaceae</i>, and decreased the abundance of <i>Verrucomicrobiota</i> and <i>Akkermansiaceae</i> in the colon contents of the ETEC-infected mice. Spearman's correlation analysis indicates that the protective effects of bacteriophage on ETEC-induced intestinal impairment, inflammation, and intestinal barrier function are associated with regulating the abundance of <i>Bacteroidota</i> and <i>Muribaculaceae</i> in the colon contents of mice. Collectively, bacteriophage administration alleviates ETEC-induced diarrhea and intestinal impairment through regulating intestinal inflammation and gut microbiota in newly weaned mice.