@article{8439508053944f7bb82a3784b9a83174,
title = "Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome",
abstract = "How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.",
keywords = "CD36, IL-17, Th17 cells, lipid absoprtion, metabolic syndrome, micobiota, mucosal immunity, obesity, segmented filamentous bacteria, sugar",
author = "Yoshinaga Kawano and Madeline Edwards and Yiming Huang and Bilate, {Angelina M.} and Araujo, {Leandro P.} and Takeshi Tanoue and Koji Atarashi and Ladinsky, {Mark S.} and Reiner, {Steven L.} and Wang, {Harris H.} and Daniel Mucida and Kenya Honda and Ivanov, {Ivaylo I.}",
note = "Funding Information: We thank Guilhermina Carriche and Iliyan Iliev for help with gnotobiotic experiments. We thank members of the Ivanov lab for technical help. We thank Sridhar Radhakrishan from ResearchDiets for custom diet design. This work was supported by funding from NIH (DK098378, AI144808, AI163069, AI146817) and Burroughs Wellcome Fund (PATH1019125) to I.I.I. and NIH (DK093674, DK113375) to D.M. Y.K was supported by fellowships from MSD Life Science Foundation , the Russell BerrieFoundation, and the Naomi Berrie Diabetes Center at CUIMC . K.H. is funded by a Grant-in-Aid for Specially Promoted Research from the Japan Society for the Promotion of Science (20H05627). H.H.W. acknowledges funding from NSF (MCB-2025515), NIH (R01AI132403, R01DK118044, R01EB031935), Burroughs Wellcome Fund (PATH1016691), and the Irma T. Hirschl Trust. Funding Information: We next investigated the mechanism by which dietary sugar displaces SFB and metabolic syndrome-protective Th17 cells. Similarly to HFD, sugar did not decrease SFB in ILC3-deficient mice (Figure S6A), suggesting that sugar does not directly affect these Th17-inducing bacteria. To account for host effects, we treated SFB-monocolonized WT animals with 10% sucrose in the drinking water. In contrast to SPF mice (Figure 4C), dietary sugar did not affect SFB levels in monocolonized mice (Figure 5A). Therefore, displacement of SFB by sugar requires the presence of commensal microbes. To identify commensal species that mediate the effects of sugar, we compared microbiota composition of animals fed NCD, HFD, or NCD + 10% sucrose in the drinking water (Figures 5B–5F). HFD-fed and sugar-treated animals had distinct microbiota composition from that of NCD-fed animals but also significantly differed from each other (Figure 5B). This allowed us to narrow down microbiota differences between Th17-depleting (HFD and sugar) and Th17-supporting (NCD) diets. At the family level, Erysipelotrichaceae, Ruminococcaceae, and Lachnospiraceae were upregulated in both Th17-depleting diets (Figure 5C). Erysipelotrichaceae was by far the highest and most significantly enriched family in both HFD and sugar over the NCD (Figure 5C). Erysipelotrichaceae expansion has been reported in metabolic disorders, including DIO in mice (Turnbaugh et al., 2008), as well as in obese humans (Zhang et al., 2009). Erysipelotrichaceae expansion in our dataset contained several operational taxonomic units (OTU). However, one particular OTU, identified as Faecalibaculum rodentium (Frod), was consistently overrepresented in both HFD and sugar-treated animals (Figures 5D–5F). We confirmed expansion of Frod in HFD and sugar-treated mice by qPCR (Figure 5G). Comparison of SFB and Frod levels in individual animals identified strong inverse correlation between the two microbiota members (Figure 5H). Sugar-mediated Frod expansion was dose-dependent (Figure S6B) and was also present in other dietary treatments that eliminated SFB (Figure S6C) but not in dietary treatments that maintained SFB (Figure S6D). HFD-mediated expansion of Frod did not require SFB (Figure S6E). Moreover, it preceded the loss of SFB in SFB-positive animals (Figure S6F). We therefore hypothesized that Frod expansion may be responsible for the loss of SFB in SPF mice. In agreement with this hypothesis, neither sugar nor HFD increased Frod in ILC3-deficient mice, which maintain SFB (Figure S6G; data not shown). To investigate whether this is because of inability of Frod to colonize or expand in ILC3-deficient mice, we compared colonization kinetics following dietary intervention. For this, we first eliminated endogenous Frod by pre-treating WT and ILC3-deficient STOP/CD4 mice with ampicillin (Amp). We next introduced exogenous Frod by oral gavage and followed colonization kinetics. To examine Frod, expansion animals were also given 10% sucrose in the drinking water (Figure 5I). Shortly after Frod gavage (day 2), both WT and STOP/CD4 mice showed similarly high levels of Frod in feces (Figures 5J and 5K), suggesting that Frod is capable of colonizing ILC3-deficient animals. Sugar in the drinking water led to a robust expansion of Frod in WT mice by day 10 (Figure 5J). In contrast, Frod was almost undetectable at day 10 in sugar-treated STOP/CD4 mice (Figure 5K). The foregoing results demonstrate that sugar-mediated expansion of Frod requires ILC3.We find that dietary sugar depletes SFB indirectly by expanding other gut bacteria. We identify Faecalibaculum rodentium as one such microbe and show that it is sufficient to displace SFB and decrease SFB-induced Th17 cells. Frod colonizes the mucosal surface of ileum and colon (Zagato et al., 2020) and as we report here can be found in close proximity to SFB in gnotobiotic animals, suggesting that displacement could be mediated by direct interactions between the two species. This is also supported by the fact that in our colony, Frod is present in low abundance in NCD-fed SPF mice without displacing SFB. SFB displacement required expansion of Frod by sugar or relatively large amounts of Frod in gnotobiotic animals, which suggests that an abundance threshold is required for Frod to displace SFB. The mechanisms by which Frod inhibits SFB will be important to investigate in the future. An equally important question is whether other microbes have similar effects. We consider it likely that other commensals can also negatively affect Th17 cell-inducing microbiota. Our results demonstrate that dietary effects on immunoregulatory microbes can be mediated by microbe-microbe interactions.We thank Guilhermina Carriche and Iliyan Iliev for help with gnotobiotic experiments. We thank members of the Ivanov lab for technical help. We thank Sridhar Radhakrishan from ResearchDiets for custom diet design. This work was supported by funding from NIH (DK098378, AI144808, AI163069, AI146817) and Burroughs Wellcome Fund (PATH1019125) to I.I.I. and NIH (DK093674, DK113375) to D.M. Y.K was supported by fellowships from MSD Life Science Foundation, the Russell BerrieFoundation, and the Naomi Berrie Diabetes Center at CUIMC. K.H. is funded by a Grant-in-Aid for Specially Promoted Research from the Japan Society for the Promotion of Science (20H05627). H.H.W. acknowledges funding from NSF (MCB-2025515), NIH (R01AI132403, R01DK118044, R01EB031935), Burroughs Wellcome Fund (PATH1016691), and the Irma T. Hirschl Trust. Conceptualization, Y.K. and I.I.I.; methodology, Y.K. Y.H. and I.I.I.; software, Y.H. and H.H.W.; formal analysis, Y.K. and Y.H.; investigation, Y.K. M.E. Y.H. A.M.B. L.P.A. T.T. K.A. and M.S.L.; resources, H.H.W. D.M. K.H. and I.I.I.; data curation, Y.K. M.E. and Y.H.; writing—original draft, Y.K. and I.I.I.; writing — review and editing, M.E. Y.K. Y.H. A.M.B. S.L.R. D.M. K.H. and I.I.I.; supervision, S.L.R. H.H.W. D.M. K.H. and I.I.I.; funding acquisition, Y.K. and I.I.I. H.H.W. is a scientific advisor of SNIPR Biome, Kingdom Supercultures, and Fitbiomics, who were not involved in the study. K.H. is a scientific advisory board member of Vedanta Biosciences and 4BIO CAPITAL, who were not involved in the study. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = sep,
day = "15",
doi = "10.1016/j.cell.2022.08.005",
language = "English",
volume = "185",
pages = "3501--3519.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "19",
}
