Assessment of Gut Microbiota-Derived Amino Acid Metabolite Production in Patients With MASLD

Summary

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver disorders ranging from simple steatosis-a relatively benign and non-progressive condition-to metabolic dysfunction-associated steatohepatitis (MASH), characterized by hepatocellular inflammation. MASLD is now the leading cause of chronic liver disease worldwide, affecting approximately one in three adults, particularly those with obesity or type 2 diabetes. Recent studies have highlighted a strong interconnection between the gut microbiota, the liver, metabolism, and the immune system, collectively referred to as the gut-liver axis. Alterations in the gut microbiota are observed at all stages of MASLD, and several microbial metabolites-such as trimethylamine, bile acids, short-chain fatty acids, and ethanol-have been implicated in disease progression. Emerging evidence points to a role for gut-derived metabolites of tryptophan (Trp) and phenylalanine (Phe), including phenylacetic acid (PAA), 3-(4-hydroxyphenyl)-lactate (HPL), and phenyllactate (PL). These compounds have been associated with the severity of MASLD, particularly with hepatic steatosis and fibrosis. Elevated plasma levels of aromatic amino acids (AAAs), such as L-phenylalanine and L-tyrosine, are also correlated with increased hepatic fat content. A newly identified Phe-derived metabolite, N-acetyl-phenylalanine (NAPA), together with PAA, HPL, and PL, has been shown to correlate with hepatic steatosis. These metabolites can induce steatosis both in vitro and in vivo, acting through the disruption of endoplasmic reticulum-mitochondria interactions. They therefore represent potential new therapeutic targets. These four metabolites of interest (NAPA, PAA, HPL, PL) can be produced both by gut bacteria and through endogenous human metabolism. Positive correlations between plasma NAPA concentrations and specific bacterial species have been observed, although the responsible taxa remain to be identified. HYPOTHESIS We hypothesize that the gut microbiota of MASLD patients produces aromatic amino acid-derived metabolites, contributing to the elevated plasma concentrations observed in these patients Two complementary strategies will be used : Human Microbiota Culture and Fecal Microbiota Transplantation

Eligibility

Inclusion Criteria:

* For patients and healthy volunteers:

  * Age between 18 and 80 years.
  * Non-diabetic participant (fasting blood glucose \< 1.26 g/L, or absence of insulin therapy or oral antidiabetic medication).
  * Body mass index (BMI) between 18 and 30 kg/m².
  * For women of childbearing potential, use of at least one recognized effective contraceptive method.
  * Very regular bowel movements every 24 to 48 hours.
  * Participant living within 100 km of the Lyon Sud Hospital Center (CHLS).
  * Participant willing to participate in the study and providing written informed consent.
  * Participant affiliated with the general French Social Security system or an equivalent scheme.
* For patients:

  * Presence of MASLD according to the definition of the European Association for the Study of the Liver (EASL), defined by hepatic steatosis on imaging performed within the previous year (abdominal ultrasound, abdominal CT scan, magnetic resonance imaging, or controlled attenuation parameter (CAP) measured by FibroScan) and at least one cardiometabolic criterion among: dyslipidemia, arterial hypertension, overweight (BMI ≥ 25 kg/m²), impaired glucose tolerance, or type 2 diabetes.
  * No history of liver transplantation.
  * No excessive alcohol consumption (less than 20 g/day for women and less than 30 g/day for men).
  * Patient followed in the Endocrinology, Diabetes and Nutrition Department at Lyon Sud Hospital.

Exclusion Criteria:

* For patients and healthy volunteers:

  * Participant with active inflammatory, infectious, cardiovascular, or neoplastic disease.
  * Participant with a history of colectomy, small bowel resection, or cholecystectomy.
  * Participant who received antibiotics, prebiotics, or probiotics within the past 3 months.
  * Participant using laxatives (more than 2 doses per day over the past 3 months).
  * Participant with chronic constipation.
  * Pregnant, parturient, or breastfeeding women.
  * Participant deprived of liberty by judicial or administrative decision.
  * Participant receiving psychiatric care.
  * Participant institutionalized for reasons other than research.
  * Adult participant under legal protection (guardianship or trusteeship).
  * Participant who does not understand the French language and cannot provide informed consent.
  * Participant already enrolled in a study presenting a conflict of interest with the present study.
* For healthy volunteers

  * Known liver disease
  * No long-term drug medication except oral contraception for women.

Conditions3

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