Breed-Driven Microbiome Heterogeneity Regulates Intestinal Stem Cell Proliferation via Lactobacillus-Lactate-GPR81 Signaling.

2024-06-27
Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11(33)

PubMed: 38937989
DOI: 10.1002/advs.202400058

Study Design

Population: pigs of genetically distinct breeds (obese Meishan and lean Yorkshire)
Methods: Employing pigs of genetically distinct breeds (obese Meishan and lean Yorkshire); experiments using in-house developed porcine jejunal organoids; live L. amylovorus and its metabolite lactate were tested, and heat-killed L. amylovorus was compared

Animal Study

Genetically lean and obese individuals have distinct intestinal microbiota and function. However, the underlying mechanisms of the microbiome heterogeneity and its regulation on epithelial function such as intestinal stem cell (ISC) fate remain unclear. Employing pigs of genetically distinct breeds (obese Meishan and lean Yorkshire), this study reveals transcriptome-wide variations in microbial ecology of the jejunum, characterized by enrichment of active Lactobacillus species, notably the predominant Lactobacillus amylovorus (L. amylovorus), and lactate metabolism network in obese breeds. The L. amylovorus-dominant heterogeneity is paralleled with epithelial functionality difference as reflected by highly expressed GPR81, more proliferative ISCs and activated Wnt/β-catenin signaling. Experiments using in-house developed porcine jejunal organoids prove that live L. amylovorus and its metabolite lactate promote intestinal organoid growth. Mechanistically, L. amylovorus and lactate activate Wnt/β-catenin signaling in a GPR81-dependent manner to promote ISC-mediated epithelial proliferation. However, heat-killed L. amylovorus fail to cause these changes. These findings uncover a previously underrepresented role of L. amylovorus in regulating jejunal stem cells via Lactobacillus-lactate-GPR81 axis, a key mechanism bridging breed-driven intestinal microbiome heterogeneity with ISC fate. Thus, results from this study provide new insights into the role of gut microbiome and stem cell interactions in maintaining intestinal homeostasis.

Research Insights

Supplement	Dose	Health Outcome	Effect Type	Effect Size	Source
Lactobacillus amylovorus	—	Activated Wnt/Beta-Catenin Signaling	Beneficial	Moderate	View source The L. amylovorus-dominant heterogeneity is paralleled with epithelial functionality difference as reflected by highly expressed GPR81, more proliferative ISCs and activated Wnt/β-catenin signaling.
Lactobacillus amylovorus	—	Enhanced Intestinal Epithelial Cell Growth	Beneficial	Moderate	View source Experiments using in-house developed porcine jejunal organoids prove that live L. amylovorus and its metabolite lactate promote intestinal organoid growth.
Lactobacillus amylovorus	—	Increased Intestinal Stem Cell Proliferation	Beneficial	Moderate	View source live L. amylovorus and its metabolite lactate promote intestinal organoid growth... L. amylovorus and lactate activate Wnt/β-catenin signaling in a GPR81-dependent manner to promote ISC-mediated epithelial proliferation