粪便微生物群移植通过改善 db/db 小鼠肠道微生物群的代谢重编程来改善 2 型糖尿病。

Fecal microbiota transplantation ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota in db/db mice.

机构信息

Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University Second Affiliated Hospital, Nanjing, Jiangsu, China.

Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.

出版信息

BMJ Open Diabetes Res Care. 2023 May;11(3). doi: 10.1136/bmjdrc-2022-003282.

DOI:10.1136/bmjdrc-2022-003282

PMID:37253485

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10230930/

Abstract

INTRODUCTION

Gut microbiome (GM) deregulation has been implicated in major conditions such as obesity and type 2 diabetes (T2DM). Our previous prospective study indicated that fecal microbiota transplantation (FMT) successfully improved patients with T2DM. We hypothesized that FMT may be a potential therapeutic method for T2DM, but its precise mechanisms in T2DM remains to be elucidated.

RESEARCH DESIGN AND METHODS

Eight db/m mice were FMT donors and control mice, and 16 genetically diabetic db/db mice were equally divided into two groups (db/db+phosphate-buffered saline (PBS) group, db/db+FMT group). The db/db+FMT group was administered fresh fecal suspension (0.2 mL/mice) daily for 4 weeks. Analysis of the GM and serum metabolome was carried out by 16S ribosomal RNA sequencing and liquid chromatogram-mass spectrometry, respectively. Effects of FMT on the gut barrier and pancreas were assessed using protein assays, messenger RNA, immunohistology and clinical indicators testing.

RESULTS

Our results showed that FMT treatment of db/db mice relieves a series of clinical indicators, including fasting plasma glucose, serum insulin and oral glucose tolerance test among others. Compared with non-diabetic control mice, db/db+PBS mice exhibited decreased abundance of Ruminococaceae, Porphyromonadaceae and increased abundance of Rikenellaceae and Lactobacillaceae. FMT treatment reversed this effect on the microbiome. Eleven metabolites were changed between the db/db+PBS and db/db+FMT groups. Correlation analysis showed that the structural changes of the GM were correlated with host metabolite levels. We further showed that FMT treatment of db/db mice improved intestinal barrier function, reduced inflammation and caused an alteration in the number of circulating immune cells.

CONCLUSIONS

FMT-mediated changes in the GM, serum metabolites, intestinal epithelial barrier, inflammation and circulating immune cells play an important role in the efficacy of FMT on T2DM disease progression.

摘要

简介

肠道微生物群（GM）失调与肥胖和 2 型糖尿病（T2DM）等主要疾病有关。我们之前的前瞻性研究表明，粪便微生物群移植（FMT）成功改善了 T2DM 患者的病情。我们假设 FMT 可能是 T2DM 的一种潜在治疗方法，但 FMT 在 T2DM 中的确切机制仍有待阐明。

研究设计和方法

8 只 db/m 小鼠作为 FMT 供体和对照小鼠，16 只遗传糖尿病 db/db 小鼠等分为两组（db/db+磷酸盐缓冲盐水（PBS）组，db/db+FMT 组）。db/db+FMT 组每天给予新鲜粪便混悬液（0.2 mL/只），持续 4 周。通过 16S 核糖体 RNA 测序和液相色谱-质谱分别分析 GM 和血清代谢组。使用蛋白质测定、信使 RNA、免疫组织化学和临床指标检测评估 FMT 对肠道屏障和胰腺的影响。

结果

我们的结果表明，FMT 治疗 db/db 小鼠可缓解一系列临床指标，包括空腹血糖、血清胰岛素和口服葡萄糖耐量试验等。与非糖尿病对照小鼠相比，db/db+PBS 小鼠的 Ruminococcaceae、Porphyromonadaceae 丰度降低，Rikenellaceae 和 Lactobacillaceae 丰度增加。FMT 治疗逆转了这种对微生物群的影响。db/db+PBS 和 db/db+FMT 两组之间有 11 种代谢物发生变化。相关性分析表明，GM 的结构变化与宿主代谢物水平相关。我们进一步表明，FMT 治疗 db/db 小鼠改善了肠道屏障功能，减少了炎症，并导致循环免疫细胞数量发生改变。