Development of Microbial Therapeutics for Metabolic-associated Fatty Liver Disease: From Mechanistic Investigations to Clinical Trials

Overview

The goal of this clinical trial is to investigate the efficacy and safety of pasteurized Akkermansia muciniphila strain NTUH\_Amuc03 (pAKK NTUH\_Amuc03) in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)Patients. The main question it aims to answer is: Does pAKK NTUH\_Amuc03 trend to reduce the body weight, improve abnormal blood lipids , NASLD activity score, and HOMA-IR ? Researchers will compare pAKK NTUH\_Amuc03 to a placebo (a look-alike substance that contains no Akk) to see if pAKK NTUH\_Amuc03 works to MASLD. Participants will: 1. Take capsule with pAKK NTUH\_Amuc03 or a placebo every day for 3 months 2. Visit the clinic once every 4 weeks for checkups and tests

Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)is an improved diagnostic standard derived from Non-Alcoholic Fatty Liver Disease (NAFLD), emphasizing the correlation between fatty liver and metabolic dysfunction. Compared to NAFLD, which requires the exclusion of various conditions for diagnosis, the diagnostic criteria for MASLD can enhance the homogeneity of study subjects. It also addresses various groups with coexisting liver diseases, aiding in the efficiency and applicability of new drug development. MASLD has a prevalence rate of approximately one-fourth of the global population. If left untreated and worsens, it may lead to liver fibrosis, cirrhosis, or even liver cancer. Due to the significant medical burden associated with MASLD and the lack of FDA-approved treatments, the development of therapeutic methods for MASLD is an urgent issue. Past literature indicates that diet and gut microbiota play crucial roles in the progression of MASLD. The composition of the diet affects gut microbiota and intestinal barrier function. In cases of dysbiosis, harmful substances produced by gut microbiota, including pathogen-associated molecular patterns (PAMPs) and microbiota-dependent metabolites (MDMs), enter the liver through the portal vein via the leaky gut, resulting in toxicity. The pathogenic pathways exacerbating MASLD through gut microbiota dysbiosis, collectively termed the gut-liver axis, are not fully understood. Some animal studies have found dietary supplements to regulate gut microbiota beneficial for improving MASLD. Although most lack clinical evidence, incorporating food components that regulate gut microbiota and immune function into the diet indeed holds potential for treating MASLD. Next-generation probiotics have been found in past studies to improve liver lipid metabolism and regulate gut microbiota. They may slow the progression of MASLD by modulating the gut-liver axis. Previous studies by our team applied the pasteurized Akkermansia muciniphila strain NTUH\_Amuc03 (pAKK NTUH\_Amuc03), in preclinical animal studies to alleviate fatty liver disease progression. In experiments with mice induced with high-fat, high-fructose, high-cholesterol diets, pAKK NTUH\_Amuc03 trended to reduce the body weight, improve abnormal blood lipids in mice, NASLD activity score, and HOMA-IR. These results indicate the potential of pAKK NTUH\_Amuc03 to slow the progression of MASLD. Therefore, this project aims to further evaluate the efficacy and safety of pAKK NTUH\_Amuc03 in MASLD patients through clinical trials.