# Insights from the high-altitude animal gut adaptation model: mechanisms of obesity regulation via microbiota-derived metabolite homeostasis and the gut-X axis

## TL;DR

High-altitude animals adapt to extreme environments through gut microbiota changes that help regulate metabolism and may offer insights for obesity treatment.

## Contribution

This review introduces the role of microbiota-derived metabolites and gut-X axis pathways in high-altitude adaptation and obesity regulation.

## Key findings

- Short-chain fatty acids (SCFAs) enhance intestinal barriers and influence gut-brain axis to regulate feeding behavior.
- Secondary bile acids (SBAs) act via the gut-liver axis to modulate host lipid and energy metabolism.
- Microbial metabolites coordinate through gut-X axis pathways to maintain metabolic homeostasis in high-altitude environments.

## Abstract

The unique environmental conditions at high altitudes drive the gut microbiota of resident animals to develop distinct structural and functional traits, thereby offering an ideal natural model for investigating the synergistic adaptation of hosts and microorganisms to extreme environmental stressors. This review systematically expounds the mechanism of metabolic adaptation of gut microbiota to high-altitude through the phenotypic characteristics of “high productivity and low inflammation,” and understands the mediating effect of short-chain fatty acids and secondary bile acids, which are derived metabolites of flora. SCFAs can enhance the intestinal barrier, regulate the function of immune cells, act on the gut-brain axis, and then affect the feeding behavior. SBAs, as signal molecules, regulate the lipid and energy metabolism of the host through the gut-liver axis. This division of labor and coordination, driven by different metabolites and achieved through specific gut-X axis pathways, constitutes a microecological regulatory network that enables the host to maintain metabolic homeostasis in high-altitude areas. Understanding this natural model can reveal the role of “flora metabolite organ axis” in maintaining health. It can also provide reference direction for obesity intervention caused by high-fat diet (HFD) and other factors, such as regulating the function of gut microbiota through strategies such as dietary regulation, probiotics and prebiotics supplementation, and fecal microbiota transplantation (FMT), and regulating the specific gut–X axis pathway, so as to restore metabolic balance.