Postbiotic gut bacteria site-specific immunomodulators improve liver steatosis, inflammation, and fibrosis in obese mice with MASLD

Obesity promotes metabolic dysfunction-associated steatotic liver disease (MASLD). Gut microbiota can influence MASLD through local communication between the gut and liver. Bacterial components are often conceptualized only as contributors to chronic inflammation. However, certain postbiotics can protect against chronic inflammation and dysmetabolism by activating specific immune responses during obesity. Site-specific innate immune training can direct compartmentalized immune responses. We hypothesized that site-specific immunomodulation by gut-derived inactivated bacterial-based stimuli (i.e., postbiotics) would improve features of MASLD. We found that biweekly subcutaneous injections of an inactivated bacterial preparation of a gut bacterium (QBECO from <i>Escherichia coli</i>) improved markers of steatosis, inflammation, and fibrosis indicative of MASLD in obese mice. QBECO lowered liver mass, triglycerides, F4/80 macrophages, eosinophil peroxidase activity, and collagen content in the liver without altering food intake or body mass in obese mice. QBECO increased whole body lipid oxidation without altering total energy expenditure in obese mice. QBECO had an immunomodulatory effect that lowered liver eosinophil peroxidase activity, lowered liver nitrite/arginase ratio, and increased CD163 positive cells, a marker of M2 macrophages in the liver of obese mice. We confirmed that multiple gut bacteria-derived postbiotics improved MASLD as injections of an inactivated bacterial preparation of <i>Proteus mirabilis</i> (QBPMI) also lowered markers of steatosis, inflammation, and fibrosis in obese mice. A postbiotic from <i>Klebsiella variicola</i> (QBKPN), a bacterium typically pathogenic outside the gut, did not alter MASLD in obese mice. Therefore, site-specific immunomodulators derived from gut bacteria can improve the hallmarks of MASLD without causing weight loss.<b>NEW & NOTEWORTHY</b> This study demonstrates that site-specific immunomodulators (SSIs), prepared from inactivated bacteria, can attenuate liver steatosis, inflammation, and fibrosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Gut bacteria-derived SSIs improved hallmarks of MASLD without altering body weight or food intake, but an SSI derived from a bacterium typically pathogenic outside the gut did not alter MASLD. Therefore, gut-derived SSI postbiotics can improve MASLD.