Work

The histidine crossroad: An integrative theory of the gut–liver–vascular axis in MASLD

Year: 2026

Type: article

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous and multisystemic condition in which cardiovascular disease remains the leading cause of mortality. Paradoxically, cardiovascular risk in MASLD is itself highly variable and cannot be fully explained by the degree of hepatic involvement or the presence of conventional cardiometabolic risk factors. This clinical disconnect underscores the need for novel pathophysiological models that go beyond traditional paradigms. In this review, we propose a hypothesis-generating framework in which microbial L-histidine metabolism, particularly its biotransformation into imidazole propionate (ImP) through the bacterial urdA pathway, may contribute to the gut-liver-vascular crosstalk observed in MASLD. Availabble evidence suggests a dual mechanism: depletion of bioavailable histidine, which may impair protective signaling through TAAR1, and systemic accumulation of ImP, a bioactive metabolite that has been shown in experimental models to interfere with insulin signaling in hepatocytes and activates proinflammatory and proatherogenic cascades in endothelial tissue. Based on this evidence, we introduce the ImP⁺/urdA^high profile as a putative functional biotype that may help generate testable hypotheses for microbiota-guided risk stratification in MASLD. Future studies should determine whether this profile identifies patients with residual cardiometabolic risk and whether targeted modulation of the histidine-ImP axis can improve hepatic or vascular outcomes.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2026.119550