Science - USA (2022-05-27)

27 MAY 2022 • VOL 376 ISSUE 6596 937

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concentrations in human ALS has yet to be

demonstrated ( 5 ). Thus, this represents a

potentially clinically important microbial

metabolite–brain signaling pathway that

might, in the future, be modulated to allevi-

ate ALS symptoms ( 5 ) and potentially other

diseases of aging.

Harnessing discoveries in microbiota–

brain connections could improve clinical

outcomes in patients with neurological dis-

orders. Recent studies in ASD demonstrate

the potential for clinically relevant findings.

A substantial body of preclinical and clin-

ical evidence demonstrates a role for the

gut microbiota in ASD ( 11 ). Although caus-

ative microbiome-associated mechanisms in

ASD in humans have not been established,

case-control studies demonstrate alterations

in gut microbiota composition, as well as

altered plasma and fecal metabolic pheno-

types, in individuals with ASD when com-

pared with typically developing children

and adolescents (12, 13). Moreover, several

bacterial taxa and signaling pathways are

associated with clinical symptoms and sever-

ity ( 12 ). To translate these findings, it will be

necessary to move beyond correlative evi-

dence linking microbiota to ASD to specific

microbiota–brain mechanisms.

A recent study identified a microbial metab-

olite pathway that affects anxiety-like behav-

ior in mice, a clinical symptom often present

in ASD ( 6 ). Previous preclinical and clinical

work implicated a pathophysiological impact

of larger amounts of the microbiota-derived

aromatic metabolite 4-ethylphenyl sulfate

(4-EPS) on behavior in the maternal immune

activation mouse model of ASD and in in-

dividuals with ASD ( 12 , 14 ). It was demon-

strated that the gut commensal bacterium

Bacteroides ovatus can metabolize tyrosine,

a common dietary amino acid, to produce

p-coumaric acid, which in turn can be metab-

olized by a second commensal bacterium,

Lactobacillus plantarum, to produce 4-EP,

which is then sulfonated by host cells to pro-

duce 4-EPS. Indeed, 4-EPS was detected in

the serum and brain tissue of mice colonized

with bacterial strains engineered to produce

4-EP (4-EP+) ( 6 ). Brain changes in 4-EP+ mice

included differential expression of oligoden-

drocyte maturation and myelination genes,

lower structural connectivity, and increased

anxiety-like behavior. Furthermore, treat-

ment of 4-EP+ mice with clemastine fuma-

rate, to promote oligodendrocyte maturation,

improved behavior, suggesting that a gut-

derived metabolite can signal to the brain

to influence anxiety-like behavior through

effects on oligodendrocytes and myelination

( 6 ). The mechanism of how increased 4-EPS

concentrations affect oligodendrocyte mat-

uration, myelination, and brain connectivity

has not been identified.

In a parallel study, 4-EPS was identified

as an actionable therapeutic target with po-

tential clinical benefit in ASD ( 7 ). A proof-

of-concept experiment in mice showed that

oral administration of the gastrointestin-

al-restricted adsorbent drug AB-2004, which

binds and sequesters aromatic metabolites

( 15 ), reduced 4-EPS concentrations in the

urine of 4-EP+ mice and ameliorated anxiety-

like behavioral deficits ( 7 ). A companion

phase 1 open-label clinical trial demonstrated

that oral administration of AB-2004 was

safe and well tolerated in adolescents with

autism and reduced both anxiety and irrit-

ability, particularly in individuals with high

scores on these indices at baseline ( 7 ). In this

pilot clinical trial, treatment with AB-

for 8 weeks resulted in reduced urinary and

plasma concentrations of 4-EPS and other

gut-derived aromatic metabolites at the end

of treatment, although metabolite concentra-

tions returned to baseline 4 weeks after the

end of treatment ( 7 ). The study also reports

potential benefits on core autism behaviors,

social communication, and repetitive behav-

iors ( 7 ). This preliminary observational trial

suggests that targeting gut-derived metabo-

lites in ASD may be beneficial.

Translation of mechanistic insights dis-

covered in animal models to clinical popula-

tions can guide researchers to move beyond

correlation and association toward clini-

cally actionable microbiota–brain signaling

mechanisms. Pathophysiological changes

can result from depletion of a protective mi-

crobial metabolite, such as NAM, and from

elevation of a detrimental microbial me-

tabolite, such as 4-EPS, suggesting an op-

portunity to provide supplements or thera-

peutically target the microbe and/or the

metabolite, respectively. Moving from basic

science discoveries to innovative clinical

interventions is challenging. Bacterial taxa

that play a role in animal models may not be

the same in human disease. Identifying spe-

cific compositional and functional changes

in microbial metabolite signaling in clinical

samples is required to validate targets. The

substantial clinical heterogeneity in neu-

rological disorders is also challenging and

necessitates multiple parallel approaches

to develop microbial, pharmacological, di-

etary, and lifestyle treatment strategies to

improve clinical outcomes. j

REFERENCES AND NOTES

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5. E. Blacher et al., Nature 572 , 474 (2019).


6. B. D. Needham et al., Nature 602 , 647 (2022).


7. A. Stewart Campbell et al., Nat. Med. 28 , 528 (2022).


8. R. Sender, S. Fuchs, R. Milo, PLOS Biol. 14 , e
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9. N. Braidy et al., Antioxid. Redox Signal. 30 , 251 (2019).


10. X.-H. Zhu, M. Lu, B.-Y. Lee, K. Ugurbil, W. Chen, Proc. Natl.
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11. H. E. Vuong, E. Y. Hsiao, Biol. Psychiatry 81 , 411 (2017).


12. B. D. Needham et al., Biol. Psychiatry 89 , 451 (2021).


13. F. Liu et al., Transl. Psychiatry 9 , 43 (2019).


14. E. Y. Hsiao et al., Cell 155 , 1451 (2013).


15. T. Niwa et al., Nephrol. Dial. Transplant. 6 , 105 (1991).

ACKNOWLEDGMENTS

J.A.F. is funded by the Natural Sciences and Engineering

Research Council of Canada (RGPIN-2018-06834), the

Canadian Institutes of Health Research (451234), and the

Ontario Brain Institute (POND, CAN-BIND). J.A.F. has received

consulting and/or speaker fees from Takeda Canada and

Rothmans, Benson & Hedges Inc.

10.1126/science.abo

(^1) Department of Psychiatry and Behavioural Neurosciences,
McMaster University, Hamilton, ON, Canada.^2 Center for
Depression Research and Clinical Care, Department of
Psychiatry, UT Southwestern Medical Center, Dallas, TX,
USA. Email: [email protected]
Akkermansia
muciniphila
Nicotinamide
ALS: Loss of beneficial metabolite
Altered metagenome
Serum and cerebro-
spinal fluid nicotinamide
Altered metagenome
Plasma and fecal 4-EPS
AB-2004 treatment
reduced anxiety and
Bacteroides ovatus irritability
Lactobacillus
plantarum
Tyrosine
p-Coumaric
acid
4-Ethylphenyl
Mouse model In humans
Autism: Gain of detrimental metabolite
La
pla
actobacillus
plantarum
4-E4-Ethylphenylhlph l
A. muciniphila
Serum nicotinamide
Disease severity
4-EPS in serum and brain
Anxiety-like behavior
Altered oligodendrocyte
gene expression
Structural connectivity
AB-2004 treatment
normalized anxiety-like
behavior
N NH
2
CH 2 CH 3
O
OH
HO
COOH
NH 2
OH
HO
O
Microbial metabolite–brain signaling pathways
Mechanistic insights from animal studies show that gut bacteria–derived metabolites affect
brain function. Comparable changes in gut microbial metabolites in human amyotrophic
lateral sclerosis (ALS) and autism spectrum disorder suggest that exploration of therapeutic
approaches, such as AB-2004 to reduce 4-ethylphenyl sulfate (4-EPS), is warranted.