Abstract
Dysbiosis of the gut microbiota has been implicated in the pathogenesis of metabolic syndrome (MetS) and may impair host metabolism through harmful metabolites. Here, we show that Desulfovibrio, an intestinal symbiont enriched in patients with MetS, suppresses the production of the gut hormone glucagon-like peptide 1 (GLP-1) through the production of hydrogen sulfide (H2S) in male mice. Desulfovibrio-derived H2S is found to inhibit mitochondrial respiration and induce the unfolded protein response in intestinal L cells, thereby hindering GLP-1 secretion and gene expression. Remarkably, blocking Desulfovibrio and H2S with an over-the-counter drug, bismuth subsalicylate, improves GLP-1 production and ameliorates diet-induced metabolic disorder in male mice. Together, our study uncovers that Desulfovibrio-derived H2S compromises GLP-1 production, shedding light on the gut-relayed mechanisms by which harmful microbiota-derived metabolites impair host metabolism in MetS and suggesting new possibilities for treating MetS.
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Data availability
Raw and processed data of 16S-seq, GLUTag RNA-seq and intestinal L cell scRNA-seq can be accessed at the Gene Expression Omnibus (GEO) under the SuperSeries accession no. GSE220938. The metagenomic sequencing data can be accessed at GEO under accession no. GSE262397. SILVA128 reference sequence was acquired through QIIME2 plugin RESCRIPt. The mouse reference genome (GRCm38 vM25) was downloaded from GENCODE (https://www.gencodegenes.org). Standard PlusPF database (release 1/12/2024) is available on the Kraken 2 website (https://benlangmead.github.io/aws-indexes/k2). All other data generated in this study are provided as source data or Supplementary Information. Source data are provided with this paper.
Code availability
No custom code or software was generated in this study.
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Acknowledgements
We thank D. Drucker at the Lunenfeld–Tanenbaum Research Institute for providing the GLUTag cell line, C. Zhang at Shanghai Jiao Tong University for sharing patient data11 and Y. Liu at Wuhan University for insightful discussions. We also thank the SKLGE Core Facility at Fudan University for mouse husbandry and equipment and thank other members of the Yu laboratory for technical assistance. This work was supported by a National Key Research and Development Program of China grant 2021YFA0804703 (X.Y.), a National Natural Science Foundation of China grant 92157110 (X.Y.) and a Science and Technology Research Program of Shanghai 2023ZX01 (X.Y.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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X.Y. conceptualized the project. X.Y., M.S. and L.C. supervised the project, interpreted results and wrote the manuscript. Q.Q., H.Z., Z.J., C.W., M.X., B.C., B.L., L.P.D., X.L., R.F., M.Q., Y.L. and D.M. conducted the investigation. X.Z., W.W., W.S., H.H. and H.W. provided methodological instructions.
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Extended data
Extended Data Fig. 1 Correlation of Desulfovibrio and GLP-1 in mouse models.
a, Body weights of WT, TCRb−/− and TCRd−/− mice (n = 6 for all groups). b, Active GLP-1 concentrations in the blood of WT, TCRb−/− and TCRd−/− mice (n = 6 for all groups). c, Body weights of WT, TCRb−/−, TCRb−/−+T, and TCRb−/−-cohoused mice (n = 7, 4, 4, 4 for WT, TCRb−/−, TCRb−/−+T, and TCRb−/−-cohoused, respectively). d, GLP-1 concentrations in WT and rederived TCRb−/− mice (n = 5 for both groups). e, Top 10 phyla in the fecal microbiota of WT, TCRb−/−, TCRb−/−+T, and TCRb−/−-cohoused mice (n = 7, 4, 3, 4 for WT, TCRb−/−, TCRb−/− + T, and TCRb−/− cohoused, respectively). f, Correlation analysis between GLP-1 concentrations and the abundance of F16 (of phylum TM7), Enterobacteriaceae, and Ruminococcaceae (n = 7, 4, 3, 4 for WT, TCRb−/−, TCRb−/−+T, and TCRb−/−-cohoused, respectively). g, Differential microbial abundance analysis between GLP-1high (TCRb−/− and TCRb−/− + T) and GLP-1low (WT and TCRb−/−-cohoused) mice, with refined 16S ASV annotation by BLAST. h, mWGS analysis of Desulfovibrio species and strains between WT and TCRb−/− mice, with bar colors indicating adjusted p values and red blocks indicating the abundance in WT mice (n = 7 for both groups). i, mWGS reads mapped to Desulfovibrio desulfuricans DSM 642 (n = 7 for both groups). Data are presented as Means ± SEMs, except for the boxplots (f,i, center line, median; box limits, upper and lower quartiles; whiskers, Tukey; points, outliers). Statistical analysis was performed with 2-way ANOVA with Sidak’s corrections (a), 1-way ANOVA with Tukey’s corrections (b,c), two-tailed unpaired t test (d,i), Spearman’s correlation analysis with two-tailed t test (f), LEfSe (g), and DESeq2 (h).
Extended Data Fig. 2 Dynamics of Desulfovibrio during HFD feeding in mice and high-fiber diet intervention in humans.
a, Relative Desulfovibrio abundance in the feces of HFD-fed mice, points linked by a line indicating data from a single mouse (n = 7 for all groups). b, Absolute Desulfovibrio abundance normalized against fecal DNA concentrations(n = 7 for all groups). c, Absolute Desulfovibrio abundance normalized against the weights of feces (n = 7 for all groups). d, Body weights in diet-induced obesity (DIO) mice (n = 8, 12 for chow and HFD-fed groups, respectively). e-f, Correlations between Desulfovibrio species and postprandial GLP-1 production in patients with T2DM that were subjected to high-fiber diet intervention11. e, Bubble plots showing the rho values (color) and p values (size), with * indicating statistical significance (p < 0.05). f, Scatter plots showing the correlation between key Desulfovibrio species and the area-under-curve (AUC) values of GLP-1. Data are presented as Means ± SEMs. Statistical analysis was performed with 1-way ANOVA with Dunnett’s corrections (a,b,c), two-tailed unpaired t test (d), and Spearman’s correlation analysis with two-tailed t test (e,f).
Extended Data Fig. 3 Desulfovibrio colonization in the mouse intestine.
a, Representative image of fluorescently labeled Desulfovibrio DSM 642 (red) in vitro (n = 3). b, Colonization densities of Desulfovibrio DSM 642 in male and female germ-free mice, with the gray dotted line indicating the Desulfovibrio abundance in SPF mice (n = 3 for all groups). c, Reduction of microbiota density in antibiotics-treated (Abx) mice (n = 10 for both groups). d, Body weights of Abx and Desulfovibrio DSM 642-colonized male and female mice after 3-week colonization (n = 7 for both groups). e, Relative abundance of Desulfovibrio in SPF mice gavaged with Desulfovibrio DSM 642 (n = 8 for both groups). f, Relative abundance of Desulfovibrio in mice colonized with the Cr-selected microbiota alone or together with Desulfovibrio DSM 642 (n = 6 for both groups). g, Body weights of mice colonized with the Cr-selected microbiota alone or together with Desulfovibrio DSM 642 (n = 6 for both groups). Data are presented as Means ± SEMs. Statistical analysis was performed with 2-way ANOVA with Sidak’s corrections (b), and two-tailed unpaired t test (c,d,e,f,g).
Extended Data Fig. 4 Effects of H2S on GLP-1 production.
a, DPP-4 activities (n = 7) and Dpp4 expression (n = 6) in the intestine of Desulfovibrio DSM 642-colonized mice. b, L cell number in Desulfovibrio DSM 642-colonized mice, determined by immunostaining against GLP-1 (n = 3 for both groups). c, Design of the GLP-1 reporter cell line, GLARE. d-e, Secretion of Gaussia luciferase (d, n = 4) and GLP-1 (e, n = 2) by GLARE cells in response to glucose stimulation. f, Cell viability after NaHS treatment (n = 3). g, Effects of NaHS on the enzymatic activity of Gaussia Luciferase (GLUC), with GLUC secreted by HEK293T cells transfected with a GLuc-encoding plasmid (n = 4). h, Detection of H2S dissipated from NaHS-supplemented cell culture media by the lead acetate assay (n = 1). i, H2S in cell culture media supplemented with NaHS (n = 1). j, Differential abundance of genes in the dissimilatory sulfate reduction pathway between WT and TCRb−/− mice (n = 7). k, mWGS reads aligned to the dsrAB genes of Desulfovibrio DSM 642 in WT and TCRb−/− mice. l-m, Correlations between genes in the dissimilatory sulfate reduction pathway and postprandial GLP-1 production in patients with T2DM that were subjected to high-fiber diet intervention11. l, Bubble plots showing the rho values (color) and p values (size), with * indicating p < 0.05. m, Scatter plots showing the correlation between key genes and the area-under-curve (AUC) of GLP-1 production. n, H2S in the culture of E.coli MG1655, E.coli DH5α, and Desulfovibrio DSM 642 (n = 2). o, H2S in the culture of control E.coli, phsABC+ E.coli, and Desulfovibrio DSM 642 (n = 3). p, Colonization densities of the vector control and phsABC+ E.coli in mice (n = 3). Data are presented as Means ± SEMs. Statistical analysis was performed with Unpaired t test (a,b,p), 1-way ANOVA with Tukey’s corrections (d,g) or Dunnett’s correction (f), DESeq2 (j), and Spearman’s correlation analysis with two-tailed t test (l,m). Illustration was created with BioRender.com with modifications (c,h).
Extended Data Fig. 5 H2S-induced mitochondria dysfunction in L cells.
a, Counts of L cells isolated from Desulfovibrio DSM 642-colonized GcgCre:GFP mice by FACS sorting (n = 4 for both groups). b, Heatmap showing top 5 markers for cell clusters by scRNA-seq analysis. c, Feature plots showing the expression of enteroendocrine cell markers Gcg, Pyy, Nts, and Sct. d, scRNA-seq analysis of the sulfide oxidization unit (SOU) genes in mouse L cells, including Sqor, Ethe1, Tst, and Suox. e, Expression of the sulfide oxidization unit (SOU) genes in FACS-purified bulk mouse L cells detected by qPCR, shown as ΔCt compared to 18S rRNA (n = 6 for all groups). f, Extracellular acidification rate (ECAR) by control and NaHS-treated cells measured by the Seahorse XF Cell Mito Stress Test (n = 6 for both groups). g, Adenylyl cyclases (AC) activity in control and NaHS-treated cells (n = 6 for both groups). Data are presented as Means ± SEMs. Statistical analysis was performed with two-tailed unpaired t test (a,d). Illustration was created with BioRender.com with modifications (e).
Extended Data Fig. 6 Regulation of Gcg expression by UPR.
a, Expression of Pcsk1 and Pyy in the intestine of Abx and Desulfovibrio DSM 642-colonized mice (n = 6 for both groups). b, Violin plots comparing the expression of Pcsk1, Pyy, Chga, and Chgb in L cells from control (Abx) and Desulfovibrio DSM 642-colonized mice by scRNA-seq. c, Correlation analysis between the Desulfovibrio abundance and GCG expression in COAD samples of the TCMA database. d, Gcg expression in Rotenone-treated GLUTag cells (n = 4 for all groups). e, Screening of GLP-1-regulating compounds with a custom metabolite/drug library. f-g, Effects of NaHS and GSH on intracellular ROS, detected with Dichlorodihydrofluorescein (DCF). (f) Histogram of DCF intensities. (g) Percentages of DCF+ cells (n = 6, 5, 6 for Ctrl, NaHS, and GSH group, respectively). h, PCA analysis of transcriptomes of cells treated with NaHS and GSH (n = 3 for all groups). i, GSEA analysis of transcriptomes of cells treated with NaHS and GSH (n = 3 for all groups). j, Xbp1 splicing in cells treated with Bismuth-preabsorbed culture supernatant of Desulfovibrio DSM 642 (n = 3 for all groups). k-m, Xbp1 splicing and Gcg expression in cells treated with classical UPR-inducing agents, Tunicamycin (k, n = 4 for all groups), 2-Deoxy-D-glucose (l, n = 4 for all groups), and Brefeldin A (m, n = 4,3 for control, and BFA, respectively). Data are presented as Means ± SEMs. Statistical analysis was performed with two-tailed unpaired t test (a,b,k,l,m), Spearman’s correlation analysis with two-tailed t test (c), and 1-way ANOVA with Tukey’s corrections (d,g,j). Illustration was created with BioRender.com with modifications (d,e).
Extended Data Fig. 7 The impact of Desulfovibrio on HFD-induced obesity.
a, H2S content in the chow and HFD as well as in the feces of chow- and HFD-fed mice (n = 5 for all groups). b, Absolute quantification of Desulfovibrio and Bilophila in the feces of HFD-fed mice (n = 7,10 for Desulfovibrio and Bilophila, respectively). c, Desulfovibrio abundance in mice colonized with the Cr-selected microbiota alone or together with Desulfovibrio DSM 642 before or after HFD feeding (n = 6 for all groups). Data on day 0 was the same data shown in Fig. 2i. d, Body weight gain of mice colonized with the Cr-selected microbiota alone or together with Desulfovibrio DSM 642 after HFD feeding (n = 6 for all groups). Data are presented as Means ± SEMs. Statistical analysis was performed with 2-way ANOVA with Sidak’s corrections (a,c,d) and two-tailed unpaired t test (b). Illustration was created with BioRender.com with modifications (c).
Extended Data Fig. 8 Safety of Bismuth administration in mice.
a, Experimental design. b, Body weights of mice treated with Bismuth for 8 weeks (n = 6 for both groups). c, Weight of eWAT tissues (n = 6 for both groups). d, Home-cage behavior (n = 6 for both groups). e, Tissue pathology (n = 6 for both groups). f, Blood biochemistry (n = 6 for both groups). g, Gating strategy of blood immune cell analysis (n = 6 for both groups). h, Blood immune cell quantification (n = 6 for both groups). Data are presented as Means ± SEMs. Statistical analysis was performed with two-tailed unpaired t test (b,c,f,h) and 2-way ANOVA with Sidak’s corrections (d). Illustration was created with BioRender.com with modifications (a).
Extended Data Fig. 9 Effect of Bismuth administration on the gut microbiota in mice.
a, Relative abundance of major microbiota members in mice treated with Bismuth for 8 weeks (n = 6 for both groups). Data are presented as Means ± SEMs. Statistical analysis was performed with two-tailed unpaired t test (a).
Extended Data Fig. 10 Mitigation of HFD-induced metabolic dysfunctions by Bismuth.
a, Body weights of HFD-fed mice treated with Bismuth starting around week 4 (n = 6 for both groups). b, Aggregated weight changes of HFD-fed mice treated with Bismuth from 3 independent experiments, normalized to weights at the end of week 3 (the week before Bismuth treatment) (n = 20, 21 for control and Bismuth treatment, respectively). c, Voluntary locomotor activities of control and Bismuth-treated mice, determined by the travel distance of mice in an open field arena (n = 7 for both groups). d-e, Xbp1 splicing in the intestine of Bismuth-treated mice, with the ratios of spliced Xbp1 (Xbp1s) in total Xbp1 (d) and representative gel images (e) shown (n = 5, 6 for control and Bismuth groups, respectively). f, Glucose response curve of ITT (n = 7 for both groups). g, AUC of the glucose response curve in ITT (n = 7 for both groups). h-k, Sequential testing of control and Bismuth-treated mice. (h) Body weight changes of mice, with timepoints of overnight fasting and bleeding marked with arrowheads. (i) Glucose response curve of OGTT. (j) AUC of OGTT responses. (k) Fasting GLP-1. (n = 11, 12 for control and Bismuth, respectively; n = 11 for both groups in k at week 10). l, Body weights of HFD-fed mice treated with Bismuth starting at day 0 (n = 13 for both groups). m, Body weights of DIO mice after 16 weeks of HFD feeding (n = 9 for both groups). Data are presented as Means ± SEMs. Statistical analysis was performed with 2-way ANOVA with Sidak’s corrections (a,b,j,k,l) or no corrections (f), and two-tailed unpaired t test (c,d,g,m). Illustration was created with BioRender.com with modifications (a,h,l).
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Qi, Q., Zhang, H., Jin, Z. et al. Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice. Nat Metab 6, 1601–1615 (2024). https://doi.org/10.1038/s42255-024-01068-x
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DOI: https://doi.org/10.1038/s42255-024-01068-x
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