Simple butyrate may be the key behind increased regulatory T cells in the colon.
REG3γ on the Frontline
The cells of the intestinal epithelial layer generate antimicrobial peptides to prevent bacteria crossing the mucus layer and interacting with them. One well-known antimicrobial peptide is REG3γ. It is found mainly in the small intestine and is secreted after detection of pathogens or by inflammatory stimuli. To fully characterize its role during bacterial infection, scientists from Wageningen University in the Netherlands generated a REG3γ deficient mouse and examined its intestinal responses. Loss of REG3γ allowed bacteria to cross the mucus in the ileum, which caused signs of mild inflammation. It also changed the mucus distribution. When the mice were infected with two types of intestinal pathogens, Salmonella enteritidis and Listeria monocytogenes, the inflammatory response was increased but not coupled with increased bacterial translocation to internal tissues, suggesting that while it plays a protective role, it’s loss is compensated by other inflammatory mechanisms.
Improved Carbon Monoxide Therapy
Carbon monoxide (CO) is known to have beneficial anti-inflammatory properties and is considered as a possible treatment for inflammatory bowel disease (IBD). It is also a candidate for reducing inflammation in other diseases, like acute pancreatitis. Researchers from Stanford University found that CO, delivered via a special CO releasing molecule (CORM-2) prevented inflammation-associated mortality and damage in a model of acute pancreatitis. They found that this beneficial effect was mediated by loss of TLR4 activation on macrophages, which also led to reduced TNFα secretion. This would suggest that CO therapy using CORM-2 could also be beneficial in an IBD setting.
Butyrate, the Regulatory T Cell Generator
The idea of microbiota influencing T regulatory cells (Treg) isn’t new, however, the mechanisms behind the phenomenon weren’t particularly clear. Researchers from the University of Tokyo now know a bit more. They found that the short chain fatty acid butyrate produced by Clostridia bacteria plays a major role. They found that germ-free mice had very low numbers of Foxp3+ Treg (both natural and induced), and providing germ-competent mice with butyrate-inducing diets markedly increased their numbers in the colon. The butyrate diets were so effective that they had a protective effect in a colitis model. It will be interesting to see if these studies are followed by clinical studies with IBD patients in the future.
References
- Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., et al. (2014). Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature, 504(7480), 446–450. doi:10.1038/nature12721
- Loonen, L. M., Stolte, E. H., Jaklofsky, M. T., Meijerink, M., Dekker, J., van Baarlen, P., & Wells, J. M. (2013). REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunology, 1–9. doi:10.1038/mi.2013.109 [Epub ahead of print]
- Xue, J., & Habtezion, A. (2013). Carbon monoxide–based therapy ameliorates acute pancreatitis via TLR4 inhibition. The Journal of Clinical Investigation. doi:10.1172/JCI71362DS1 [Epub ahead of print]