Gut microbial metabolites restore hormone-producing cells in obesity

New research from scientists at the Marshall University Joan C. Edwards School of Medicine reveals that certain gut microbial byproducts may hold promise as a novel therapy for obesity-associated metabolic complications by restoring critical hormone-producing cells in the intestine. 

The study, published this month in the International Journal of Molecular Sciences, focuses on enteroendocrine cells (EECs)-specialized cells in the gut that play a key role in metabolic regulation by releasing hormones such as glucagon-like peptide-1 (GLP-1), which stimulate insulin secretion and suppress appetite. In obesity, these cells are diminished in number and function, contributing to insulin resistance and poor metabolic health. 

Researchers investigated how microbial metabolites derived from dietary tryptophan-an amino acid found in protein-rich foods-may help restore EEC numbers. Specifically, they studied the effects of indole, a key tryptophan metabolite produced by gut bacteria, on intestinal stem cell differentiation into EECs. 

Using a combination of human intestinal organoids, known as "mini-gut", and rat models, the research team discovered that obesity led to a significant drop-about 60%-in the number of hormone-producing cells in the intestines. However, when human gut organoids were treated with indole or with the culture medium of a probiotic bacterial strain grown in tryptophan, the number of these cells more than doubled. This effect was blocked when a specific cell receptor called the aryl hydrocarbon receptor (AhR) was turned off, suggesting this pathway plays a key role in the process. 

Our findings suggest that microbial metabolites derived from dietary tryptophan can reverse obesity-associated reductions in hormone-secreting gut cells. This points to a potential therapeutic strategy that leverages the gut microbes to improve metabolic outcomes in obesity." 

Alip Borthakur, Ph.D., assistant professor of biomedical sciences at the Joan C. Edwards School of Medicine and principal investigator and corresponding author on the study

The study provides foundational evidence supporting the development of microbiota-targeted interventions-such as probiotic or dietary approaches-to boost incretin hormone production to improve glucose metabolism and regulate appetite in people with obesity. 

In addition to Borthakur, the study's co-authors include: undergraduate student Morrison Chicko, graduate students James Hart and Hassan Mansour, doctoral student Harshal Sawant and faculty members Subha Arthur, Ph.D., and Jennifer Haynes, Ph.D.

"It has been exciting to mentor four enthusiastic, intelligent, curious and dedicated Marshall students at different times of the study," Borthakur said. "They were thrilled to use the 'mini gut' model, a 3D human intestinal organoid model that truly represents the architecture and compositional complexity of the native human gut." 

This study was supported by National Institutes of Health funding from the National Institute of Allergy and Infectious Diseases (NIAID): (AI130790-03) and National Institute of General Medical Sciences (NIGMS) (Project #4 of COBRE: P20 GM 121299-05) to Dr. Borthakur.