Consortia of microbes could reduce inflammation and promote colon health, say researchers
A study has shown that two products of bacterial bile metabolism boost the conversion of precursor T cells into peripheral Tregs, which suppress chronic inflammation in the colon.
A new study has revealed a novel means by which bacterial colonies in the small intestine support the generation of regulatory T cells (Tregs). The researchers say their findings demonstrate that a microbial metabolite – the organic acid isoDCA – boosts the local generation of the immunosuppressive immune cells in the colon. These locally generated, or ‘peripheral’, Tregs help dampen chronic intestinal inflammation, a major driver of colorectal cancers.
The study was conducted by researchers at Ludwig Cancer Research, who say that although the study does not directly address cancer prevention, its findings have implications for the field.
“People have been thinking about using commensal microbes to treat inflammatory disorders of the colon,” said lead researcher Ludwig MSK Director Alexander Rudensky. “One approach is to develop a new class of drugs made from a defined consortia of microbes that would limit inflammation and promote colonic health, reducing the risk of colon cancer in people. Bacterial consortia that produce isoDCA and other metabolites that promote anti-inflammatory activity in colon-resident immune cells could be one of the components of such interventions.”
Gut microbes, which are critical to digestion and metabolism, also support many other important processes ranging from immune regulation to brain development. Rudensky has long explored the cross-talk between commensal bacteria and Tregs, which primarily mature in the thymus but can also be induced from precursor T cells in other tissues, especially the colon. These peripheral Tregs, he has shown, shield beneficial gut microbes from immune attack and suppress chronic intestinal inflammation.
“There are two-way communications between the host and its commensal microbial community, where the host must be informed of the composition of that community and respond to that information,” explained Rudensky. “This implies that a likely means of communication between the microbial community and the host immune system would be through the metabolic products of commensal bacteria, since metabolic support is among the main services commensal microbes provide to their hosts.”
The researchers screened a spectrum of bile acids produced by bacterial metabolism in co-cultures of the precursor T cells from which Tregs arise and dendritic cells, which help direct the generation of Tregs, to discover if they influenced the local environment in the colon.
The screen revealed that two products of bacterial bile metabolism – ω-MCA and isoDCA – significantly boosted the conversion of precursor T cells into peripheral Tregs. Focusing on isoDCA, which is more abundant in the human intestine, Rudensky and his colleagues found that the bile acid exerted its effects not on the precursor T cells, but on dendritic cells.
IsoDCA, they found, opposes the signals issued by a bile acid sensor in dendritic cells, the farnesoid X receptor (FXR). This weakens the dendritic cells’ expression of genes that induce protective immune responses, pushing them into an anti-inflammatory state in which they drive the generation of peripheral Tregs.
Rudensky and his colleagues next conducted synthetic biology experiments in mouse models to confirm the biological veracity of their findings and the results reflected those obtained in cell culture. Mice colonised with bacteria engineered to make isoDCA had many more peripheral Tregs in their intestines than those colonised with the same bacteria lacking the capability.
The findings were published in Nature.