Editors' ChoiceGut Inflammation

Selected Microbes Light the Flame

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Science Translational Medicine  08 Aug 2012:
Vol. 4, Issue 146, pp. 146ec142
DOI: 10.1126/scitranslmed.3004704

As shown time and time again, Mom was right: A balanced diet is key to reaping healthy biological effects from what’s on your plate. Although past research has shed light on the various effects of food on health, many aspects of this complex relationship remain unclear. Now, Hashimoto and colleagues add a new dimension to our understanding of how a poor diet disturbs the gastrointestinal balance that is required to respond to inflammatory stimuli.

The authors used a mouse model in which the gene that encodes angiotensin-converting enzyme 2 (ACE2) was knocked out (ACE2 knockout mice); ACE2, associated with a beneficial role in the cardiovascular system, digests angiotensin differently from its homolog ACE, the target in the renin-angiotensin system of ACE-inhibitor drugs used to lower blood pressure. The intestinal architecture did not unveil differences between the ACE2 knockout and wild-type animals. However, a chemical challenge induced a more pronounced inflammatory response in the colon of ACE2 knockout mice than in the wild-type controls. When wild-type mice were put on a protein-free diet, the chemically induced inflammatory lesions were as severe as those in the mutant mice, suggesting a role for nutrients in modulating the inflammatory response. In the ACE2 knockout mice, biodisposition of dietary amino acids was diminished, probably because the intestine and kidney of the mice do not express the transporter B0AT1, which mediates the uptake of neutral amino acids such as tryptophan. Lack of this essential amino acid in the diet markedly promoted inflammation after chemical irritation. Conversely, supplementing tryptophan as a dipeptide—a form of this amino acid that does not rely on B0AT1 for uptake by gut cells—ameliorated chemically induced inflammation. The authors concluded that gut depletion of tryptophan in the ACE2 knockout mice enhanced susceptibility to inflammation.

The depletion of tryptophan also correlated with depression of antimicrobial peptide synthesis by intestinal epithelial cells and alteration of the bacterial composition of the ileocaecal gut, which was restored to the wild-type composition after tryptophan repletion. The relevance of the microbes to confer disease was underscored when the authors showed that transplantation of the altered microbiome from ACE2 knockout mice into germ-free wild-type animals produced the inflammatory phenotype after exposure to the chemical irritant.

This intriguing new work integrates nutrients, antimicrobials, and microbes as key regulators of intestinal inflammation in the context of a low-protein diet. As it becomes evident that the microbiota in and on us are in deep symbiosis with us, definition of their functions in mechanisms of health and disease may yield transformative therapeutic approaches.

T. Hashimoto et al., ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487, 477–481 (2012). [Full Text]

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