Developing Microbial Therapy for MASLD: From Mechanism to Clinical Validation

Official title

Development of Microbial Therapeutics for Metabolic Dysfunction-Associated Steatotic Liver Disease: From Mechanistic Investigations to Clinical Trials

Overview

Metabolic dysfunction-associated steatotic liver disease (MASLD), redefined in 2020, is an improved diagnostic standard evolved from non-alcoholic fatty liver disease (NAFLD), emphasizing the correlation between hepatic steatosis and metabolic dysfunction. Compared to NAFLD, which relies on exclusion-based diagnosis, MASLD criteria enhance population homogeneity in studies and accommodate patients with coexisting liver diseases, thereby improving the efficiency and relevance of drug development. MASLD affects approximately one-quarter of the global population. If left untreated, it may progress to liver fibrosis, cirrhosis, or hepatocellular carcinoma. Given its high clinical burden and the current lack of FDA-approved therapies, effective treatments for MASLD are urgently needed. Previous studies suggest that diet and gut microbiota play crucial roles in the pathogenesis of MASLD. Dietary composition influences microbial balance and intestinal barrier function. In dysbiosis, gut-derived harmful substances such as pathogen-associated molecular patterns (PAMPs) and microbiota-derived metabolites (MDMs) may translocate via a leaky gut to the liver through the portal vein, contributing to hepatic injury. These processes, often described as the gut-liver axis, remain incompletely understood. Animal studies have shown that dietary components regulating gut microbiota may help alleviate MASLD. While clinical evidence remains limited, incorporating microbiota-modulating and immune-regulating food ingredients holds potential. Next-generation probiotics have demonstrated benefits in improving hepatic lipid metabolism and modulating gut microbiota, potentially slowing MASLD progression through gut-liver axis modulation. Our previous research investigated a pasteurized Akkermansia muciniphila strain, NTUH\_Amuc03 (pAKK\_LWHK0003), which attenuated fatty liver progression in preclinical models. In mice subjected to a high-fat, high-fructose, high-cholesterol diet, pAKK\_LWHK0003 administration resulted in reduced body weight, improved dyslipidemia, lowered NAFLD activity scores, and improved HOMA-IR. These findings support the potential of pAKK\_LWHK0003 in slowing MASLD progression. This study aims to evaluate further the clinical efficacy and safety of pAKK\_LWHK0003 in individuals with MASLD.

Detailed description

The aim of this study was to evaluate the effects of administering indigenously derived inactivated Akkermansia muciniphila (pAKK\_LWHK0003) on improving fatty liver in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and to assess its clinical safety.

Interventions

• Biological Pasteurized Akkermansia muciniphila LWHK0003_low dose
  400 mg/capsule/days. Duration: 120 days
• Biological Pasteurized Akkermansia muciniphila LWHK0003_medium dose
  400 mg/capsule/day. Duration: 120 days
• Biological Pasteurized Akkermansia muciniphila LWHK0003_high dose
  400 mg/capsule/day. Duration: 120 days
• Other Placebo
  400 mg/capsule/day. Duration: 120 days

Primary outcome measures

• Liver steatosis, fibrosis, liver stiffness, and FIB-4 index [Time frame: From enrollment to the end of treatment, up to 52 weeks]

Eligibility criteria

Inclusion criteria

• Fibroscan，CAP ≧ 260db/m

Exclusion criteria

A. Pregnant women or women who are breastfeeding. B. Use of probiotics and prebiotic-related products (including yogurt, yogurt, Yakult, etc.) within 14 days before the screening visit.

C. Patients who have used antibiotics (except skin lotions) or antifungal drugs within 30 days before the screening visit.

D. Use of glucagon-like peptide-1 receptor agonists (GLP1-RAs) within six months prior to the screening visit.

E. Use of drugs that may affect the evaluation index within 14 days before the screening visit, during the screening visit, or during the planned trial period, such as steroids, immunosuppressants, or anti-inflammatory drugs, or drugs containing ingredients for treating hepatitis or affecting fat metabolism, including HMG-CoA reductase inhibitors (statins), fibrates, silymarin, thiazolidinediones, metformin, cholestyramine, ezetimibe, orlistat, and sodium-glucose transporter type 2 inhibitors (SGLT2i). This restriction does not apply if the above-mentioned drugs have been used continuously for more than six months and the dosage is not changed during the trial.

F. Those who have had severe gastrointestinal infection diarrhea symptoms within 14 days before the screening visit (more than three watery stools in 24 hours).

G. Have the following medical history or laboratory abnormalities:

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Taiwan · 1 center

• National Taiwan University Hospital — Taipei

Identifiers

NCT: NCT07488975 · LL-IRB-2403

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗