<em>Lactobacillus acidophilus</em> Attenuates Ulcerative Colitis by Strengthening Intestinal Barrier Integrity and Modulating Microbiota-Immune Crosstalk

As a chronic idiopathic inflammatory disease that occurs primarily in the gastrointestinal tract, the cure rate for ulcerative colitis (UC) has been very low. UC has become a global public health issue with increasing incidence and recognition. Therefore, finding safe and effective drugs to treat UC is urgent. Meanwhile, different probiotics have demonstrated beneficial effects on this condition, thus increasing the interest in developing probiotic treatments. This study investigated the potential therapeutic effects of a novel <em>L. acidophilus </em>strain isolated from porcine guts on UC using a dextran sodium sulfate (DSS) induced mouse model. Treatment with <em>L. acidophilus </em>considerably alleviates colitis progression and restores the expression of intestinal barrier structures and functional proteins. Furthermore, the <em>L. acidophilus</em> increased the abundance of the symbiotic bacteria <em>norank_f__Muribaculaceae</em> and <em>norank_f__norank_o__Clostridia_UCG-014</em> while decreasing that of pathogenic <em>Escherichia-Shigella</em> to modulate directly microbial homeostasis. Mechanistically, the <em>L. acidophilus</em> largely regulates the expression of key regulatory proteins of TLR4/NF-κB, Nrf2/Keap1 and NLRP3/caspase-1 signaling pathways in colon tissue and regulates bile acid metabolism. Especially, <em>L. acidophilus</em> not only maintains the integrity of the intestinal barrier by upregulating the expression of tight junction proteins (TJPs), reduces metabolic endotoxemia, thereby inhibiting the activation of inflammatory signaling pathways and alleviating pathological symptoms such as damage to colonic epithelial cells and infiltration of inflammatory cells, but also modulates bile acid synthesis via the FXR/FGF15 signaling pathway, thus regulating the levels of cytokines and immune cell differentiation. In addition, microbiome phenotype prediction and bacterial functional potential prediction analysis demonstrated that the <em>L. acidophilus</em> supplementation<strong> </strong>regulated gut microbiota function involving inflammatory<strong> </strong>injury, metabolism, immune response, and pathopoiesia. Intriguingly, the <em>L. acidophilus</em> treatment restored the proportion of Th1/Th2 cells and Th17/Treg cells and the expression of specific inflammatory factors to maintain the immune balance, especially in intestinal epithelial cells. In conclusion, our results revealed that this novel <em>L. acidophilus</em><em> </em>may have anti-inflammatory, antioxidant stress, anti-pyroptosis, regulation of bile acid metabolism, alleviation of endothelial dysfunction and intestinal dysbiosis effects, and it shows comparable efficacy to mesalazine in alleviating the pathological symptoms of UC mice. These findings provide theoretical guidance for the clinical treatment of <em>L. acidophilus</em> and pave the way for further exploration of its interaction with host immunity.