https://www.economist.com/science-and-technology/2021/02/10/microbial-ecosystems-in-the-mouth-and-gut-are-linked-to-many-ills

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[20210213_stp003]

Both ends against the middle
Microbial ecosystems in the mouth and gut are linked to many ills

Understanding how will help treatments

Science & technologyFeb 13th 2021 edition
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Feb 10th 2021

CYBERSPACE

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"ITHINK IT'S unlikely that any condition in the body is one where the
microbiome isn't involved." That is the considered opinion of Iain
Chapple, one of the speakers at this week's meeting of the American
Association for the Advancement of Science (AAAS), held online this
year instead of in Phoenix, Arizona, as originally planned. Dr
Chapple was, until 2020, head of dentistry at Birmingham University,
in Britain, and is still an active researcher in the field. Mouths
are notorious breeding grounds for hostile bacteria, as anyone who
has ever had a toothache can attest. But even a healthy mouth is
inhabited by lots of bugs (pictured above).

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Meanwhile, at the other end of the alimentary canal, the large
intestine contains so many microbes that they probably outnumber the
cells of the human body. Both bacterial populations have coevolved
with their hosts for millions of years, so Dr Chapple is almost
certainly right about the intimate connection between them and the
body. A pair of sessions at the AAAS discussed some of the latest
relevant findings.

Dr Chapple has been seeking a link between gum disease and rheumatoid
arthritis. In periodontitis, to give gum disease its proper name, the
number of bacteria in the crevice between a tooth and its
surroundings rises from thousands to millions. The gums being well
supplied with blood vessels, such bacteria can hitch a ride to the
rest of the body. This fact has been linked not only with arthritis,
but also with diabetes, Alzheimer's disease and, according to Purnima
Kumar of Ohio State University, who helped to organise the session in
question, over 50 other conditions.

Gummed up

Rheumatoid arthritis comes in many forms, but all involve the immune
system attacking the body's joints. Dr Chapple's studies indicate
that Porphyromonas gingivalis, one of the hitchhiking bacteria, can
provoke such a reaction. The next step, he suggests, is to look at a
group of arthritis-free individuals who have periodontitis and see
whether they subsequently develop arthritis more frequently than
average members of the population.

The arthritis link is still tentative. That with diabetes is not.
Bacteria associated with periodontitis have long been known to
disrupt the body's ability to absorb glucose, resulting in the
heightened levels of that sugar in the bloodstream which are
diabetes's distinctive feature. The connection seems to work the
other way around, too. High glucose levels disrupt the body's
inflammatory system, leading to a host of complications, including
gum disease.

In new research, Dr Kumar has mapped networks of connections between
various bacterial species and the components of the immune system
with which they interact. She has done this in three groups of
people: those with periodontitis, those with both periodontitis and
diabetes, and those with neither. Her work has shown that these
networks break down completely in people with both diseases. That
limits the immune system's influence and prevents it cleaning house.
Treating people's periodontitis boosted their networks, but did so
more slowly in those with diabetes.

Both the arthritis and the diabetes connections are interesting. But
the most intriguing possible connection of all is that between
periodontitis and Alzheimer's disease. Mark Ryder of the University
of California, San Francisco, thinks they are linked by substances
known as gingipains. These cause the entanglement of neuronal
proteins called tau. Tau tangles are a symptom of Alzheimer's, and
people with this illness have high levels of gingipains in their
hippocampi, a pair of brain regions involved in memory formation.
Small-scale trials suggest that gingipain inhibitors may improve
cognition, but bigger samples are needed for conclusive results. Dr
Ryder has therefore launched a trial involving 570 patients, the
results of which are expected by the end of the year.

An army marches in its stomach

At the other end of the alimentary canal, evidence is accumulating of
a connection between the microbiome and another neurological illness,
Parkinson's disease. This started with the observation that many
people who develop Parkinson's first experience digestive
difficulties such as constipation. That prompted the discovery that
certain species of gut bacteria are often present in abnormally large
numbers in those with Parkinson's.

One such species is E. coli (see below). This is a common bug, but
according to Timothy Sampson, a researcher at Emory University School
of Medicine in Atlanta, Georgia, only in Parkinson's patients is it
found attached to the inner surface of the colon. The protein it
attaches itself with is called Curli, and Curli bears a strong
similarity to alpha synuclein, a protein the accumulation of which in
the brain causes Parkinson's-related symptoms. Molecules of alpha
synuclein spur the production of more of their kind, and this
accelerates the spread of the disease, so this discovery has provoked
speculation that Curli-bearing E. coli could be provoking the body to
behave in self-destructive ways.

[20210213_S]
Gutsy bacteria

Dr Sampson has tested this hypothesis in mice. He bred a strain of E.
coli that cannot make Curli and injected mice with it, while
injecting others with unmodified bacteria. Those that received
Curli-producing bacteria expressed higher levels of synuclein and
demonstrated symptoms like involuntary rigidity which, when seen in
people, are associated with Parkinson's disease. That is tantalising.
Should this result hold up in future trials, Dr Sampson hopes it
might be possible to identify those who are susceptible to
Parkinson's long before they begin to show symptoms.

Digestive troubles also seem linked to autism--a link strengthened
when Sarkis Mazmanian of the California Institute of Technology
studied the gut floras of people with autism and identified elevated
levels of several relevant bacterial products. Speaking at the
meeting, Dr Mazmanian discussed his research on one of these
substances, 4-ethylphenol (4EP). This is transformed by the body into
4-ethylphenylsulphate (4EPS). In studies in mice, he has shown that 4
EPS activates brain regions linked to emotional behaviours and may
also reduce connectivity between neurons in important ways. He and
his team claim, as well, that mice with 4EP-producing bacteria in
their guts display social behaviour which mirrors symptoms of autism
in human beings. In particular, the animals seem more anxious (they
are more likely than their peers to hug the walls of an enclosed
space), and less sociable (their communicative squeaks are shorter).

This work is controversial. Some have questioned the statistical
robustness of Dr Mazmanian's earlier papers; others, the very notion
that murine behaviour can say anything useful about a complex human
condition. Overcoming that second objection means experimenting on
people. And this is what Rosa Krajmalnik-Brown of Arizona State
University is doing. Having found that certain microbes are
consistently absent from children with autism, she and her team
attempted a wholesale repopulation by emptying the guts of several
autistic infants of their resident flora and inoculating faecal
enemas taken from healthy contemporaries.

This study yielded intriguing results. The diversity of microbes in
her patients' guts increased throughout a ten-week period of
treatment. That led to positive consequences which remained in some
children even two years after the treatment had finished. As might be
expected, their gastrointestinal symptoms abated. But their behaviour
improved, too.

Dr Krajmalnik-Brown is well aware of the limitations of this
investigation. For one thing, it involved no controls, so the
possibility exists that she was observing a placebo effect. Nor were
food journals kept for the children after the initial treatment had
concluded, so a change in diet may have been responsible for the
positive results. She hopes to correct some of these gaps in larger
trials that are now under way with the aim of getting regulatory
approval for the procedure as a form of treatment. She also hopes to
make therapeutic microbial cocktails in the laboratory, rather than
relying on natural samples.

One further matter of interest in the microbiomes at opposite ends of
the alimentary canal is the extent to which they interact. Does the
mouth, for instance, dictate which microbes make their way down to
the gut? Or does it wield its influence only when the microbiome in
the gut allows it to do so? Or is there no link at all? At the
moment, these are questions without answers. But mapping the
microbial connections between the canal's two ends will surely
provide material for many conferences to come. #

This article appeared in the Science & technology section of the
print edition under the headline "Both ends against the middle"

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