Science 28Feb2020

By Jane Ferguson

T

he early-life period is a critical time:

Events that affect fetal development

can have lifelong implications. Sub-

tle disturbances during human fetal

development affect not only major

developmental outcomes, but also phe-

notypes that may not manifest for decades,

such as risk of cardiometabolic disease ( 1 ).

Despite this, pregnancy remains a poorly un-

derstood physiologic state, and

there is relatively little mecha-

nistic knowledge of how the

maternal environment affects

future disease risk. Studies sug-

gest that maternal microbiota

influence cardiometabolic dis-

ease risk in offspring; however,

the mechanisms underlying this

relationship are elusive. On page

1002 of this issue, Kimura et al.

( 2 ) find that, in mice, maternal

diet and consequent gut microbi-

ota–derived propionate protects

against future obesity and meta-

bolic dysregulation in offspring.

Microbiota, the commensal

organisms residing in a par-

ticular host location, are under-

explored modulators of health

and disease. Microbiota in the

gut, at the interface of human

dietary and systemic metabo-

lism, may have particular rel-

evance for obesity and cardio-

metabolic disease. However,

despite intense interest, there remains a

knowledge gap between the myriad of hy-

pothesized functions attributable to gut

microbiota and those that have actually

been demonstrated through mechanistic

interrogation. Key functions of gut micro-

biota include digestion of diet-derived nu-

trients, which contain components that are

not digestible by the host such as complex

polysaccharides and fibers. This microbial

action generates short-chain fatty acids

(SCFAs), which translocate into the blood-

stream and enter host metabolism. SCFAs,

including propionate, acetate, and butyrate,

can be used as a source of fuel by the host,

but also function as active signaling mol-

ecules ( 3 ). SCFAs have thus been implicated

as key metabolites linking the microbiota to

host metabolic outcomes, including obesity

and insulin sensitivity ( 4 ), and are generally

considered to be protective from metabolic

diseases, although data are conflicting ( 5 ).

The mechanisms linking maternal meta-

bolic status during pregnancy to cardiometa-

bolic disease risk in offspring remain elusive.

Maternal microbiota are an emerging tar-

get of investigation, potentially modulating

both maternal health and fetal development.

Despite speculation that transfer of microbes

from mother to infant may occur in utero, it

is generally accepted that microbial coloni-

zation does not occur in a meaningful way

until birth, when, depending on the method

of birth, maternal vaginal or skin microbes

colonize the infant gut ( 6 ). Thus, the mater-

nal microbiota likely influence fetal develop-

ment in utero through intermediates.

Kimura et al. probed the role of microbial

SCFA production on fetal development and

outcomes in mouse models. Mice whose

mothers were housed in a germ-free facility,

and consequently did not have gut micro-

biota during pregnancy, were highly suscep-

tible to high-fat diet–induced obesity later

in life. Further, these offspring displayed

evidence of glucose intolerance and insu-

lin resistance, suggesting cardiometabolic

disease. The absence of maternal micro-

biota during pregnancy affected offspring

irrespective of vaginal or cesarean birth,

and there were no significant differences

in the gut microbiota of the adult offspring

of germ-free versus conventionally housed

mice, suggesting that the effects were not

mediated through offspring microbiota.

However, there were significant differences

in the amounts of circulating acetate, pro-

pionate, and butyrate in both the mothers

and embryos when comparing germ-free

and conventionally housed mice.

Kimura et al. examined ex-

pression of the SCFA receptors,

G protein–coupled receptor

41 (Gpr41) and Gpr43, in the

brain, intestine, and pancreas

of embryos and adult mice.

High expression in embryonic

tissues suggested that embryos

were sensing maternal-derived

SCFAs through Gpr41 and

Gpr43. However, they observed

lower Gpr41 expression in the

germ-free mice. Loss of Gpr41

expression in mice resulted in

defects in sympathetic nerve

projections to the heart, which

were also apparent in germ-

free offspring. The ability of

the SCFAs to activate sympa-

thetic neuronal differentiation

was confirmed in vitro, with

propionate having the greatest

effect. In mice lacking Gpr43,

the authors found SCFA- and

microbiota-dependent defects in

embryonic enteroendocrine and

pancreatic b-cell development. These data

strongly suggest that altered SCFA signal-

ing through GPR41 and GPR43 in embryonic

tissues could affect development. Indeed,

Kimura et al. showed that the offspring of

mice fed a low-fiber diet during pregnancy

had increased risk of obesity and insulin

resistance. The deleterious effects of a low-

fiber diet could be rescued with propionate

supplementation. When pregnant mice were

given antibiotics, there was no difference in

the metabolic parameters of the offspring of

high-fiber versus low-fiber diet–fed mothers,

confirming the importance of maternal mi-

crobiota in mediating protection.

INSIGHTS | PERSPECTIVES

sciencemag.org SCIENCE

GRAPHIC: V. ALTOUNIAN/

SCIENCE

MICROBIOLOGY

Maternal microbial molecules

affect offspring health

Intestinal molecules during pregnancy in mice may

protect offspring from metabolic disease

Division of Cardiovascular Medicine,

Vanderbilt University Medical Center, Nashville, TN, USA.

Email: [email protected]

Dietary

fber

Microbiota

Propionate

Neural cell

development

Sympathetic

nerve projections

to the heart

Pancreatic b cell

and enteroendocrine

cell development

Protection against

metabolic disease

in adulthood

Maternal

intestinal tract Embryonic development

Maternal

circulation

GPR4 1

GPR4 1

GPR43

978 28 FEBRUARY 2020 • VOL 367 ISSUE 6481

Microbial protection from metabolic disease

Digestion of fiber by microbiota generates short-chain fatty acids (SCFAs).

In pregnant mice, SCFAs, particularly propionate, regulate embryonic

development through G protein–coupled receptor 41 (GPR41) and GPR43.

This protects offspring from metabolic disease in adulthood.

Published by AAAS