Angiotensin-converting enzyme 2 (ACE2)—an important regulator of the renin–angiotensin system—has been identified as the vital link between dietary amino acid homeostasis, intestinal immunity, microbiota composition and susceptibility to colitis in mouse models in a new study published in Nature. The findings provide clues as to how malnutrition leads to intestinal inflammation and diarrhoea.

Knowing that ACE2 controls the expression of the neutral amino acid transporter B0AT1 in the gut, Josef Penninger, Philip Rosenstiel and colleagues investigated the in vivo function of ACE2. First, they confirmed that Ace2-knockout mice had low serum levels of neutral amino acids (notably tryptophan), but found no morphological changes to the intestine. However, when challenged with the irritant dextran sodium sulphate (DSS; an established experimental model of colitis), Ace2 mutant mice developed more severe colitis and diarrhoea than wild-type mice.

Next, mice were fed a protein-free diet (to eliminate dietary amino acids) and then challenged with DSS (1% dose to induce only very mild colitis). Importantly, both wild-type and Ace2 mutant mice fed this diet developed severe colitis, indicating that protein malnutrition alters the severity of intestinal inflammation. Concentrating on a specific amino acid, the authors found that Ace2 deficiency impaired local tryptophan homeostasis, which could be alleviated, along with the severe colitis phenotype, by tryptophan supplementation.

Further investigations revealed that Ace2-knockout mice, and normal mice fed a low-tryptophan diet, had reduced levels of antimicrobial peptides in the small intestine. Moreover, the composition of the gut microbiota was altered in Ace2 mutant mice. Crucially, transplantation of gut microbiota from Ace2-knockout mice transferred the inflammatory phenotype and susceptibility to colitis to germ-free mice.

“The host intestinal tract and its microbes have co-evolved ... to form a balanced state that is essential for health,” notes Rosenstiel. Importantly, as tryptophan was proven to be an important amino acid, Penninger proposes that simple dietary interventions could be used to normalize gut bacteria, and potentially relieve symptoms, in people with colitis.