Ludwig MSK study reveals bile metabolite of gut microbes boosts immune cells

April 15, 2020

APRIL 15, 2020, NEW YORK-- A Ludwig Cancer Research study has discovered a novel means by which bacterial colonies in the small intestine support the generation of regulatory T cells--immune cells that suppress autoimmune reactions and inflammation. The study, led by Ludwig MSK Director Alexander Rudensky and published in Nature, demonstrates that a microbial metabolite--the organic acid isoDCA--boosts the local generation of the immunosuppressive immune cells in the colon. Such locally generated, or "peripheral", regulatory T cells (Tregs) help dampen chronic intestinal inflammation, a major driver of colorectal cancers.

Though the study does not directly address cancer prevention, its findings have intriguing implications for the field--which is why the study was funded in part by the colon cancer prevention and early detection initiative launched in 2015 by Ludwig and the Conrad N. Hilton Foundation.

"People have been thinking about using commensal microbes to treat inflammatory disorders of the colon," says Rudensky. "One approach is to develop a new class of drugs made from 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. An authority on Tregs, 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 intestines. 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," says 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."

About 5% of the bile pumped into the intestines to help digest fat is retained in the organ, and some of it is metabolized by commensal bacteria. Rudensky and his colleagues were curious about whether the byproducts of that metabolism influence the local immune environment. To find out, they screened a spectrum of bile acids produced by bacterial metabolism for such effects in co-cultures of the precursor T cells from which Tregs arise and dendritic cells, which help direct the generation of Tregs.

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 hushes 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 elegant synthetic biology experiments in mouse models to confirm the biological veracity of their findings. The results reflected those obtained in cell culture. Mice colonized with bacteria engineered to make isoDCA had many more peripheral Tregs in their intestines than those colonized with the same bacteria lacking the capability. The same results were obtained using two other similarly engineered species of gut bacteria.
-end-
This study was supported by Ludwig Cancer Research, the Conrad N. Hilton Foundation, the U.S. National Institutes of Health, Boehringer Ingelheim and the Howard Hughes Medical Institute.

Aside from his Ludwig position, Rudensky is also chairman of the Immunology Program at Memorial Sloan Kettering Cancer Center and an investigator of the Howard Hughes Medical Institute.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for nearly 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, rreinhardt@lcr.org or +1-212-450-1582.

Ludwig Institute for Cancer Research

Related Colon Cancer Articles from Brightsurf:

New prognostic markers for colon cancer identified
The study recently published by MedUni Vienna and collaborative partners nominates ILSs as novel prognostic players orchestrating the pathobiology of metastatic colorectal cancer.

Turning colon cancer cells around
Using a modified natural substance along with current approaches could improve colon cancer treatment, according to findings by University of California, Irvine biologists.

Uncovering the pathway to colon cancer
The hidden world of genetic changes, or mutations, in healthy colon tissue has been uncovered by scientists at the Wellcome Sanger Institute and their collaborators.

Colon cancer growth reduced by exercise
Exercise may play a role in reducing the growth of colon cancer cells according to new research published in The Journal of Physiology.

Towards a better understanding of how colon cancer develops and progresses
Researchers from the University of Luxembourg have discovered a molecular mechanism that is responsible for the spread of cancer cells in the body and the development of metastases in patients with colon cancer.

New target protein for colon cancer identified
Researchers at Boston University School of Medicine (BUSM) have identified a new potential target protein (c-Cbl) they believe can help further the understanding of colon cancer and ultimately survival of patients with the disease.

Colon cancer -- Targeting tumor cell plasticity
Cell type switch helps colon cancer evade treatment, a study suggests.

A bacterial duo linked to colon cancer
Scientists have identified a combination of bacteria that appears to increase the risk of colon cancer.

New model could speed up colon cancer research
Using the CRISPR gene editing system, MIT researchers have shown they can generate colon tumors in mice that very closely resemble human colon tumors, an advance that should allow scientists to learn more about how the disease progresses and also help them test potential new drugs.

Are dialysis patients being over-screened for colon cancer?
Colonoscopies are being performed more often on healthier dialysis patients than on those with more limited life expectancies; however, overall, dialysis patients are being screened at a much higher rate relative to their life expectancy than their counterparts without kidney failure.

Read More: Colon Cancer News and Colon Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.