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Akkermansia muciniphila protects mice against an emerging tick-borne viral pathogen

Nature Microbiology volume 8, pages 91–106 (2023)Cite this article

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Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by a phlebovirus in the Bunyaviridae family. Infection can result in systemic inflammatory response syndrome with a high fatality rate, and there are currently no treatments or vaccines available. The microbiota has been implicated in host susceptibility to systemic viral infection and disease outcomes, but whether the gut microbiota is implicated in severe fever with thrombocytopenia syndrome virus (SFTSV) infection is unknown. Here, we analysed faecal and serum samples from patients with SFTS using 16S ribosomal RNA-sequencing and untargeted metabolomics, respectively. We found that the gut commensal Akkermansia muciniphila increased in relative abundance over the course of infection and was reduced in samples from deceased patients. Using germ-free or oral antibiotic-treated mice, we found that A. muciniphila produces the β-carboline alkaloid harmaline, which protects against SFTSV infection by suppressing NF-κB-mediated systemic inflammation. Harmaline indirectly modulated the virus-induced inflammatory response by specifically enhancing bile acid-CoA: amino acid N-acyltransferase expression in hepatic cells to increase conjugated primary bile acids, glycochenodeoxycholic acid and taurochenodeoxycholic acid. These bile acids induced transmembrane G-protein coupled receptor-5-dependent anti-inflammatory responses. These results indicate the probiotic potential of A. muciniphila in mitigating SFTSV infection.

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Fig. 1: Surviving SFTSV-infected patients exhibited an increased faecal abundance of Akkermansia that was inversely correlated with the severity of systemic inflammatory responses.
Fig. 2: Oral A. muciniphila administration decreases susceptibility to SFTSV infection and attenuates the resulting systemic inflammation in a mouse model.
Fig. 3: Surviving SFTSV-infected patients displayed an A. muciniphila-related increase in serum GCDCA and TCDCA that suppressed inflammatory responses in human PBMCs.
Fig. 4: A. muciniphila-driven conjugated primary BA TCDCA protects host from SFTSV infection by dampening systemic inflammatory responses in mouse model.
Fig. 5: A. muciniphila metabolite HAL enhances TCDCA production by upregulating the expression of BAAT in a mouse model.
Fig. 6: GCDCA suppresses NF-κB-mediated inflammatory responses via TGR5 signalling.

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Data availability

16S rRNA sequence data are available in the Sequence Read Archive (SRA) under BioProject accession no. PRJNA890424 and PRJNA888451. RNA-seq data are available in the SRA under BioProject accession no. PRJNA889171. Source data can be accessed on FigShare: https://doi.org/10.6084/m9.figshare.21334422. Source data are provided with this paper.

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No custom code was used.

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Acknowledgements

We thank W. Han (Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine) for providing a valuable TGR5 knockout mouse strain. This work was supported by grants from the National Key Research and Development Plan of China (2021YFC230200–02) to W.L., the National Natural Science Foundation of China (No. 32172864 and No. 82172270) to S.J.Z. and H.L., and the National Natural Science Fund for Distinguished Young Scholars (No. 81825019) to W.L.

Author information

Author notes

  1. These authors contributed equally: Jinyan Xie, Hao Li, Xiaoai Zhang, Tong Yang.

Authors and Affiliations

  1. Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, P. R. China

    Jinyan Xie, Mengjia Yue, Shuxian Chen & Shu Jeffrey Zhu

  2. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P. R. China

    Hao Li, Xiaoai Zhang, Tong Yang, Yunfa Zhang, Jingyun Li & Wei Liu

  3. The 990 Hospital, People’s Liberation Army, Xinyang, P. R. China

    Ning Cui & Chun Yuan

  4. Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China

    Shu Jeffrey Zhu

  5. School of Public Health, Peking University, Beijing, P. R. China

    Wei Liu

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Contributions

S.J.Z. and W.L. designed the experiments. J.X., H.L., X.Z., T.Y., M.Y., Y.Z. and S.C. performed the experiments. J.X., H.L., X.Z. and T.Y. conducted the bioinformatics analysis. N.C. and C.Y. collected samples and data. J.L. commented on and revised the drafts of the manuscript. S.J.Z., W.L., J.X., H.L. and T.Y. wrote the paper. S.J.Z. and W.L. supervised the research, coordination and strategy.

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Correspondence to Shu Jeffrey Zhu or Wei Liu.

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Extended data

Extended Data Fig. 1 The intestinal microbiota of surviving SFTSV-infected individuals.

(a) Relative abundance of phyla among the four groups. (b) Relative abundance of Lactobacillus, Parabacteroides and Enterococcus among the four groups (HC n = 19, Non-SF n = 176, SF-S n = 233, SF-D n = 27). (c) Serum concentration of TNF-α among the four groups and the association with the relative abundance of Akkermansia (HC n = 10, non-SF n = 25, SF-S n = 107, SF-D n = 21). HC, healthy controls; Non-SF, febrile patients without SFTSV infection; SF-S, surviving patients with SFTSV infection; SF-D, deceased patients with SFTSV infection. (d) Schematic representation of treatment with Abx, FMT, bacteria, HAL, acetate, propionate or TCDCA. The two-sided P values were examined by Student’s t test and data were presented as mean values ± SD (b, and c). R2 and exact two-sided P values calculated by Pearson’s test are shown (c).

Source data

Extended Data Fig. 2 Microbiota reconstitution with A. muciniphila prevents SFTSV early infection and inhibits resulting systemic inflammatory responses.

(a) qPCR of 16 s rRNA genomic copies in faeces from PBS-treated, Abx-treated or FMT-transferred mice at 2 days after transfer (n = 6). (b) qPCR of IL-1β and IL-6 mRNA (right) and SFTSV RNA (left) in spleens from Abx-treated mice with or without FMT (faeces from recovered SFTSV mice) and infected with SFTSV at 3 days post-infection (n = 6). (c) H. E. staining of lung, liver or spleen cross sections from Abx-treated mice with or without FMT (faeces from recovered SFTSV mice) and infected with SFTSV at 3 dpi. Boxed areas are magnified immediately in the top right corner. (d) qPCR of A. muciniphila genomic copies in faeces from SFTSV infected mice at 0- and 3-days post infection (n = 4). (e) qPCR of A. muciniphila, L. reuteri or E. faecalis genomic copies in faeces from Abx-treated or bacteria-colonized mice at 2 days post colonization (A. muciniphila n = 4, L. reuteri and E. faecalis n = 5). (f) qPCR of SFTSV RNA in the spleen, liver or lung from PBS-treated, Abx-treated or A. muciniphila-colonized mice infected with SFTSV at 3 and 5 dpi (n = 8). (g) IFA of spleen sections from Abx-treated mice colonized with or without A. muciniphila and infected with SFTSV at 3 dpi. SFTSV protein NP and IL-6 protein were double stained with the respective antibodies. (h) H. E. staining of lung, liver or spleen cross sections from Abx-treated mice colonized with or without A. muciniphila and infected with SFTSV at 5 dpi. Boxed areas are magnified immediately in the top right corner. The two-sided P values were examined by Student’s t test and data were presented as mean values ± SD (a, b, d, e and f).

Source data

Extended Data Fig. 3 A. muciniphila-associated conjugated primary bile acids GCDCA and TCDCA suppress SFTSV-induced inflammatory responses in human PBMCs in vitro.

(a) Relative mRNA levels of IL-1β and IL-6 in SFTS patients (n = 3) and (b) healthy donor PBMCs treated with GCDCA and then infected with SFTSV (MOI 1) at 24 hpi (n = 6). Data were presented as mean values ± SD (a and b).

Source data

Extended Data Fig. 4 A. muciniphila colonization in antibiotic-pretreated mice upregulates TCDCA secretion.

(a) PCA of serum from four groups: PBS-treated, Abx-treated and A. muciniphila-colonized mice infected with SFTSV at 3 dpi and nontreated mice. (b) KEGG analysis of differentially regulated metabolites between the PBS group and the Abx group. The two-sided P values were examined by Student’s t test.

Extended Data Fig. 5 TCDCA protects Abx mice by prohibiting SFTSV-induced systemic inflammation.

(a) qPCR of IL-1β or TNF-α mRNA and (b) SFTSV RNA in mouse PMBCs pretreated with TCDCA, GCDCA, TCA, TDCA or T-α-MCA and then infected with SFTSV (MOI 1) at 24 hpi (IL-1β n = 4, TNF-α and SFTSV RNA n = 6). (C) Relative mRNA transcripts of proinflammatory cytokines in SFTSV-infected mouse PBMCs treated with different doses of TCDCA and (d) respective viral loads at 24 hpi (n = 4). (e) Serum concentration of TCDCA in Abx mice treated with TCDCA (Abx n = 4, TCDCA n = 2). (f) qPCR of SFTSV RNA in the spleen and liver from PBS-treated and Abx-treated mice treated with or without TCDCA and infected with SFTSV at 3 and 5 dpi (Abx 3dpi n = 7, Abx 5dpi n = 5, TCDCA 3dpi n = 8, TCDCA 3dpi n = 7). The two-sided P values were examined by Student’s t test (a, and c). Data were presented as mean values ± SD (a to f).

Source data

Extended Data Fig. 6 A. muciniphila-associated metabolites enhance the expression of BAAT both in vivo and in vitro.

(a) Total hepatic cholesterol level of PBS-treated, Abx-treated or A. muciniphila-colonized mice at 5 days post-colonization (n = 5). (b) qPCR of Asbt mRNA in the ileum of PBS-treated, Abx-treated or A. muciniphila-colonized mice at 5 days post-colonization (n = 5). (c) qPCR of BAAT mRNA in liver from PBS-treated, Abx-treated, A. muciniphila-colonized or L. reuteri-colonized mice at 5 days post-colonization (n = 5). (d) Quantification of the proteins in Fig. 5a. The protein levels of enzymes in the bile acid biosynthesis pathways were normalized to those of ACTIN. The amount of each protein in the fasted state was defined as 1 (n = 3). (e) qPCR of BAAT mRNA in liver from GF mice colonized with or without A. muciniphila at 5 days post-colonization (n = 6). (f) Quantification of the proteins in Fig. 5b. The protein levels of enzymes in the bile acid biosynthesis pathways were normalized to those of TUBULIN. The amount of each protein in the fasted state was defined as 1 (n = 3). (g) Serum bile acid concentration of Abx-treated, A. muciniphila-colonized or L. reuteri-colonized mice at 5 days post colonization (n = 4). (h) qPCR of BAAT mRNA in Huh-7 cells treated with different fractions of A. muciniphila culture supernatants at 24 h (n = 6). (i) qPCR of BAAT mRNA in Huh-7 cells treated with different doses of 10 kDa or less filtrate with or without proteinase K digestion and the correlations with the content of 10 kDa or less filtrate (n = 6). (j) The content of acetate or propionate in the supernatant of A. muciniphila (n = 4). The two-sided P values were examined by Student’s t test and data were presented as mean values ± SD (a–j).

Source data

Extended Data Fig. 7 The A. muciniphila metabolite harmaline upregulates the expression of BAAT.

(a) Relative abundance changes of positive or negative metabolites in 10 kDa or less filtrate of A. muciniphila cultured supernatants. (b) The correlations between the content of HAL and A. muciniphila cell numbers. (c, d) qPCR of BAAT mRNA in (c) Huh-7 or (d) MPH cells treated with different doses of HAL or butyrate at 24 h (n = 5). (e) qPCR of BAAT mRNA in MPH cells transfected with siNC or siBAAT at 24 h (n = 6). (f) qPCR of BAAT mRNA in liver from PBS-treated, Abx-treated, HAL-treated or acetate-treated mice at 5 days post-treatment (n = 6). (g) Quantification of the proteins in Fig. 5g. The proteins of the bile acid biosynthesis pathway were normalized to that of ACTIN. The amount of each protein in the fasted state was defined as 1 (n = 3). The two-sided P values were examined by Student’s t test and data were presented as mean values ± SD (c–g).

Source data

Extended Data Fig. 8 The A. muciniphila metabolite harmaline prohibits systemic inflammatory responses in Abx-treated and GF mice.

(a) Serum bile acid concentration of Abx- and HAL-treated mice and (b) GF mice treated with or without A. muciniphila or HAL at 5 days post-colonization (n = 8). (c) Serum HAL concentration of PBS-treated, Abx-treated, A. muciniphila-colonized, L. reuteri-colonized, HAL-treated mice at 2 days post colonization (n = 3). (d) Serum HAL concentrations of recovered patients with SFTSV infection and recovered febrile patients without SFTSV infection. Serum samples were collected approximately two weeks after symptom onset (n = 13). (e) IFA images of spleen sections from GF mice treated with or without HAL at 3 dpi. SFTSV protein NP and IL-6 protein were double stained with the respective antibodies. (f) H. E staining of lung, liver or spleen cross sections from GF mice treated with or without HAL and infected with SFTSV at 3 dpi. Boxed areas are magnified immediately in the top right corner. (g) Relative mRNA levels of IL-1β, IL-6, TNF-α (left) and SFTSV RNA (right) in mouse PBMCs that were pretreated with 10 μM HAL and then infected with SFTSV (MOI 1) at 24 hpi or HAL was added to the PBMCs simultaneously with SFTSV infection (n = 6). (h) Expression of Baat and actin in the livers of Abx-treated wild-type B6 mice transiently transfected with siNC or siBAAT (N/P ratio is 6 to 8). The two-sided P values were examined by Student’s t test (a, b and d). Data were presented as mean values ± SD (a–d and g).

Source data

Extended Data Fig. 9 GCDCA suppresses SFTSV-induced inflammatory cytokine expression in THP-1 cells in a dose-dependent manner.

(a) Relative mRNA levels of IL-1β and IL-6 in THP-1PMA cells that were pretreated with 50, 100, or 150 μM GCDCA and then infected with SFTSV (MOI 1) at 24 hpi (n = 3). (b) Relative protein levels of IL-1β and IL-6 in THP-1PMA cells pretreated with 100 μM GCDCA and then infected with SFTSV (MOI 1) at 24 hpi (n = 3). (c) Relative mRNA levels of IL-1β, IL-6 (n = 3) and (d) SFTSV RNA in THP-1PMA cells (n = 6) pretreated with 10, 50, or 100 μM CDCA and then infected with SFTSV (MOI 1) at 24 hpi. The two-sided P values were examined by Student’s t test (a and c). Data were presented as mean values ± SD (a to d).

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Extended Data Fig. 10 GCDCA does not hinder SFTSV-induced inflammatory responses via the TLR8-MyD88 or NLRP3-inflammasome signalling pathways.

THP-1PMA cells were pretreated with 100 μM GCDCA and then infected with SFTSV (MOI 1) for 24 hours. (a) Relative mRNA levels of IL1B and IL6 in TLR8- or MyD88-knockdown THP-1PMA cells (n = 6). (b) Western blot of pro-IL-1β, TLR8, MyD88 and tubulin in TLR8- or MyD88-knockdown THP-1PMA cells. (c) Relative protein levels of P50, P65 and phos-P65 in THP-1PMA cells (n = 3). (d) Western blot of MyD88, IKKβ, NLRP3, ASC, CASP1 and tubulin in THP-1PMA cells. (e) SFTSV RNA level in TGR5 knockdown THP-1PMA cells (n = 6). (f) Relative protein levels of pro-IL-1β, TGR5, p50, p65 and phos-p65 in TGR5 knockdown THP-1PMA cells (n = 3). (g and h) THP-1PMA cells were pretreated with 100 μM GCDCA and then infected with SFTSV (MOI 1) for 24 hours. (g) Relative mRNA levels of IL1B and IL6 in FXR knockdown THP-1PMA cells (n = 6). (h) Western blot of pro-IL-1β, FXR and tubulin in FXR knockdown THP-1PMA cells. (i) Serum TCDCA concentration of Abx-treated TGR5 CKO mice with or without TCDCA treatment at 5 dpi. (j) qPCR of A. muciniphila genomic copies in faeces from Abx-treated or bacteria-colonized mice at 2 days post colonization (n = 3). (k) Schematic illustration of the Akkermansia muciniphila metabolite harmaline protecting against severe fever with thrombocytopenia syndrome through the bile acid-TGR5-NF-κB axis. The two-sided P values were examined by using Student’s t test (a, g and j). Data were presented as mean values ± SD (a, c, e–g and j).

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Xie, J., Li, H., Zhang, X. et al. Akkermansia muciniphila protects mice against an emerging tick-borne viral pathogen. Nat Microbiol 8, 91–106 (2023). https://doi.org/10.1038/s41564-022-01279-6

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