Dietary Divergence Along an Altitudinal Gradient Is Associated With Liver Transcriptomic and Metabolic Remodeling in a Small Mammal

Although physiological adaptations to high altitude are well-studied, the synergistic mechanisms linking foraging strategies to internal metabolism remain unclear. To investigate how dietary shifts are associated with molecular variation in plateau pikas (Ochotona curzoniae) along an altitudinal gradient, we integrated dietary analysis with liver transcriptomics and metabolomics. Results revealed a significant dietary differentiation in plateau pikas along the altitudinal gradient, shifting from a selective foraging strategy on diverse forbs at low altitudes to a tolerance foraging strategy centered on hardy sedges (Carex) and toxic locoweeds (Oxytropis) at high altitudes. Dietary differentiation along the altitudinal gradient was associated with coordinated changes in liver metabolism: low-altitude populations were enriched in metabolites related to biotic stress responses, whereas high-altitude populations showed increased accumulation of antioxidant compounds consistent with adaptation to intense abiotic stress. Transcriptomic analysis unveiled the molecular basis for this adaptation: the livers of high-altitude pikas exhibited significant upregulation of genes related to xenobiotic detoxification and energy metabolism regulation; in contrast, low-altitude populations upregulated pathways associated with cell growth and immune response. This study reveals a tightly coupled diet-gene-metabolism axis in plateau pikas. The shift in foraging strategy from selective to tolerance is a key driver of the functional shift in liver metabolism, redirecting the physiological focus from coping with biotic stress at low altitudes to counteracting abiotic stress at high altitudes. Our study highlights the importance of integrating ecological and molecular data to better understand how environmental gradients shape organismal physiology in natural populations.