Deciphering gut microbiome `chatter' to combat IBD

Date:
March 14, 2022
Source:
Earlham Institute
Summary:
Inflammatory Bowel Disease (IBD) is a life-long, chronic condition
characterized by sporadic bouts of gut inflammation causing
debilitating symptoms. Crohn's Disease and Ulcerative Colitis
-- the latter affecting around 1 in 400 people - are the two
most common types of IBD. Current treatments are ineffective and
seriously impact the quality of life of the patients and those of
their families.



FULL STORY ========================================================================== Around 500,000 people in the UK live with Inflammatory Bowel Disease
(IBD), a life-long, chronic condition characterised by sporadic bouts
of gut inflammation causing debilitating symptoms. Crohn's Disease and Ulcerative Colitis -- the latter affecting around 1 in 400 people --
are the two most common types of IBD. Current treatments are ineffective
and seriously impact the quality of life of the patients and those of
their families.


========================================================================== Scientists at the Earlham Institute, Quadram Institute and University
of East Anglia on the Norwich Research Park, have developed a new
computational biology method to better understand IBD for targeted
clinical treatments. By analysing specific differences in gut cell
types, the study deciphers cellular crosstalk to identify how beneficial bacteria communicate with our immune system to treat IBD and reduce
gut inflammation.

The human gut harbours a community of microbes, known collectively
as the microbiome, which is crucial to maintaining good health. A
disrupted microbiome can cause gut-related conditions including IBD,
an immune-linked inflammatory disease that causes abdominal pain,
diarrhea and extreme fatigue.

People with IBD tend to have reduced diversity or a change in the
balance in their gut microbiome, especially of Bacteroides and Firmicutes bacteria.

However, we still don't know how exactly this translates to the triggering
and progression of IBD. By understanding how these bacteria interact
with the gut lining, and the immune system, and how this differs in
IBD, we can better understand the causes and start developing targeted, effective treatments.

But to decipher this crosstalk across the different kingdoms of life,
you need to understand how bacteria communicate, and then how human
cells react to that information. This quest united microbiologist and immunologist Professor Simon Carding from the Quadram Institute and UEA,
with Dr Tama's Korcsma'ros, a systems biologist whose expertise lies in cellular signalling networks from the Earlham and the Quadram Institutes.

Professor Carding and his team have been investigating Bacterial
Extracellular Vesicles (BEVs), which are tiny packages created by bacteria
that they fill with various molecules and release from the cell. They
can cross the gut lining, reaching cells of the immune system where they
are recognised by receptors. The contents of the BEVs are molecular
signals that then trigger the immune cells to react, with that signal potentially cascading into widespread effects.



==========================================================================
In a healthy gut, BEVs and their cargo can contribute to anti-inflammatory responses of the immune system, but in an inflamed IBD patient's gut,
this response is lost. BEVs could therefore be used as a potential
new therapy. But currently, we don't understand enough about how they
interact with the complex immune system. Our immune response relies on different types of cells monitoring for a plethora of different signals
and interacting with each other to respond appropriately to a perceived
threat of infection locally, and systematically across the body.

To address this knowledge gap, Dr Tama's Korcsma'ros and his team used
a previously published dataset about which genes are actively making
proteins in 51 types of colon cells, from either healthy conditions
or under the effect of ulcerative colitis. Uniquely, this dataset
contained inflamed and uninflamed data from the same patients, allowing investigation of the effect of inflammation and not only the complex
disease.

The team also analysed and characterised all of the cargo proteins
obtained from BEVs made by the common gut bacterium Bacteroides thetaiotaomicron (Bt).

They then combined these datasets using an experimentally verified computational pipeline (called MicrobioLink) that predicts the
interactions between microbial and host proteins, and how these triggers complex networks of cascading signalling systems. From this they could
build up an overall picture of which microbial proteins were able to
interact with which human proteins in the different types of immune
cell and identify the differences between these networks in a healthy
gut and in IBD.

This model, called an interactome, provides a snapshot of the constant communication between gut bacteria and our own immune system. From this
the researchers could get an idea of the biological processes affected
by microbial proteins -- in healthy and inflamed UC conditions.

Many interactions were identified common across cell types, but the
research uncovered many biological processes that were specific to one
type of immune cell. Focussing specifically on one pathway known to be important in immunity and inflammation, they were also able to identify differences between the same cell types in healthy and ulcerative colitis conditions. Experiments using cell cultures grown together with BEVs
validated the predictions from the computational modelling.

"The finding that BEVs affect the immune system's pathways in a cell-type specific manner, and that they are altered in inflammatory bowel disease
is an important step to understanding the condition, and potentially could
help in developing BEVs as a therapeutic system" said Lejla Gul, first
author on the paper and an iCASE PhD student at the Earlham Institute
and the Quadram Institute, supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership.

"Studying interkingdom connections with BEVs in a cell-type specific
resolution requires multi-disciplinary expertise and various 'omics
datasets. Then you need a computational pipeline to analyse the data
from different patients.

Besides the actual scientific results, in the paper we introduce an
open-source pipeline that others can use to analyse their data" said Dr
Tama's Korcsma'ros.

"We hope that what we have demonstrated here in this study will be applied
by others for understanding the mechanisms how other bacterial species communicate with our cells, and how it may be altered in other diseases."
The study was funded by the Biotechnology and Biological Sciences Research Council, part of UK Research and Innovation (UKRI).


========================================================================== Story Source: Materials provided by Earlham_Institute. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Lejla Gul, Dezso Modos, Sonia Fonseca, Matthew Madgwick, John
P. Thomas,
Padhmanand Sudhakar, Catherine Booth, Re'gis Stentz, Simon
R. Carding, Tamas Korcsmaros. Extracellular vesicles produced by the
human commensal gut bacterium Bacteroides thetaiotaomicron affect
host immune pathways in a cell‐type specific manner that are
altered in inflammatory bowel disease. Journal of Extracellular
Vesicles, 2022; 11 (1) DOI: 10.1002/ jev2.12189 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220314120710.htm

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