< 0.05 were considered statistically significant.
False discovery rates (qvalue) of the metabolo-
mics and 16SrDNA amplicon sequencing data
were estimated with the Benjamini-Hochberg
procedure. The Smirnov-Grubbs’test was used
for evaluating outliers. The similarity of micro-
biomes was tested using PERMANOVA (per-
mutational multivariate analysis of variance).
REFERENCES AND NOTES
- P. J. Turnbaughet al., An obesity-associated gut microbiome
with increased capacity for energy harvest.Nature 444 ,
1027 – 1031 (2006). doi:10.1038/nature05414;
pmid: 17183312 - V. K. Ridauraet al., Gut microbiota from twins discordant for
obesity modulate metabolism in mice.Science 341 , 1241214
(2013). doi:10.1126/science.1241214; pmid: 24009397 - M. T. Khan, M. Nieuwdorp, F. Bäckhed, Microbial modulation of
insulin sensitivity.Cell Metab. 20 , 753–760 (2014).
doi:10.1016/j.cmet.2014.07.006; pmid: 25176147 - L. M. Coxet al., Altering the intestinal microbiota during a
critical developmental window has lasting metabolic
consequences.Cell 158 , 705–721 (2014). doi:10.1016/
j.cell.2014.05.052; pmid: 25126780 - A. D. Kosticet al., The dynamics of the human infant gut
microbiome in development and in progression toward type
1 diabetes.Cell Host Microbe 17 , 260–273 (2015). doi:10.1016/
j.chom.2015.01.001; pmid: 25662751 - J. L. Sonnenburg, F. Bäckhed, Diet-microbiota interactions as
moderators of human metabolism.Nature 535 ,56–64 (2016).
doi:10.1038/nature18846; pmid: 27383980 - I. Choet al., Antibiotics in early life alter the murine colonic
microbiome and adiposity.Nature 488 , 621–626 (2012).
doi:10.1038/nature11400; pmid: 22914093 - P. Kovatcheva-Datcharyet al., Dietary fiber-induced
improvement in glucose metabolism is associated with
increased abundance of prevotella.Cell Metab. 22 ,
971 – 982 (2015). doi:10.1016/j.cmet.2015.10.001;
pmid: 26552345 - H. J. Flint, E. A. Bayer, M. T. Rincon, R. Lamed, B. A. White,
Polysaccharide utilization by gut bacteria: Potential for new
insights from genomic analysis.Nat. Rev. Microbiol. 6 , 121– 131
(2008). doi:10.1038/nrmicro1817; pmid: 18180751 - S. Fukudaet al., Bifidobacteria can protect from enteropathogenic
infection through production of acetate.Nature 469 ,543– 547
(2011). doi:10.1038/nature09646;pmid: 21270894 - Y. Furusawaet al., Commensal microbe-derived butyrate
induces the differentiation of colonic regulatory T cells.Nature 504 ,
446 – 450 (2013). doi:10.1038/nature12721;pmid: 24226770 - G. Frostet al., The short-chain fatty acid acetate reduces
appetite via a central homeostatic mechanism.Nat. Commun.
5 , 3611 (2014). doi:10.1038/ncomms4611; pmid: 24781306 - W. J. Lee, K. Hase, Gut microbiota-generated metabolites in
animal health and disease.Nat. Chem. Biol. 10 , 416– 424
(2014). doi:10.1038/nchembio.1535; pmid: 24838170 - E. E. Canfora, J. W. Jocken, E. E. Blaak, Short-chain fatty acids
in control of body weight and insulin sensitivity.Nat. Rev.
Endocrinol. 11 , 577–591 (2015). doi:10.1038/nrendo.2015.128;
pmid: 26260141 - I. Kimuraet al., The gut microbiota suppresses insulin-
mediated fat accumulation via the short-chain fatty acid
receptor GPR43.Nat. Commun. 4 , 1829 (2013). doi:10.1038/
ncomms2852; pmid: 23652017 - I. Kimuraet al., Short-chain fatty acids and ketones directly
regulate sympathetic nervous system via G protein-coupled
receptor 41 (GPR41).Proc. Natl. Acad. Sci. U.S.A. 108 ,
8030 – 8035 (2011). doi:10.1073/pnas.1016088108;
pmid: 21518883 - A. N. Thorburnet al., Evidence that asthma is a developmental
origin disease influenced by maternal diet and bacterial
metabolites.Nat. Commun. 6 , 7320 (2015). doi:10.1038/
ncomms8320; pmid: 26102221 - P. D. Wadhwa, C. Buss, S. Entringer, J. M. Swanson,
Developmental origins of health and disease: Brief history of
the approach and current focus on epigenetic mechanisms.
Semin. Reprod. Med. 27 , 358–368 (2009). doi:10.1055/
s-0029-1237424; pmid: 19711246 - M. G. Dominguez-Belloet al., Partial restoration of the
microbiota of cesarean-born infants via vaginal microbial
transfer.Nat. Med. 22 , 250–253 (2016). doi:10.1038/
nm.4039; pmid: 26828196
20. S. Ussaret al., Interactions between gut microbiota, host
genetics and diet modulate the predisposition to obesity and
metabolic syndrome.Cell Metab. 22 , 516–530 (2015).
doi:10.1016/j.cmet.2015.07.007; pmid: 26299453
21. R. N. Carmodyet al., Diet dominates host genotype in shaping
the murine gut microbiota.Cell Host Microbe 17 ,72–84 (2015).
doi:10.1016/j.chom.2014.11.010; pmid: 25532804
22. S. Fujisakaet al., Diet, genetics, and the gut microbiome drive
dynamic changes in plasma metabolites.Cell Rep. 22 ,
3072 – 3086 (2018). doi:10.1016/j.celrep.2018.02.060;
pmid: 29539432
23. R. A. Koethet al., Intestinal microbiota metabolism of
L-carnitine, a nutrient in red meat, promotes atherosclerosis.
Nat. Med. 19 , 576–585 (2013). doi:10.1038/nm.3145;
pmid: 23563705
24. E. Y. Hsiaoet al., Microbiota modulate behavioral and
physiological abnormalities associated with
neurodevelopmental disorders.Cell 155 , 1451–1463 (2013).
doi:10.1016/j.cell.2013.11.024; pmid: 24315484
25. S. Yoshimotoet al., Obesity-induced gut microbial metabolite
promotes liver cancer through senescence secretome.
Nature 499 ,97–101 (2013). doi:10.1038/nature12347;
pmid: 23803760
26. F. De Vadderet al., Microbiota-generated metabolites promote
metabolic benefits via gut-brain neural circuits.Cell 156 ,
84 – 96 (2014). doi:10.1016/j.cell.2013.12.016; pmid: 24412651
27. J. C. McNeliset al., GPR43 potentiatesb-cell function in
obesity.Diabetes 64 , 3203–3217 (2015). doi:10.2337/
db14-1938; pmid: 26023106
28. G. Tolhurstet al., Short-chain fatty acids stimulate glucagon-
like peptide-1 secretion via the G-protein-coupled receptor
FFAR2.Diabetes 61 , 364–371 (2012). doi:10.2337/db11-1019;
pmid: 22190648
29. C. Tanget al., Loss of FFA2 and FFA3 increases insulin secretion
and improves glucose tolerance in type 2 diabetes.Nat. Med. 21 ,
173 – 177 (2015). doi:10.1038/nm.3779; pmid: 25581519
30. E. Le Poulet al., Functional characterization of human receptors for
short chain fatty acids and their role in polymorphonuclear cell
activation.J. Biol. Chem. 278 ,25481–25489 (2003). doi:10.1074/
jbc.M301403200; pmid: 12711604
31. A. J. Brownet al., The Orphan G protein-coupled receptors
GPR41 and GPR43 are activated by propionate and other short
chain carboxylic acids.J. Biol. Chem. 278 , 11312–11319 (2003).
doi:10.1074/jbc.M211609200; pmid: 12496283
32. A. Jawerbaum, V. White, Animal models in diabetes and
pregnancy.Endocr. Rev. 31 , 680–701 (2010). doi:10.1210/
er.2009-0038; pmid: 20534704
33. J. L. Pluznicket al., Olfactory receptor responding to gut
microbiota-derived signals plays a role in renin secretion and blood
pressure regulation.Proc.Natl.Acad.Sci.U.S.A. 110 , 4410– 4415
(2013). doi:10.1073/pnas.1215927110; pmid: 23401498
34. I. Kimura, A. Ichimura, R. Ohue-Kitano, M. Igarashi, Free fatty
acid receptors in health and disease.Physiol. Rev. 100 ,
171 – 210 (2020). doi:10.1152/physrev.00041.2018;
pmid: 31487233
35. N. Singhet al., Activation of Gpr109a, receptor for niacin and
the commensal metabolite butyrate, suppresses colonic
inflammation and carcinogenesis.Immunity 40 , 128– 139
(2014). doi:10.1016/j.immuni.2013.12.007; pmid: 24412617
36. K. M. Maslowskiet al., Regulation of inflammatory responses
by gut microbiota and chemoattractant receptor GPR43.
Nature 461 , 1282–1286 (2009). doi:10.1038/nature08530;
pmid: 19865172
37. K. Huberet al., Inhibitors of histone deacetylases: Correlation
between isoform specificity and reactivation of HIV
type 1 (HIV-1) from latently infected cells.J. Biol. Chem.
286 ,22211–22218 (2011). doi:10.1074/jbc.M110.180224;
pmid: 21531716
38. M. Waldecker, T. Kautenburger, H. Daumann, C. Busch,
D. Schrenk, Inhibition of histone-deacetylase activity by short-
chain fatty acids and some polyphenol metabolites formed in
the colon.J. Nutr. Biochem. 19 , 587–593 (2008). doi:10.1016/
j.jnutbio.2007.08.002; pmid: 18061431
39. A. K. Taggartet al., (D)-beta-Hydroxybutyrate inhibits
adipocyte lipolysis via the nicotinic acid receptor PUMA-G.
J. Biol. Chem. 280 , 26649–26652 (2005). doi:10.1074/
jbc.C500213200; pmid: 15929991
40. J. A. Sanfordet al., Inhibition of HDAC8 and HDAC9 by
microbial short-chain fatty acids breaks immune tolerance of
the epidermis to TLR ligands.Sci. Immunol. 1 , eaah4609
(2016). doi:10.1126/sciimmunol.aah4609; pmid: 28783689
41. S. D. Parlee, O. A. MacDougald, Maternal nutrition and risk of
obesity in offspring: The Trojan horse of developmental
plasticity.Biochim. Biophys. Acta 1842 , 495–506 (2014).
doi:10.1016/j.bbadis.2013.07.007; pmid: 23871838
42.R.C.Whitaker,J.A.Wright,M.S.Pepe,K.D.Seidel,
W. H. Dietz, Predicting obesity in young adulthood from
childhood and parental obesity.N. Engl. J. Med. 337 ,
869 – 873 (1997). doi:10.1056/NEJM199709253371301;
pmid: 9302300
- N. J. Binkin, R. Yip, L. Fleshood, F. L. Trowbridge, Birth weight
and childhood growth.Pediatrics 82 , 828–834 (1988).
pmid: 3186371 - T. Harder, E. Rodekamp, K. Schellong, J. W. Dudenhausen,
A. Plagemann, Birth weight and subsequent risk of type 2
diabetes: A meta-analysis.Am. J. Epidemiol. 165 , 849– 857
(2007). doi:10.1093/aje/kwk071; pmid: 17215379 - H. K. Nam, K. H. Lee, Small for gestational age and obesity:
Epidemiology and general risks.Ann. Pediatr. Endocrinol. Metab.
23 ,9–13 (2018). doi:10.6065/apem.2018.23.1.9;
pmid: 29609444 - F. Oberdorfer, A. Theobald, C. Prenant, A practical method for
the preparation of^11 C-acetate.Appl. Radiat. Isot. 46 , 317– 321
(1995). doi:10.1016/0969-8043(95)00008-2 - J. Miyamotoet al., Ketone body receptor GPR43 regulates lipid
metabolism under ketogenic conditions.Proc.Natl.Acad.Sci.U.S.A.
116 ,23813–23821 (2019). doi:10.1073/pnas.1912573116;
pmid: 31685604 - M. Kasubuchiet al., Membrane progesterone receptor beta
(mPRb/Paqr8) promotes progesterone-dependent neurite
outgrowth in PC12 neuronal cells via non-G protein-coupled
receptor (GPCR) signaling.Sci. Rep. 7 , 5168 (2017).
doi:10.1038/s41598-017-05423-9; pmid: 28701790 - T. Satoet al., Paneth cells constitute the niche for Lgr5 stem
cells in intestinal crypts.Nature 469 , 415–418 (2011).
doi:10.1038/nature09637; pmid: 21113151 - M. Arita, Mediator lipidomics in acute inflammation and
resolution.J. Biochem. 152 , 313–319 (2012). doi:10.1093/jb/
mvs092; pmid: 22923733 - K. Tanakaet al., Compensatory glutamine metabolism
promotes glioblastoma resistance to mTOR inhibitor
treatment.J. Clin. Invest. 125 , 1591–1602 (2015). doi:10.1172/
JCI78239; pmid: 25798620 - I. Kimuraet al., Maternal gut microbiota in pregnancy dictates
offspring metabolic phenotype, v6, Dryad (2020);
https://doi.org/10.5061/dryad.5hqbzkh29.
ACKNOWLEDGMENTS
We thank K. Igarashi for metabolome analysis; A. Nagata for SCFA
analysis; M. Arita and S. Kasuga for in vitro assay; and T. Sasaki,
M. Akehi, and H. Hirano for PET imaging.Funding:This work
was supported by research grants from the JSPS KAKENHI
(JP17H05344 to I.K., JP15H05897 and JP15H05898 to M.A.,
and JP18H04680 and JP17KT0055 to K.H.), AMED (JP18gm1010007
to I.K. and JP18gm1010004h0103 to K.H.), the Lotte Foundation
(to I.K.), the Institute for Fermentation Osaka (to I.K.), the
Takeda Science Foundation (to H.K.), the Asahi Grass Foundation
(to K.H.), and the Yakult Science Foundation (to K.H.).Author
contributions:I.K., J.M., R.O.-K., K.W., T.Y., M.O., R.A., Y.I., D.K.,
D.I., A.I., Y.T., S.T., S.K., M.W., M.I., F.N., H.K., M.S., K.I., and K.H.
performed the experiments. I.K., J.M., R.O.-K., and K.H. wrote the
manuscript. I.K., J.M., R.O.-K., J.I., G.T., H.O., M.A., H.I., and
K.H. interpreted the data. I.K. and K.H. supervised the project. All
authors read and approved the final manuscript.Competing interests:
Theauthorsdeclarenocompetinginterests.Data and materials
availability:ThesourcedataunderlyingFigs.1to6,figs.S1toS24,and
metabolome analysis have been deposited into the Dryad repository
( 52 ). The raw data for 16SrDNA amplicon sequencing have been
deposited at the DNA Data Bank of Japan (DDBJ) under the accession
nos. DRA007699 (fig. S3, A and B), DRA007700 (fig. S5, A and B),
DRA009267 (fig. S6, A and B), DRA007701 (fig. S13, A and B),
DRA009265 (fig. S19, A and B), and DRA009266 (fig. S23, A and B). All
other data generated or analyzed during this study are included in this
article and its supplementary materials.
SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/367/6481/eaaw8429/suppl/DC1
Figs. S1 to S24
Tables S1 to S5
View/request a protocol for this paper fromBio-protocol.
30 January 2019; resubmitted 25 November 2019
Accepted 13 January 2020
10.1126/science.aaw8429
Kimuraet al.,Science 367 , eaaw8429 (2020) 28 February 2020 12 of 12
RESEARCH | RESEARCH ARTICLE