A new tool for modeling the human gut microbiome

Date:
August 6, 2020
Source:
Massachusetts Institute of Technology
Summary:
Engineers have designed a device that replicates the lining of
the colon.

With the device, they can grow human colon cells along with oxygen-
intolerant bacteria that normally live in the human digestive
tract and have been implicated in Crohn's disease.



FULL STORY ========================================================================== Several thousand strains of bacteria live in the human gut. Some of
these are associated with disease, while others have beneficial effects
on human health.

Figuring out the precise role of each of these bacteria can be difficult, because many of them can't be grown in lab studies using human tissue.


==========================================================================
This difficulty is especially pronounced for species that cannot live
in oxygen-rich environments. However, MIT biological and mechanical
engineers have now designed a specialized device in which they can grow
those oxygen- intolerant bacteria in tissue that replicates the lining
of the colon, allowing them to survive for up to four days.

"We thought it was really important to contribute a tool to the community
that could be used for this extreme case," says Linda Griffith, the School
of Engineering Professor of Teaching Innovation in MIT's Department
of Biological Engineering. "We showed that you can grow these very
fastidious organisms, and we were able to study the effects they have on
the human colon." Using this system, the researchers showed that they
could grow a strain of bacteria called Faecalibacterium prausnitzii,
which lives in the human gut and protects against inflammation. They
also showed that these bacteria, which are often diminished in patients
with Crohn's disease, appear to exert many of their protective effects
through the release of a fatty acid called butyrate.

Griffith and David Trumper, an MIT professor of mechanical engineering,
are the senior authors of the study, which appears today in the journal
Med. MIT postdocs Jianbo Zhang and Yu-Ja Huang are the lead authors of
the paper.

Oxygen sensitivity The human gut's complex microbiome environment is
difficult to model using animals such as mice, in part because mice eat
a very different diet from humans, Griffith says.



========================================================================== "We've learned a huge amount from mice and other animal models, but there
are a lot of differences, especially when it comes to the gut microbiome,"
she says.

Most of the bacteria that live in the human gut are anaerobic, meaning
that they do not require oxygen to survive. Some of these bacteria can
tolerate low levels of oxygen, while others, such as F. prausnitzii,
cannot survive oxygen exposure, which makes it difficult to study them
in a laboratory. Some researchers have designed devices in which they
can grow human colon cells along with bacteria that tolerate low levels
of oxygen, but these don't work well for F. prausnitzii and other highly oxygen-intolerant microbes.

To overcome this, the MIT team designed a device that allows them to
precisely control oxygen levels in each part of the system. Their device contains a channel that is coated with cells from the human mucosal
barrier of the colon.

Below these cells, nutrients are pumped in to keep the cells alive. This
bottom layer is oxygen-rich, but the concentration of oxygen decreases
toward the top of the mucosal cell layer, similarly to what happens in
the interior of the human colon.

Just as they do in the human colon, the barrier cells in the channel
secrete a dense layer of mucus. The MIT team showed that F. prausnitzii
can form clouds of cells in the outer layer of this mucus and survive
there for up to four days, in an environment that is kept oxygen-free
by fluid flowing across it.

This fluid also contains nutrients for the microbes.

Using this system, the researchers were able to show that F. prausnitzii
does influence cell pathways involved in inflammation. They observed
that the bacteria produce a short-chain fatty acid called butyrate,
which has previously been shown to reduce inflammation. After butyrate
levels went up, the mucosal cells showed a reduction in the activity of
a pathway called NF kappa B. This reduction calms inflammation.



========================================================================== "Overall, this pathway has been reduced, which is really similar to what
people have seen in humans," Zhang says. "It seems that the bacteria
are desensitizing the mammalian cells to not overreact to the dangers
in the outside environment, so the inflammation status is being calmed
down by the bacteria." Patients with Crohn's disease often have reduced
levels of F. prausnitzii, and the lack of those bacteria is hypothesized
to contribute to the overactive inflammation seen in those patients.

When the researchers added butyrate to the system, without bacteria,
it did not generate all of the effects that they saw when the bacteria
were present. This suggests that some of the bacteria's effects may be
exerted through other mechanisms, which the researchers hope to further investigate.

Microbes and disease The researchers also plan to use their system to
study what happens when they add other species of bacteria that are
believed to play a role in Crohn's disease, to try to further explore
the effects of each species.

They are also planning a study, working with Alessio Fasano, the division
chief of pediatric gastroenterology and nutrition at Massachusetts General Hospital, to grow mucosal tissue from patients with celiac disease and
other gastrointestinal disorders. This tissue could then be used to study microbe- induced inflammation in cells with different genetic backgrounds.

"We are hoping to get new data that will show how the microbes and
the inflammation work with the genetic background of the host, to see
if there could be people who have a genetic susceptibility to having
microbes interfere with the mucosal barrier a little more than other
people," Griffith says.

She also hopes to use the device to study other types of mucosal barriers, including those of the female reproductive tract, such as the cervix
and the endometrium.

The research was funded by the U.S. National Institutes of Health,
the Boehringer Ingelheim SHINE Program, and the National Institute of Environmental Health Sciences.


========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jianbo Zhang, Yu-Ja Huang, Jun Young Yoon, John Kemmitt, Charles
Wright,
Kirsten Schneider, Pierre Sphabmixay, Victor Hernandez-Gordillo,
Steven J. Holcomb, Brij Bhushan, Gar Rohatgi, Kyle Benton, David
Carpenter, Jemila C. Kester, George Eng, David T. Breault,
Omer Yilmaz, Mao Taketani, Christopher A. Voigt, Rebecca
L. Carrier, David L. Trumper, Linda G. Griffith. Primary Human
Colonic Mucosal Barrier Crosstalk with Super Oxygen-Sensitive
Faecalibacterium prausnitzii in Continuous Culture. Med, 2020;
DOI: 10.1016/j.medj.2020.07.001 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200806153555.htm

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