Lactobacillus is a probiotic with therapeutic potential for several diseases, including
liver disease. However, the
therapeutic effect of L. plantarum against
nonalcoholic steatohepatitis (NASH) and its underlying mechanisms remain unelucidated. Therefore, we delineated the L. plantarum-mediated NASH regulation in a mouse model to understand its
therapeutic effect. We used a
choline-deficient high-fat diet (CD-HFD)-induced murine model that recapitulated the critical features of human
metabolic syndrome and investigated the effect of L. plantarum on NASH pathogenesis using transcriptomic, metagenomic, and immunohistochemistry analyses. Validation experiments were performed using liver organoids and a murine model fed a
methionine-
choline-deficient (MCD) diet. L. plantarum treatment in mice significantly decreased liver
inflammation and improved metabolic phenotypes, such as
insulin tolerance and the hepatic
lipid content, compared with those in the vehicle group.
RNA-sequencing analysis revealed that L. plantarum treatment significantly downregulated
inflammation-related pathways. Shotgun metagenomic analysis revealed that
L-arginine biosynthesis-related microbial genes were significantly upregulated in the L. plantarum group. We also confirmed the elevated
arginine levels in the serum of the L. plantarum group. We further used liver organoids and mice fed an MCD diet to demonstrate that
L-arginine alone was sufficient to alleviate liver
inflammation. Our data revealed a novel and counterintuitive
therapeutic effect of L. plantarum on alleviating NASH-related liver
inflammation by increasing circulating
L-arginine.