Lactobacillus sp. for the Attenuation of Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice

Abstract

Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD.

Keywords: Lactobacillus; MASLD; dysbiosis; liver disease; probiotic; steatosis.

Figure 1

Progression and pathogenesis of MASLD. (A). MASLD is a progression of liver disorders beginning with steatosis that can result from obesity or other consequences of metabolic syndrome. Steatosis can progress to inflammatory steatohepatitis due to oxidative stress, inflammatory cytokines, or lipotoxicity in the liver. Both steatosis and hepatitis are considered reversible conditions, though a subset of patients may progress to irreversible cirrhosis or hepatocellular carcinoma (HCC). (B). The “two-hit” hypothesis proposed that MASLD progressed first as steatosis due to insulin resistance, followed by inflammatory hits that led to hepatitis and fibrosis. The “multiple-hit” hypothesis recognizes that MASLD progression may involve simultaneous factors, including excessive lipid accumulation, oxidative stress, inflammation, and mitochondrial dysfunction, as well as gut microbe products, epigenetic factors, and lifestyle.

Figure 2

Physiological changes to the intestinal barrier in MASLD. (Left) In a healthy gut, tight junction proteins (JAM, Occludin, and Claudin) maintain the intestinal barrier and prevent pathogenic infiltration into enterocytes, while bile acid content is maintained through a bi-directional relationship with the gut microbiota. (Right) In MASLD, tight junctions are disrupted and may allow pathogenic invasion that releases systemic LPS. Bile acid content may be increased, and composition may be altered, in part due to dysbiosis resulting from loss of biodiversity of the microbiota.

Figure 3

Mechanism of action of Lactobacillus spp. Lactobacillus spp. ferments dietary fibers to produce SCFAs, SCFAs can activate AMPK, enhance fatty acid oxidation and improve insulin sensitivity. Steatosis is reduced through the inhibition of key lipogenic enzymes. Lactobacillus spp. competitively excludes opportunistic pathogens and restrains their attachment to the epithelium by producing metabolites like lactic acid, hydrogen peroxide, and bacteriocins and competing with binding sites with these pathogens. Lactobacillus strains strengthen the gut barrier by enhancing mucus production that prevents the translocation of harmful bacteria and toxins into the bloodstream. These strains also bind to epithelial cells to activate immune cells, including dendritic cells and macrophages, to produce anti-inflammatory cytokines like IFNγ and IL10. Finally, Lactobacillus MAMPs bind to TLRs, leading to modulation of NF-κB, which is involved in immune and inflammatory responses.