How gut microbes work to tame intestinal inflammation

Date:
March 16, 2022
Source:
Harvard Medical School
Summary:
Bile acids, well known for their role in dissolving fats
and vitamins, are also important players in gut immunity and
inflammation because they regulate the activity of key immune
cells linked to a range of inflammatory bowel conditions, such as
ulcerative colitis and Crohn's disease, according to new research.



FULL STORY ==========================================================================
Bile acids made by the liver have long been known for their critical
role in helping to absorb the food we ingest.


==========================================================================
But, according to a series of new studies from Harvard Medical School,
these fat- and vitamin-dissolving substances are also important players
in gut immunity and inflammation because they regulate the activity of
key immune cells linked to a range of inflammatory bowel conditions,
such as ulcerative colitis and Crohn's disease.

An initial report in 2020 mapped out the effects of bile acids on mouse
gut immunity, but left some key questions unanswered: First, just how
do bile acids get gut immune cells to perform their immune-regulatory
work? Second, which bacteria and bacterial enzymes produce these
bile acids? Third, do these bile acids play a role in human intestinal inflammation? Now, two studies led by the same team of investigators --
one published March 16 in Nature and one published inCell Host & Microbein
2021 -- answer these questions and add further clarity to the initial observations. The research, conducted at the intersection of chemical
biology, microbiology, and immunology, was co-led by Sloan Devlin,
assistant professor of biological chemistry and molecular pharmacology,
and Jun Huh, associate professor of immunology at HMS.

The studies identify three bile acid metabolites and corresponding
bacterial genes that produce molecules that affect the activity of inflammation- regulating immune cells. The work also demonstrates that
the presence and activity of these bacteria and the immune molecules they produce are notably reduced in patients with inflammatory bowel disease
(IBD).

"We carry trillions of bacteria in and on our bodies, and a growing
body of research indicates that gut bacteria can affect host immune
responses," Huh said. "Our findings provide a novel mechanistic insight
into how these bacteria work to mediate immune regulation in the gut."
The findings, based on experiments in mice and human stool samples,
reveal the identity of three critical microbial players in this cascade
and the bacterial genes that regulate bile acid modification. Furthermore,
they show that intestinal samples from patients with conditions such as ulcerative colitis or Crohn's disease have markedly lower levels of both
the anti-inflammatory molecules and the bacterial genes responsible for
their production.

The findings bring scientists a step closer to developing small-molecule treatments and live bacterial therapeutics that regulate intestinal inflammation.

"All three molecules and the bacterial genes that we discovered that
produce these molecules are reduced in patients with IBD," Devlin
said. "Restoring the presence of either the compounds or the bacteria
that make them offers a possible therapeutic avenue to treat a range of inflammatory diseases marked by these deficiencies and affecting millions
of people worldwide."

========================================================================== Story Source: Materials provided by Harvard_Medical_School. Original
written by Ekaterina Pesheva. Note: Content may be edited for style
and length.


========================================================================== Journal References:
1. Paik, D., Yao, L., Zhang, Y. et al. Human gut bacteria produce TE17-
modulating bile acid metabolites. Nature, 2022 DOI:
10.1038/s41586-022- 04480-z
2. Wei Li, Saiyu Hang, Yuan Fang, Sena Bae, Yancong Zhang, Minghao
Zhang,
Gang Wang, Megan D. McCurry, Munhyung Bae, Donggi Paik,
Eric A. Franzosa, Fraydoon Rastinejad, Curtis Huttenhower,
Lina Yao, A. Sloan Devlin, Jun R. Huh. A bacterial bile acid
metabolite modulates Treg activity through the nuclear hormone
receptor NR4A1. Cell Host & Microbe, 2021; 29 (9): 1366 DOI:
10.1016/j.chom.2021.07.013 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220316120813.htm

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