A reciprocal interaction between L-lysine and Holdemanella biformis modulates intestinal barrier function and anxiety in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a prevalent stress-associated disorder characterised by gut barrier dysfunction and gut-brain axis disturbances. However, the interplay between host metabolites and gut microbes in IBS pathogenesis remains incompletely understood. Here, through integrated microbiome and metabolome profiling of faecal sample from seafarers before and after long-term voyages, we identify a reciprocal interaction between the essential amino acid l-lysine and the gut bacterium Holdemanella biformis (H. biformis). l-lysine was depleted in individuals with voyage-induced IBS, whereas H. biformis abundance increased concurrently. In a mouse model of diarrhoea-predominant IBS, l-lysine supplementation restored intestinal barrier integrity, reduced visceral hypersensitivity, and alleviated anxiety-like behaviours through modulation of tryptophan metabolism. In contrast, oral administration of H. biformis improved tight junction protein expression but paradoxically worsened anxiety-like phenotypes. In vitro, both l-lysine and H. biformis supernatant promoted epithelial wound healing and ZO-1 expression. Mechanistically, H. biformis degrades l-lysine via lysine degradation pathway, while l-lysine suppresses H. biformis growth possibly by downregulating pathways involved in carbohydrate and energy metabolism. These findings reveal a stress-sensitive, bidirectional metabolic loop in between l-lysine and H. biformis, with complementary but opposing effects on gut and neurological function. Targeting this axis may offer new strategies for IBS and other gut-brain axis disorders.