Microbiota–Metabolite–Host Crosstalk Mediates the Impact of Dietary Energy Levels on Colonic Homeostasis in High-Altitude Ruminants

The colon plays a crucial role in energy metabolism and intestinal health of ruminants during various physiological stages. Plateau ruminants have long been subjected to extreme environments characterized by hypoxia, cold, and nutritional scarcity, which makes their dependence on energy metabolism particularly pronounced. However, existing research on the regulatory effects of dietary energy levels on the colonic function of plateau ruminants is still quite limited. This study involved 60 healthy male Pamir yaks with consistent body conditions, which were randomly divided into three groups: a low-energy diet group (YG, Neg 1.53 MJ/kg), a medium-energy diet group (QG, Neg 2.12 MJ/kg), and a high-energy diet group (RG, Neg 2.69 MJ/kg). Each yak was provided with 5 kg of mixed feed daily over a 170-day feeding trial. The results indicated that a high-energy diet enhanced growth performance in yaks (<i>p</i> < 0.05). However, it also induced local colonic inflammation, decreased levels of immune factors (IgA, IgG, and IL-10), and increased the abundance of potentially pathogenic bacteria, such as <i>Klebsiella</i> and <i>Campylobacter</i> (<i>p</i> < 0.05). Conversely, a medium-energy diet fostered the proliferation of beneficial bacteria such as <i>Bradymonadales</i>, <i>Parabacteroides</i>, and <i>Mogibacterium</i> (<i>p</i> < 0.05), and preserved immune homeostasis. Additionally, multi-omics analysis revealed that the QG group was significantly enriched in key metabolic pathways, including pyruvate metabolism and glycine, serine, and threonine metabolism and panto-thenate and CoA biosynthesis pathways, among others (<i>p</i> < 0.05), demonstrating a synergistic regulatory effect among the microbiome, metabolism, and host. In summary, a moderate-energy diet can promote the proliferation of beneficial bacteria in the extreme environment of the plateau. By regulating pathways such as Amino acid, Nucleotide, and Lipid metabolism, it coordinates the expression of key host genes and metabolite levels, effectively balancing immune signals and energy metabolism. This interaction establishes a beneficial microbial-metabolism-host pattern that supports colon health.