Carnosine improves colonic hyperpermeability through the brain histamine H1 receptor, basal forebrain cholinergic neurons, adenosine A2B receptors and vagus nerve in rats

Leaky gut is implicated in disorders such as irritable bowel syndrome (IBS) and Alzheimer's disease (AD). Our previous study demonstrated that brain histamine H1 receptor signaling—mediated via basal forebrain cholinergic neurons (BFCNs), adenosine A2B receptors, and the vagus nerve—regulates intestinal barrier function. In this study, we investigated the role of carnosine, a dipeptide composed of beta-alanine and L-histidine, in modulating intestinal barrier integrity. In an LPS-induced leaky gut rat model, intracisternal administration of carnosine improved colonic permeability as determined by the Evans blue dye method. This effect was abolished by brain H1 receptor antagonism, vagotomy, and inhibition of either BFCNs or adenosine A2B signaling, suggesting that carnosine acts via these central pathways. Similarly, high-dose intraperitoneal carnosine alleviated colonic hyperpermeability, with its effect also blocked by the same interventions. Additionally, exercise reduced LPS-induced hyperpermeability—an effect eliminated by brain histamine H1 receptor blockade. These findings indicate that peripheral carnosine, including muscle-derived carnosine, contributes to the central regulation of the intestinal barrier. Enhanced barrier integrity, which reduces visceral hypersensitivity, suggests that carnosine may be an effective therapeutic for IBS. Moreover, the decline in muscle carnosine observed in sarcopenia, coupled with an increased dementia risk, supports its therapeutic potential for AD. Collectively, the present study underscores the promise of carnosine and muscle-derived strategies in managing leaky gut-related disorders.