Phuah, P. | bioRxiv Science

bioRxiv2025

The microbial tryptophan metabolite indole acts on the gastrointestinal tract to improve glucose homeostasis by enhancing GLP-1 secretion and L-cell differentiation

Aims/hypothesisGrowing evidence implicates gut microbiota-derived metabolites in metabolic homeostasis. Indole, a microbial tryptophan metabolite, has been reported to enhance Glucagon-like peptide-1 (GLP-1) secretion in vitro, and its derivatives have been inversely associated with risk of type 2 diabetes (T2D). We hypothesised that indole acts via the gastrointestinal tract to modulate glucose homeostasis, and aimed to test this hypothesis using in vitro and in vivo models. MethodsThe acute effects of indole on GLP-1 secretion in vitro, and on glucose tolerance and hormone secretion in mice, were determined. Subsequently, the effects of indole on intestinal epithelial cell fate and L-cell differentiation in murine ileal organoids and in vivo were studied. Finally, the utility of chronic indole administration in a murine model of T2D was explored. ResultsIndole stimulated in vitro GLP-1 secretion in a concentration-dependent manner, and improved acute glucose control in vivo. Additionally, we demonstrate that indole drives enteroendocrine L-cell differentiation in murine ileal organoids, resulting in increased L-cell density and longer-term glucoregulatory benefits in vivo. Finally, sub-chronic indole administration improved glucose tolerance and insulin sensitivity in diabetic mice. Conclusions/interpretationOur findings identify indole as an anti-diabetic molecule that acts on the gut, and raise the possibility of incorporating indole into nutraceutical supplements to aid in the treatment or prevention of T2D. This highlights the importance of gut microbiota-derived metabolites in metabolic health and opens new avenues for developing novel strategies to combat T2D. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIGut microbiota-derived metabolites play a role in metabolic homeostasis. C_LIO_LIIndole, a microbial tryptophan metabolite, enhances GLP-1 secretion in vitro. C_LIO_LIIndole derivatives are inversely associated with type 2 diabetes (T2D) risk. C_LI What is the key question?O_LIDoes indole act on the gut to modulate glucose homeostasis? C_LI What are the new findings?O_LIIndole stimulates GLP-1 secretion and improves acute glucose control in vivo. C_LIO_LIIndole drives enteroendocrine L-cell differentiation in murine ileal organoids, increasing L-cell density and long-term glucoregulatory benefits. C_LIO_LISub-chronic indole administration improves glucose tolerance and insulin sensitivity in mice with type 2 diabetes, showing the potential of gut microbiota-derived metabolites as therapeutic targets. C_LI How might this impact clinical practice in the foreseeable future?O_LIIndole could be incorporated into nutraceutical supplements for T2D prevention or treatment. C_LI

physiology↗

bioRxiv2025

NodoMap: a spatio-cellular map of the mouse nodose ganglia

The vagus nerve is a key component of the parasympathetic nervous system, innervating multiple abdominal organs to monitor and regulate their function. It forms the main neural pathway between the gastrointestinal tract and the brain, playing a major role in the regulation of energy homeostasis. The cell bodies for vagal sensory neurons reside in the nodose ganglia, with the left and right ganglia reported to have distinct roles in food intake and reward. Here, we have integrated our own single nucleus RNA sequencing data with multiple publicly available datasets to create a database of 108,482 nuclei and cells, and combined this with spatial transcriptomics to present a spatio-cellular transcriptional map of the mouse nodose ganglia, the NodoMap. Nodose ganglia neuronal cells clustered into twenty-two different subtypes, all found in both left and right nodose ganglia, but with significant differences in gene expression between left and right ganglia across multiple neuronal subtypes. Overnight fasting modulated gene expression across specific neuronal subtypes, including nutrient responsive pathways. Spatial transcriptomics showed that while vagal neuronal types were highly interspersed, patterns of organisation into cellular neighbourhoods could be observed, with neighbourhoods identified of predominantly non-neuronal cells and of different neuronal populations accompanied by glial-like cells. Thus, NodoMap provides a detailed atlas of the mouse nodose ganglia in a spatial context, providing a platform for vagovagal neurocircuit analysis, and serving as an important resource to identify targets for pharmacotherapies for metabolic disease.

physiology↗

bioRxiv2025

Enteropancreatic neurons drive the glucoregulatory response to ingested lipid

Enteropancreatic neurons project from the small intestinal wall to the pancreas. Though well positioned to mediate the effects of ingested nutrients on pancreatic function, the metabolic role of these neurons is unclear. Diets rich in olive oil promote weight loss and improve remission rates in patients with T2DM. Here, we show that olive oil improves acute glucose tolerance by stimulating insulin release via neurotensin receptor type 1 (NTSR1)-expressing enteropancreatic neurons. These neurons are necessary for the effects of olive and neurotensin on glucose tolerance, and their activation is sufficient to improve glucose tolerance. These findings suggest a mechanism by which dietary olive oil regulates blood glucose levels and present a novel functional role for enteropancreatic neurons in regulating glucose homeostasis.

physiology↗