936 27 MAY 2022 • VOL 376 ISSUE 6596 science.org SCIENCE
causal relationship between oral micro-
biota dysbiosis and systemic disease has
not been fully addressed, characteristic
alterations in the oral microbiota in spe-
cific disease conditions could have value
as a diagnostic tool. Considering that the
concurrent expansion of oral microbes in
the intestine is often associated with the
development of systemic inflammatory
diseases, combined examination of sali-
vary and fecal microbiota may improve di-
agnostic accuracy. Indeed, a combinatorial
analysis of oral and stool microbiota im-
proved discrimination of CRCs from colon
polyps ( 15 ).
Conventional treatments of oral diseases
have limited effects in restoring a healthy
bacterial community, underscoring the
need to develop approaches to manipulate
the oral ecosystem. Clinical studies of fecal
microbiota transplantation have raised the
possibility of developing oral microbiota
transplantation. Additionally, oral bac-
teria–derived molecules may be promis-
ing targets for intervention. For example,
nitrate-containing oral hygiene products
might help promote beneficial bacteria.
Additional approaches to target the oral
microbiota could also include genetically
modified bacteria that secrete desired pro-
teins and bacteriophages to target specific
microbes. Bacteriophages have high host
specificity and typically infect and kill
a single bacterial species, and therefore
could be used to rationally manipulate
the oral microbiota structure by targeting
keystone pathobionts. Employing multiple
strategies simultaneously will likely maxi-
mize the benefit of future oral microbiota-
targeted therapeutics for the advancement
of oral and overall health. j
REFERENCES AND NOTES
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Dewhirst, G. G. Borisy, Proc. Natl. Acad. Sci. U.S.A. 113 ,
E791 (2016). - S. A. Wilbert, J. L. Mark Welch, G. G. Borisy, Cell Rep. 30 ,
4003 (2020). - J. O. Lundberg, M. Carlström, E. Weitzberg, Cell Metab.
28 , 9 (2018). - T. Maekawa et al., Cell Host Microbe 15 , 768 (2014).
- J. A. Fellows Yates et al., Proc. Natl. Acad. Sci. U.S.A. 118 ,
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(2019). - K. Atarashi et al., Science 358 , 359 (2017).
- J. Lloyd-Price et al., Nature 569 , 655 (2019).
- M. R. Rubinstein et al., Cell Host Microbe 14 , 195 (2013).
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ACKNOWLEDGMENTS
T hanks to O. Sampetrean, W. Suda, and L. Takayasu for helpful
discussions. K.H. is a scientific advisory board member of
Vedanta Biosciences and 4BIO CAPITAL.
10.1126/science.abnPERSPECTIVEModulating brain function
with microbiota
M icrobial metabolites identified in animal models and
human neurological diseases could be therapeutic targets
By Jane A. Foster1,F
rom the discovery of roles of the gut
microbiota in metabolic disorders such
as obesity ( 1 ) to recent discoveries of
gut microbiota modulating responses
to cancer immunotherapy ( 2 ), micro-
biome research has expanded to all
areas of biomedical research over the past
15 years. A vital role for gut microbiota–
brain communication in brain development,
behavior, and function has emerged ( 3 ).
Research using germ-free mice has played
a considerable role in identifying brain sys-
tems that may be regulated by microbiota,
including blood-brain barrier permeability,
brain volume, neural circuitry, myelination,
and alterations in microglia ( 3 ). Microbial-
derived molecules, including neurotransmit-
ters, short-chain fatty acids, bile acids, lac-
tate, and vitamins, exert local effects in the
gastrointestinal environment but can also
enter the circulation to act at remote sites,
including the brain ( 4 ). Recent efforts to
translate preclinical findings in amyotrophic
lateral sclerosis (ALS) and autism spectrum
disorder (ASD) to the clinic highlight the po-
tential for clinically important discoveries in
microbiota–brain research ( 5 – 7 ).
Microbe–host interactions at the intesti-
nal barrier play diverse roles in pathogen de-
fense, immune system development, energy
metabolism, and gastrointestinal physiology
and homeostasis. In the context of the gut-
brain axis, neural, endocrine, metabolic, and
immune pathways facilitate microbiota-to-
brain signaling ( 3 ). In the search to identify
direct mechanisms that connect gut micro-
biota to brain health, the potential role of
microbial metabolite pathways has become
evident. Microbial genes outnumber host
genes such that the genetic and metabolic
potential of the metagenome substantially
adds to the biochemical flexibility of the host
( 8 ). Precise mapping of the biological mecha-
nisms that connect gut microbiota to brain
function is needed to identify microbiome-
associated modulators that contribute to
pathophysiological processes and to assess
their causative effects in human disease.
Recent studies of microbiota–brain con-
nections have effectively translated mecha-nistic findings in animal models to corre-
sponding clinical populations ( 5 – 7 ) (see the
figure). For example, a microbial metabolite
signaling pathway identified in an animal
model of ALS is comparable to metabolite
alterations in serum from patients with ALS
( 5 ). ALS is a neurodegenerative motor neu-
ron disease that leads to muscle weakness
and atrophy. Microbiota depletion worsened
ALS-like motor symptoms in superoxide dis-
mutase-1 mutant (Sod1G93A) mice, a model of
ALS ( 5 ). Metagenomic sequencing revealed
compositional and functional differences
between the gut microbiome from Sod1G93A
mice and wild-type littermates. Notably, sev-
eral bacterial genera were associated with
disease features, and bacterial genes encod-
ing enzymes involved in nicotinamide (NAM)
and nicotinate, or niacin (NA), metabolism
were reduced in Sod1G93A mice ( 5 ). Dietary
NAM and NA, commonly known as vitamin
B3, are precursors for nicotinamide ade-
nine dinucleotide (NAD) ( 9 ), which plays an
essential role in cellular metabolism. NAD
concentrations in brain tissue, measured
using magnetic resonance spectroscopy, are
reduced in aging (9, 10), demonstrating the
potential of this signaling cascade as a thera-
peutic target in aging-associated diseases.
Using a probiotic approach, coloniza-
tion of antibiotic-treated Sod1G93A mice with
ALS-associated Akkermansia muciniphila
had a beneficial effect on disease severity,
whereas colonization with ALS-associated
Ruminococcus torques or Parabacteroides
distanonis exacerbated ALS symptoms in
antibiotic-treated Sod1G93A mice. Moreover,
improvement in disease severity after
A. muciniphila colonization of Sod1G93A mice
was associated with enrichment of NAM
biosynthetic intermediates in serum, and in-
dependent supplementation of Sod1G93A mice
with NAM also improved behavioral and
neurological motor tests ( 5 ).
In a cohort of 37 ALS patients, reduced
serum and cerebrospinal fluid (CSF) concen-
trations of NAM compared with 29 healthy
individuals were observed. Compositional
differences in gut microbiota between
ALS patients and healthy individuals were
also found; however, a specific role for
Akkermansia or other taxa in affecting NAMSPECIAL SECTION THE SYSTEMIC MICROBIOME