Preventive Effects of Probiotic Formula on Metabolic Stress Associated Physical Fatigue in Forced Swimming and LPS-Induced Mouse Models.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by persistent fatigue and post-exertional symptom exacerbation, frequently associated with immune and metabolic disturbances. To evaluate the therapeutic potential of a probiotic formula, HH-205M, we employed a composite mouse model combining forced swimming stress (FSS) and repeated lipopolysaccharide (LPS) administration. FSS-LPS exposure induced pronounced fatigue-like phenotypes, including reduced physical endurance capacity in treadmill and weight-loaded swimming tests, delayed recovery in post-swim grooming behavior, and increased thermal pain sensitivity. These behavioral impairments were accompanied by elevated serum creatine kinase (CK), lactate dehydrogenase (LDH), and lactate levels, indicating systemic metabolic stress. At the tissue level, FSS-LPS increased lipid peroxidation and upregulated pro-inflammatory cytokine expression while suppressing antioxidant gene expression in the gastrocnemius muscle. Furthermore, expression of lactate-related genes, Hcar1 (GPR81) and Slc16a1 (MCT1), was reduced, suggesting disruption of lactate transport and sensing pathways under chronic stress and inflammatory conditions. HH-205M supplementation attenuated the elevations in circulating fatigue-related biomarkers, moderated oxidative and inflammatory responses, and restored Hcar1 and Slc16a1 expression. These molecular changes were paralleled by improvements in endurance performance and nociceptive sensitivity. HH-205M administration was also associated with distinct shifts in gut microbial composition, including enrichment of Akkermansia and Bacteroides and reduced relative abundance of Alistipes. Collectively, these findings indicate that the FSS-LPS composite model recapitulates inflammation-associated metabolic disturbances relevant to fatigue-like conditions and that HH-205M administration is associated with concurrent improvements in behavioral and molecular parameters in this model.