Research in mice shows how diet alters immune system function through a
gut microbe

Date:
November 16, 2021
Source:
Harvard Medical School
Summary:
Research in mice demonstrates how diet alters a gut microbe
molecule that, in turn, prompts immune cells to downregulate
inflammation. The study elucidates molecular mechanism behind
long-standing belief that diet, microbiota, and immunity influence
one another in myriad ways. If affirmed in larger animals and
humans, the findings could inform the design of small-molecule
drugs that regulate immune response to treat inflammatory conditions


FULL STORY ==========================================================================
The cliche' "you are what you eat" has been used for hundreds of years to illustrate the link between diet and health. Now, an international team of researchers has found the molecular proof of this concept, demonstrating
how diet ultimately affects immunity through the gut microbiome.


==========================================================================
The work, conducted in mice, reveals that what animals consume initiates
the release of a metabolic byproduct from a specific gut microbe that,
in turn, modulates the animals' gut immunity.

The findings, published Nov.10 in Nature, offer a unifying explanation
for the complex interplay between diet, gut microbiota, and immune
function. They are the result of collaboration among scientists at Harvard Medical School, Brigham and Women's Hospital, Seoul National University,
and Monash University in Australia.

The experiments pinpoint a microbial molecule, the synthesis and release
of which are influenced by host diet. That molecule, in turn, stimulates
the activation and signaling of a subset of cells known as natural killer
(NK) T cells, which are involved in immune regulation and implicated in
a range of inflammatory conditions.

While scientists have surmised for a long time that diet plays a role
in immune health, the new study elucidates the precise molecular cascade
behind this interplay, said study senior author Dennis Kasper, professor
of immunology in the Blavatnik Institute at Harvard Medical School.

"We have shown how diet affects the immune system through a microbial
mediator in the gut, and this is a really striking example of the diet-microbiota- immunity triad at play," Kasper said. "What this work
really does is provide a step-by-step pathway from beginning to end that explains how and why this triad works and how diet ultimately affects the immune system." If confirmed in larger animals and eventually in humans,
the findings can help inform the design of small-molecule treatments
that enhance both intestinal and overall immunity, the researchers said.



========================================================================== "Gut-resident microbes produce molecules with enormous structural
diversity. We used microbial and chemical tools to elucidate how these molecules are synthesized by gut bacteria and how they act in the host
gut," said study first author Sungwhan Oh, a principal investigator at the Center for Experimental Therapeutics and Reperfusion Injury at Brigham
and Women's Hospital and a former postdoctoral fellow in the Kasper
lab."Our findings yield fascinating insights about the microbiome, diet,
and immune function and provide interesting clues about how molecules made
by our inner neighbors can be used to design therapies." In a series of experiments, the team identified the immune-signaling cascade triggered
by the metabolic breakdown of dietary amino acids in the mouse gut.

This multistep pathway begins with an animal consuming food that
contains branched-chain amino acids, so named for the tree branch-like structure of one of their molecular chains. The branched-chain amino
acids are then taken up by B. fragilis,a gut-resident microbe, and
converted by a specific enzyme into sugar-lipid molecules that also
have branched chains.B. fragilis then releases branched-chain molecules
that are spotted and picked up by a class of immune- signaling cells
known as antigen-presenting cells, which in turn induce NK T cells
to exercise their immunoregulatory response through upregulating inflammation-controlling genes and immune-regulatory chemicals.

Notably, the experiments demonstrated that it is the branching of the
chain structure that initiates the cascade. Straight-chain versions of
the molecule did not yield the same effect. Furthermore, the team found
that B.

fragilisalters the structure of the sugar-lipid molecules that it
metabolizes and renders them better capable of binding to receptors on
specific immune cells and initiating a signaling cascade that culminates
in downregulating inflammation.

The work also showed that each of three different branched-chain amino
acids consumed by mice yielded slightly different structural changes
to the bacterial lipid molecules, resulting in different patterns of
binding with immune cells.

Study coinvestigator Seung Bum Park, professor of chemistry at Seoul
National University, synthesized, and the Harvard team tested, 23
different configurations of the microbe-made immunomodulatory molecule
to determine how each one interacts with the immune cells that regulate inflammation.



==========================================================================
The Harvard team's experiments revealed that synthetic, lab-made
branched-chain lipid molecules induced NK T cells to release the immune-signaling chemical IL- 2, whereas the lab-made straight-chained
versions of these molecules did not.

Thus activated, the NK T cells, in turn, induced the expression of genes
that regulate immunity but not of genes that drive inflammation.

Using a structural biology approach, Jamie Rossjohn, professor of
biochemistry and molecular biology at Monash Biomedicine Discovery
Institute in Australia, elucidated how the lipid structure engages with
and binds to antigen presenting cells -- the immune cells that give NK
T cells the go-ahead to produce anti- inflammatory chemicals.

In a final step, the researchers treated mice with ulcerative colitis
with the branched-chain sugar-lipid molecule. Animals that received
treatment with the branched-chain molecule fared much better than
untreated animals. They not only gained weight, but when researchers
examined the gut cells of the mice under a microscope, they observed
that these cells also had minimal signs of colon inflammation.

Taken together, the experiments provide a structural and molecular
explanation of previously observed anti-inflammatory effects of this
class of sugar-lipids produced by the gut microbe B. fragilis.

"This work offers a great example of transdisciplinary discovery-based
research aimed at answering a major question in biomedical sciences,
namely, how the immune system can be modulated by the interplay between
diet and the microbiota," Rossjohn said.

In 2014, Kasper and colleagues published a study showing that a
sugar-lipid molecule released by B. fragilishad anti-inflammatory
effects on the gut and protected mice from colitis, but the scientists
did not know how these molecules were made by the microbe, nor the
specific structural features of the sugar-lipids that conferred the anti-inflammatory effect. The current study answers this question
demonstrating that the sugar-lipid molecules made by this particular
organism are branched-chain and it is precisely that branched-chain
structure that allows them to bind to immune cells in a way that dampens
these cells' proinflammatory signaling.

"Our new work demonstrates that the branching of the lipid structure
induces a very different response -- the branching in the structure
induces an anti- inflammatory rather than a proinflammatory response,"
Kasper said.

The findings offer hope that inflammatory diseases mediated by these NK
T cells could one day be treated with inflammation-dampening microbial molecules made in the lab, the researchers said.

The exact function of NK T cells -- the immune cells that the microbe-made molecule ultimately activates to control colonic inflammation in mice --
is not well-understood, Kasper said. However, given that these cells
line the human gastrointestinal tract and the lungs and are also found
in the liver and spleen, they likely play a significant role in immune regulation. Previous research points to these cells' likely involvement
in a range of inflammatory conditions, including ulcerative colitis,
and to a possible role in airway inflammatory conditions such as asthma.

"We can never isolate enough of these immune-modulatory molecules from
bacteria for therapeutic use, but the beauty of this is now we can
synthesize them in the lab," Kasper said. "The idea would be that we'd
have a drug that can modulate inflammation in the colon and beyond."
Co-authors included T. Praveena, Heebum Song, Ji-Sun Yoo, Da-Jung Jung,
Deniz Erturk-Hasdemir, Yoon Soo Hwang, ChangWon Lee, Je'ro^me Le Nours,
Hyunsoo Kim, Jesang Lee, and Richard Blumberg.

The work was supported by National Institutes of Health grants
K01-DK102771, R01-AT010268, and R01-DK044319; by Department of Defense
grant W81XWH-19-1- 0625; by Brigham and Women's Hospital Department of Anesthesiology, Perioperative and Pain Medicine Basic Science Grant;
by the National Research Foundation of Korea grants 2014R1A3A2030423
and 2012M3A9C404878; and by the Australian Research Council grant
CE140100011 and Australian Research Council Laureate Fellowship and
Future Fellowships.

Relevant disclosures Oh, Blumberg, and Kasper have filed a patent
for Bacteroides fragilis a- galactosylceramides(BfaGCs) and related
structures. Oh, Park, and Kasper have filed a patent on the functions
of BfaGCs and related structures.

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


========================================================================== Journal Reference:
1. Sungwhan F. Oh, T. Praveena, Heebum Song, Ji-Sun Yoo, Da-Jung
Jung, Deniz
Erturk-Hasdemir, Yoon Soo Hwang, ChangWon C. Lee, Je'ro^me Le Nours,
Hyunsoo Kim, Jesang Lee, Richard S. Blumberg, Jamie Rossjohn,
Seung Bum Park, Dennis L. Kasper. Host immunomodulatory lipids
created by symbionts from dietary amino acids. Nature, 2021; DOI:
10.1038/s41586-021-04083-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211116175057.htm

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