Abstract
Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1,2,3,4,5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.
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Data availability
All of the data supporting the findings of this study are included in the Article and Supplementary Tables 1–7. The metagenomic and phosphoproteomic data were uploaded to a public database (China National Microbiology Data Center (NMDC), under accession numbers NMDC10018157 and NMDC10018158, respectively). The following public databases were used in this study: NCBI reference database and Metaquery database. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of the People’s Republic of China (nos 91857115 and 31925021), the National Key Research and Development Program of China (no. 2018YFA0800700), the National Natural Science Foundation of the People’s Republic of China (nos 82130022, 81921001, 92057103, 31872820 and 82070588), the National Cancer Institute Intramural Research Program, the National Key Research and Development Program of China (no. 2022ZD0213000) and the Innovative Research Team of High-Level Local Universities in Shanghai and a Key Laboratory Program of the Education Commission of Shanghai Municipality (ZDSYS14005). We thank the members of the CHESS-MAFLD consortium for their coordination and platform support for this study.
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C.J. conceptualized and designed the study. B.C., L.S., G.Z., Z.S., K.W., L.Y., F.X., P.W., Y.D., Q.N., Q.W., Z.Z., J.X., J.L., Y. Luo., J.C., K.W.K., R.Z., Y.X. and M.-H.Z. performed the experiments and analysed the data. C.J., F.J.G., C.Y., Y. Li and M.-H.Z. supervised the study. B.C., L.S., G.Z. and C.J. wrote the manuscript with input from all of the authors. All of the authors edited the manuscript and approved the final manuscript.
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Extended data figures and tables
Extended Data Fig. 1 Gut microbiota composition differences between smokers with high nicotine and low nicotine levels.
a, Quantification of the nicotine concentrations in lung, ileum content, ileum tissue, brain, liver, eWAT and serum samples obtained from s.c. injection mouse model for two weeks (SPF, n = 8 mice/group). b, Top 10 species of gut bacteria in humans that show high correlation with the known nicotine-degrading enzyme, nicA. These species were identified by MetaQuery. c–i, 30 smokers who were further divided into the HN (high nicotine, n = 16) and LN (low nicotine, n = 14) groups according to their ileal nicotine levels. Ileal nicotine concentrations in HN and LN groups. The data did not obey the normal distribution determined by the Shapiro normality test; thus, the median was used as a break point, and divided into two groups (c). α-diversity of the gut microbiota between the LN and HN individuals, as indicated by the ACE (d), Chao1 (e) and Shannon indices (f). Partial least squares discriminant analysis (PLS-DA) using the Bray-Curtis distance (g). Taxonomic cladograms were generated by LefSe of metagenomic analysis data. The blue colour indicates enriched taxa in the LN group, and the red colour indicates enriched taxa in the HN group. The size of each circle is proportional to the taxon’s abundance (h, i). Data are the means ± s.e.m. b, Correlations were assessed by nonparametric Spearman’s test. c–f, Two-tailed Student’s t-test.
Extended Data Fig. 2 Identification of B. xylanisolvens as a nicotine degrader.
a, Growth curves of B. xylanisolvens with or without nicotine in culture medium (n = 3/group). b, Nicotine concentration in B. xylanisolvens in vitro cultivation compared with control (BHI medium with nicotine supplementation, n = 5/group). c, 1H NMR spectrum (top) and 13C NMR spectrum (bottom) of HPB. d, Production of HPB in B. xylanisolvens in vitro supplementation compared with control (BHI medium with nicotine supplementation, n = 5/group). e, Nicotine and HPB concentrations in ileal tissues of the smoking exposure mouse model for two weeks (SPF, n = 6 mice/group). f, Nicotine and HPB concentration in ileal tissues of the subcutaneous injection mouse model for two weeks (SPF, n = 6 mice/group). g, Structural comparison of the SWISS-MODEL50-predicted B. xylanisolvens NicX and predicted Pseudomonas putida NicA. The Root-Mean-Square-Deviation (RMSD) of 242 aligned residues is 1.323 Å. h, Nonlinear regression for nicotine degradation catalysed by purified NicX. The reaction mixture contained 1 mM FMN, 25 mM Tris-HCl (pH 7.6), 20 ng NicX, and nicotine at different concentrations at 37 °C, n = 3/group. i, Schematic diagram illustrating the workflow for nicX gene deletion in B. xylanisolvens. The diagram was created using BioRender. j, Production of HPB in E. coli and E. coli + nicX in vitro cultivation (LB medium with nicotine supplementation, n = 5/group). k, Production of HPB in B. xylanisolvens and B. xylanisolvens-ΔnicX in vitro cultivation in culture medium (BHI medium with nicotine supplementation, n = 5/group). l, Growth curves of WT and nicX-KO B. xylanisolvens. (n = 3/group). Data are the means ± s.e.m. a, b, l, Two-tailed Student’s t-test. d, j, k, Two-tailed Mann-Whitney U-test. e, f, for Nicotine, one-way ANOVA with Dunnett’s T3 post hoc test; for HPB, Kruskal-Wallis test with Dunn’s test. Experiments in a, b, d, h, j, k, l were performed three times independently.
Extended Data Fig. 3 B. xylanisolvens transplantation alleviates nicotine-accelerated NASH.
HFHCD-fed SPF mice were treated with PBS, B. xylanisolvens colonization, nicotine water, nicotine water plus B. xylanisolvens colonization, and nicotine water plus nicX knock-out B. xylanisolvens colonization for 20 weeks (n = 6 mice/group). a, Faecal B. xylanisolvens abundance analyses of mice by qPCR. b, Ileal nicotine concentrations. c, Body weight gain. d, Body mass composition. e, Liver weights. f, Liver weight–to–body weight ratios. g, h, Serum ALT (g) and AST (h) levels. i, Hepatic TG content. j, Serum TG content. k, Hepatic CE content. l, Serum CE content. m, Serum NEFA content. n–r, Histology scores of hepatic steatosis (n), lobular inflammation (o), ballooning (p), NAFLD activity (q), and fibrosis stage (r). s–u, Relative mRNA levels of genes related to hepatic lipid metabolism (s), inflammation (t) and fibrosis (u). Data are the means ± s.e.m. c, e–i, k–m, One-way ANOVA with Tukey’s post hoc test. a, b, j, One-way ANOVA with Dunnett’s T3 post hoc test. d, n–u, Kruskal-Wallis test with Dunn’s test.
Extended Data Fig. 4 Nicotine-induced activation of intestinal AMPKα.
a, b, Activation of the AMPKα in ileal organoids after treatment with nicotine at different concentrations for 4 h (n = 3 independent experiments). c, Western blot analysis indicated that ileal AMPKα was activated in the nicotine drinking mouse model (SPF, n = 6 mice/group). d, e, Western blot analysis indicated that ileal AMPKα was activated in the smoking mouse model (d) and the subcutaneous injection mouse model (e) (SPF, n = 3 mice/group). f, Western blot analysis of ileal primary enterocytes isolated from WT, Prkaa1ΔIE and Prkaa2ΔIE mice (SPF) and then cultured with or without nicotine (1 μg ml−1) treatment for 4 h. Experiments were performed with n = 4 mice/group. g, Western blot analysis showing ileal AMPK signalling in the nicotine drinking mouse model transplanted with Control or B. xylanisolvens (SPF, n = 6 mice/group). h, i, Western blot analysis showing ileal AMPK signalling in the nicotine drinking mouse model transplanted with E. coli or nicX knock-in E. coli (h); and WT or nicX knock-out B. xylanisolvens (i) (SPF, n = 6 mice/group). j, Western blot analysis showing AMPK signalling in SW480 cells incubated with nicotine (1 μg ml−1) or HPB (1 μg ml−1) for 4 h. This result is representative of 3 independent experiments. In c–e, g–i, mice were supplied nicotine plus HFHCD for two weeks. Data are the means ± s.e.m. (b).
Extended Data Fig. 5 Intestinal AMPKα1 deficiency improves NASH via decreasing ceramide generation.
Eight-week-old male Prkaa1fl/fl and Prkaa1ΔIE mice were administered a HFHCD plus nicotine water for 20 weeks (SPF, n = 8 mice/group). a, Liver weight. b–e, Serum TG (b), hepatic CE (c), serum CE (d) and serum NEFA (e) contents. f–j, Histology scores of hepatic steatosis (f), lobular inflammation (g), ballooning (h), NAFLD activity (i), and fibrosis stage (j). k-m, Relative mRNA levels of genes related to hepatic lipid metabolism (k), inflammation (l) and fibrosis (m). n, o, Eight-week-old male Prkaa1fl/fl (WT) and Prkaa1ΔIE (KO) mice were administered a HFHCD plus nicotine water for 20 weeks (SPF, Prkaa1fl/fl, n = 12 mice; Prkaa1ΔIE, n = 11 mice). PLS-DA analysis of lipid metabolites in the ileum (n). Random forest analysis showing the top 10 lipid metabolites that lead to differences in the ileal lipid profiles (o). p, A schematic diagram illustrating the workflow of phosphorylated proteomics. Created with BioRender. q, Volcano map of phosphorylated proteomics analysis from ileal epithelia of Prkaa1fl/fl (WT) and Prkaa1ΔIE (KO) mice (n = 5 mice/group) administered a HFHCD plus nicotine water for 20 weeks. Relative fold change (log2) of phosphorylated sites abundance was determined by comparing KO versus WT, and P values (–log10) were calculated by two-tailed t-test. Data are the means ± s.e.m. a–e, Two-tailed Student’s t-test. f–m, Two-tailed Mann- Whitney U-test.
Extended Data Fig. 6 AMPKα phosphorylates SMPD3 protein which became more stable by escaping from ubiquitination degradation.
a, Effect of nicotine (1 μg ml−1) treatment on Smpd3 mRNA levels in ileal organoids (n = 3/group). b, PRKAA1-WT or PRKAA1-KD (kinase domain mutant) was introduced into SW480 cells, and the cells were then treated with vehicle or nicotine (1 μg ml−1) for 12 h. c, GPS2.0 predicts potential kinases and phosphorylation sites for SMPD3. d, The S208/209 peptide of SMPD3 satisfied the AMPK substrate motif and was conserved in different species (data from NCBI database). e, Mass spectrometry analysis of the phosphorylation at Ser209 on SMPD3. f, HFHCD-fed Prkaa1fl/fl and Prkaa1ΔIE mice (SPF) were treated with nicotine water for 2 weeks, and organoids were then isolated and cultured for 7 days and treated with nicotine (1 μg ml−1) for the last 3 days. Western blot analysis showing the stability of SMPD3 after the administration of CHX. g, Mass spectrometry analysis of the ubiquitination at Lys103 on SMPD3. h, The Lys63 ubiquitination of SMPD3 in SW480 cells transfected with SMPD3-flag (WT and K103R) with or without nicotine treatment. i, The SMPD3 ubiquitination in SW480 cells transfected with SMPD3-flag (WT, S209A or S209A/K103R) and treated with or without nicotine. j, Phosphorylation level (S209) of SMPD3 was detected by anti-p-SPMD3 (S209) antibody in SW480 cells transfected with SMPD3-flag (WT or S209A) and treated with or without nicotine. k, Ubiquitination level (K103) of SMPD3 was detected by anti-ubi-SMPD3 (K103) antibody in SW480 cells transfected with SMPD3-flag (WT or K103R) and treated with or without nicotine. For e, g-k, nicotine (1 μg ml−1) treatment for 24 h. Data are the means ± s.e.m. Experiments in a, b, e–k were performed three times independently. a, One-way ANOVA with Tukey’s post hoc test.
Extended Data Fig. 7 Interaction between p-AMPKα and SMPD3 in intestinal ceramide production.
a-c, HFHCD-fed SPF mice were treated with nicotine water or nicotine water plus 10 mg/kg GW4869 (by daily gavage) for 2 weeks, and ileal organoids were then isolated and cultured for 7 days and treated with GW4869 (10 μM) and nicotine (1 μg ml−1) for the last 3 days before the detection of ceramide production and secretion (n = 5 mice/group). a, nSMase activity. b, Ceramide profiles in isolated organoids. c, Ceramide profiles in the supernatant of isolated organoids. d-f, HFHCD-fed Prkaa1fl/fl and Prkaa1ΔIE mice (SPF) were treated with nicotine water for 2 weeks, and organoids were then isolated and infected with LV (lentivirus)-Ctrl or LV-Smpd3, the infected organoids were plated and cultured for 7 days and treated with nicotine (1 μg ml−1) for the last 3 days before the detection of ceramide production and secretion. Western blot analysis for verifying SMPD3 overexpression. (n = 3 mice/group) (d). Ceramide profiles in isolated organoids. (n = 8 mice/group) (e). Ceramide profiles in the supernatant of isolated organoids. (n = 8 mice/group) (f). g, HFHCD-fed WT mice were transplanted with PBS, B. xylanisolvens colonization, nicotine water, nicotine water plus B. xylanisolvens colonization, and nicotine water plus nicX knock-out B. xylanisolvens colonization for 20 weeks (SPF, n = 6 mice/group), and ileal tissues were collected for ceramide profile analysis. Data are the means ± s.e.m. a, b, Two-tailed Student’s t-test. c, Two-tailed Mann-Whitney U-test. f, One-way ANOVA with Tukey’s post hoc test. e, g, Kruskal-Wallis test with Dunn’s test.
Extended Data Fig. 8 Ceramide supplementation eliminates the beneficial effects derived from intestinal AMPKα1 deficiency.
Eight-week-old male Prkaa1fl/fl and Prkaa1ΔIE mice were treated with or without 10 mg/kg ceramide (d18:1/16:0) by daily i.p. injection under HFHCD plus nicotine water treatment for 20 weeks (SPF, Prkaa1fl/fl, n = 8 mice; Prkaa1ΔIE, n = 7 mice; Prkaa1ΔIE + Ceramide, n = 8 mice). a, Ileal ceramide profiles. b, Liver weights. c, Liver weight–to–body weight ratios. d, e, Serum ALT (d) and AST (e) levels. f–j, Hepatic TG (f), serum TG (g), hepatic CE (h), serum CE (i) and serum NEFA (j) contents. k, Representative H&E staining (upper), Oil Red O staining (middle) and Sirius Red staining (lower) of liver sections (n = 4 mice/group, 3 images/mouse). Scale bar, 100 µm. l–p, Histology scores of steatosis (l), lobular inflammation (m), hepatocyte ballooning (n), NAFLD activity (o) and fibrosis stage (p). q–s, Relative mRNA levels of genes related to hepatic lipid metabolism (q), inflammation (r) and fibrosis (s). Data are the means ± s.e.m. d–g, i, One-way ANOVA with Tukey’s post hoc test. h, One-way ANOVA with Dunnett’s T3 post hoc test. a–c, j, l–s, Kruskal-Wallis test with Dunn’s test.
Extended Data Fig. 9 Inhibition of SMPD3 ameliorates nicotine-induced NASH.
Eight-week-old male SPF mice were randomly grouped and administered vehicle or 10 mg/kg GW4869 by daily gavage under HFHCD plus nicotine water treatment for 20 weeks (Nicotine, n = 5 mice; Nicotine + GW4869, n = 7 mice). a, Ileal ceramide profiles. b, Liver weights. c, Liver weight–to–body weight ratios. d, e, Serum ALT (d) and AST (e) levels. f-j, Hepatic TG (f), serum TG (g), hepatic CE (h), serum CE (i) and serum NEFA (j) contents. k, Representative H&E staining (left), Oil Red O staining (middle) and Sirius Red staining (right) of liver sections (n = 3 mice/group, 3 images/mouse). Scale bar, 100 µm. l–p, Histology scores of steatosis (l), lobular inflammation (m), hepatocyte ballooning (n), NAFLD activity (o) and fibrosis stage (p). q–s, Relative mRNA levels of genes related to hepatic lipid metabolism (q), inflammation (r) and fibrosis (s). Data are the means ± s.e.m. b, e, g–j, r, Two-tailed Student’s t-test. a, c, d, f, l-q, s, Two-tailed Mann-Whitney U-test.
Extended Data Fig. 10 B. xylanisolvens-mediated nicotine degradation negatively correlates with clinical NASH.
In 41 smokers with NAFLD, NAFL n = 11, borderline NASH n = 16, definite NASH n = 14. a–c, Relative abundances of B. xylanisolvens associated with steatosis score (a), ballooning score (b), and lobular inflammation (c) in smokers with NAFLD. In 42 non-smokers with NAFLD, including NAFL (n = 11), borderline NASH (n = 14), and definite NASH (n = 17). d, Bacterial taxonomic profiling of the gut microbiota from non-smokers with different NAFLD stages at the species level. e, Relative abundances of B. xylanisolvens associated with different NAFLD stages in non-smokers with NAFLD. f-h, Relative abundances of B. xylanisolvens associated with steatosis score (f), ballooning score (g), and lobular inflammation (h) in non-smokers with NAFLD. i, j, Correlative analysis of B. xylanisolvens with ALT (i) and AST (j). Correlations between variables were assessed by linear regression analysis. Linear correction index R square and P values were calculated. k, Summary diagram illustrating the role of microbial nicotine degradation in ceramide modulation and NAFL-NASH progression. Created with BioRender. Data are the means ± s.e.m. a–c, e–h, Kruskal-Wallis test with Dunn’s test.
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Chen, B., Sun, L., Zeng, G. et al. Gut bacteria alleviate smoking-related NASH by degrading gut nicotine. Nature 610, 562–568 (2022). https://doi.org/10.1038/s41586-022-05299-4
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DOI: https://doi.org/10.1038/s41586-022-05299-4
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