Science 28Feb2020

RESEARCH ARTICLE SUMMARY

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MICROBIOTA

Maternal gut microbiota in pregnancy influences

offspring metabolic phenotype in mice

Ikuo Kimura†, Junki Miyamoto, Ryuji Ohue-Kitano, Keita Watanabe, Takahiro Yamada,
Masayoshi Onuki, Ryo Aoki, Yosuke Isobe, Daiji Kashihara, Daisuke Inoue, Akihiko Inaba,
Yuta Takamura, Satsuki Taira, Shunsuke Kumaki, Masaki Watanabe, Masato Ito, Fumiyuki Nakagawa,
Junichiro Irie, Hiroki Kakuta, Masakazu Shinohara, Ken Iwatsuki, Gozoh Tsujimoto, Hiroaki Ohno,
Makoto Arita, Hiroshi Itoh, Koji Hase†

INTRODUCTION:In recent decades, the rapid
expansion of antibiotic use and intake of
high-calorie, low-fiber diets have contributed
to disturbances in the gut microbial commu-
nity, predisposing humans to various diseases
such as metabolic syndrome. Although the in-
fluence of microbiota on the postnatal environ-
ment has been well documented, much less is
known regarding the impact of gut microbiota
at the embryonic stage. Although accumu-
lating evidence supports the notion of the
developmental origins of health and disease
(DOHaD), the underlying mechanisms remain
obscure. In this study, we explored the im-
pact of maternal gut microbiota on embry-
onic development and disease susceptibility
late in life.

RATIONALE:Gut microbiota–derived metabolites
represented by short-chain fatty acids (SCFAs;

e.g., acetate, propionate, and butyrate) not only

fuel host cells but also serve as signaling mol-

ecules between the gut microbiota and extra-

intestinal organs. GPR41 and GPR43 belong to

the free fatty acids receptor (FFAR) family and

are receptors for SCFAs. We have previously

corroborated the biological importance of

FFARs in energy metabolism through inter-

actions with dietary ingredients, as well as gut

microbiota–derived metabolites. Gut micro-

bial SCFAs regulate host energy homeostasis

via GPR41 and GPR43 in the sympathetic ner-

vous system, adipose tissues, pancreas, and in-

testine. A recent study further showed that the

gut microbiota of pregnant mice influence im-

mune and brain functions of offspring. These

findings raise the possibility that maternal

SCFAs play a key role in the regulation of dis-

ease susceptibility during postnatal life in the

context of the DOHaD theory.

RESULTS:We found that maternal microbiota

during pregnancy imparts resistance to obe-

sity to their offspring. Pregnant mice were

bred under specific pathogen–free (SPF) and

germ-free (GF) conditions, after which new-

borns were raised by foster mothers under

conventional conditions to align growth en-

vironments after birth. The offspring from GF

mothers were highly susceptible to metabolic

syndrome characterized

by an exacerbation of obe-

sity and glucose intoler-

ance in association with

reduced energy expend-

iture upon high-fat diet

consumption during adult-

hood. A similar phenotype was also observed

in offspring from mice fed a low-fiber (LFi)

diet during pregnancy. Treatment of preg-

nant GF or LFi-fed mice with SCFA rendered

adult offspring resistant to obesity. SCFA in

the colonic lumen of pregnant mice reached

the embryos via the maternal liver and blood-

stream. Notably, the sympathetic nerves, in-

testinal epithelium, and pancreas of embryos

highly expressed GPR41 and/or GPR43 to

sense SCFAs originating from the maternal

gut microbiota. Deficiency in embryonic GPR41

and GPR43 signaling compromised energy

metabolism because of sympathetic dysfunc-

tion and hyperglycemia during the prenatal

period. The SCFA-GPR41 and SCFA-GPR43

axes facilitate the development of neural cells,

GLP-1–expressing enteroendocrine cells, and

pancreaticbcells, thereby shaping embryonic

energy metabolism. This developmental proc-

ess contributes to maintaining postnatal en-

ergy homeostasis.

CONCLUSION:We determined that, during preg-

nancy, the maternal gut microbiota confers

resistance to obesity in offspring via the SCFA-

GPR41 and SCFA-GPR43 axes. During preg-

nancy, SCFAs from the maternal gut microbiota

were sensed by GPR41 and GPR43 in the sym-

pathetic nerve, intestinal tract, and pancreas

of the embryo, influencing prenatal develop-

ment of the metabolic and neural systems.

These findings indicate that the maternal

gut environment during pregnancy is a key

contributor to metabolic programming of

offspringtopreventmetabolicsyndrome.

Thus, the gut microbiota of pregnant mice

provides an environmental cue that fine-

tunes energy homeostasis in offspring to pre-

vent the developmental origin of metabolic

syndrome.

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RESEARCH

Kimuraet al.,Science 367 , 1002 (2020) 28 February 2020 1of1

The list of author affiliations is available in the full article online.

*These authors contributed equally to this work.

†Corresponding author. Email: [email protected] (I.K.);

[email protected] (K.H.)

Cite this article as I. Kimuraet al.,Science 367 , eaaw8429

(2020). DOI: 10.1126/science.aaw8429

Facilitation of neural, enteroendocrine,

and pancreatic development

Prevention of metabolic

syndrome in adulthood

GPCR

HO

O

Acetate

HO

O

Propionate

HO

O

Butyrate

Gut microbial metabolites;

SCFAs

Maternal gut

microbiota

Dietary Fiber

Embryonic

SCFA-receptors

Germ-free

During pregnancy, maternal gut microbiota influences offspring propensity for obesity via
embryonic SCFA receptors.The maternal gut microbial SCFA-embryonic GPR41 and GPR43 axes
facilitate the development of neural cells, GLP-1–expressing enteroendocrine cells, and pancreatic
bcells to shape the development of energy metabolism in offspring, even as adults. GPCR,
Gprotein–coupled receptor.

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at http://dx.doi.

org/10.1126/

science.aaw8429

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