Original Basic Science—General

Intestinal Dysbiosis Correlates With Sirolimus-induced Metabolic Disorders in Mice

Han, Yuqiu MM¹; Wu, Li MM¹; Ling, Qi MD²; Wu, Pin MD³; Zhang, Chenzhi MD²; Jia, Longfei MB⁴; Weng, Honglei MD⁵; Wang, Baohong MD^1,6

Author Information

¹ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

² Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China.

³ Division of Throat Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

⁴ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, China.

⁵ Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

⁶ Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, China.

Received 18 March 2020. Revision received 23 September 2020.

Accepted 25 September 2020.

This study was supported by Major Program of National Natural Science Foundation of China (81790633, 81790630), the Science Fund for Distinguished Young Scholars of Zhejiang Provincial Natural Science Foundation of China (LR16H260001, LR18H030001), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5-045).

The authors declare no conflicts of interest.

B.W. designed and managed the experiments. B.W. and Y.H. wrote the article. Y.H., L.W., Q.L., P.W., C.Z. and L.J. performed the experiments. B.W. and H.W. reviewed and edited the article.

Y.H., L.W., and Q.L. have contributed equally to this work.

Additional Information may be found online in the supporting information tab for this article. All 16S rRNA microbiome sequences supporting the findings of this study have been deposited in NCBI with primary access code PRJNA436876, and uploaded in the open-source microbiome sharing database SRA (https://trace.ncbi.nlm.nih.gov/Traces/sra/) with the study ID SRP134053.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Baohong Wang, MM, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, Hangzhou 310003, China. ([email protected]).

Transplantation 105(5):p 1017-1029, May 2021. | DOI: 10.1097/TP.0000000000003494

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Abstract

Background.

Long-time use of pharmacological immunosuppressive agents frequently leads to metabolic disorders. Most studies have focused on islet toxicity leading to posttransplantation diabetes mellitus. In contrast, the link between intestinal dysbiosis and immunosuppressive drug-induced metabolic disorders remains unclear.

Methods.

We established a mouse model of metabolic abnormality via sirolimus treatment. Fecal microbiota was examined using 16S rRNA gene MiSeq sequencing. Intestinal barrier function was assessed using fluorescein isothiocyanate-dextran assay and mucus immunostaining. Systemic inflammation was determined using a multiplexed fluorescent bead-based immunoassay.

Results.

Sirolimus induced dyslipidemia and glucose intolerance in mice in a dose-dependent manner. Interestingly, the clinical-mimicking dose of sirolimus altered the intestinal microbiota community, which was characterized by the enrichment of Proteobacteria, depletion of Akkermansia, and potential function shifts to those involved in lipid metabolism and the immune system. In addition, the clinical-mimicking dose of sirolimus reduced the thickness of the intestinal mucosal layer, increased the intestinal permeability, and enriched the circulating pro-inflammatory factors, including interleukin (IL)-12, IL-6, monocyte chemotactic protein 1, granulocyte-macrophage colony stimulating factor, and IL-1β. Our results showed a close association between intestinal dysbiosis, intestinal barrier failure, systemic inflammation, and metabolic disorders. Furthermore, we demonstrated that oral intervention in the gut microbiota by Lactobacillus rhamnosus HN001 protected against intestinal dysbiosis, especially by depleting the lipopolysaccharide-producing Proteobacteria, and attenuated the sirolimus-induced systemic inflammation, dyslipidemia, and insulin resistance.

Conclusions.

Our study demonstrated a potentially causative role of intestinal dysbiosis in sirolimus-induced metabolic disorders, which will provide a novel therapeutic target for transplant recipients.