Antibiotic exposure alters the LEAP-2/ghrelin axis and anti-inflammatory tone in aged male rat liver and adipose tissue.

Abstract

Liver-expressed antimicrobial peptide-2 (LEAP-2), the endogenous antagonist of the ghrelin receptor (GHSR1a), counterbalances ghrelin in an energy- and inflammation-dependent manner. Aging is accompanied by endocrine and immunometabolic shifts that may influence this axis. We investigated whether a short course of broad-spectrum antibiotics (vancomycin-metronidazole-neomycin-ampicillin; VMNA) alters LEAP-2 and ghrelin levels in the liver and epididymal white adipose tissue (WAT) of aged male rats, and whether these changes coincide with modifications in IL-10, TNF-α, and IL-1β. Antibiotic treatment lowered LEAP-2 in both liver and WAT. Ghrelin decreased in both tissues, but the reduction reached significance only in WAT, whereas the hepatic decrease was nonsignificant. Consequently, the LEAP-2/ghrelin ratio declined in the liver and showed a nonsignificant upward trend in WAT. Inflammatory profiling revealed that IL-10 decreased in both tissues, whereas TNF-α and IL-1β remained unchanged. These findings demonstrate that even a one-week antibiotic regimen induces tissue-specific alterations in the LEAP-2/ghrelin axis-characterized by reduced hepatic LEAP-2 signaling, suppressed adipose ghrelin, and diminished anti-inflammatory tone. Overall, the data suggest that aged male rats exhibit heightened vulnerability to antibiotic-induced perturbations in LEAP-2/ghrelin regulation, underscoring the interplay between microbiota-related influences, inflammaging, and age-associated metabolic imbalance.