Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study.

Chih-Yiu Tsai,Yu-Hsien Chou,Chi-Neu Tsai,Meng-Chuan Huang,Chia-Hung Lin,Po-Yu Liu,Hsiu-Chen Lu,Hsin-Yun Chen

doi:10.3389/fendo.2021.814770

Abstract

BackgroundsGlucagon-like peptide-1 receptor agonist (GLP-1 RA) is probably one of more effective antidiabetic agents in treatment of type 2 diabetes mellitus (T2D). However, the heterogenicity in responses to GLP-1 RA may be potentially related to gut microbiota, although no human evidence has been published. This pilot study aims to identify microbial signatures associated with glycemic responses to GLP-1 RA.Materials and MethodsMicrobial compositions of 52 patients with T2D receiving GLP-1 RA were determined by 16S rRNA amplicon sequencing. Bacterial biodiversity was compared between responders versus non-responders. Pearson’s correlation and random forest tree algorithm were used to identify microbial features of glycemic responses in T2D patients and multivariable linear regression models were used to validate clinical relevance.ResultsBeta diversity significantly differed between GLP-1 RA responders (n = 34) and non-responders (n = 18) (ADONIS, P = 0.004). The top 17 features associated with glycohemoglobin reduction had a 0.96 diagnostic ability, based on area under the ROC curve: Bacteroides dorei and Roseburia inulinivorans, the two microbes having immunomodulation effects, along with Lachnoclostridium sp. and Butyricicoccus sp., were positively correlated with glycemic reduction; Prevotella copri, the microbe related to insulin resistance, together with Ruminococcaceae sp., Bacteroidales sp., Eubacterium coprostanoligenes sp., Dialister succinatiphilus, Alistipes obesi, Mitsuokella spp., Butyricimonas virosa, Moryella sp., and Lactobacillus mucosae had negative correlation. Furthermore, Bacteroides dorei, Lachnoclostridium sp. and Mitsuokella multacida were significant after adjusting for baseline glycohemoglobin and C-peptide concentrations, two clinical confounders.ConclusionsUnique gut microbial signatures are associated with glycemic responses to GLP-RA treatment and reflect degrees of dysbiosis in T2D patients.

Highlights

An increasing incidence of type 2 diabetes mellitus (T2D) is a severe health issue worldwide, causing high morbidity and mortality with resulting healthcare costs expected to reach US $825B annually by 2030 [1]
The top 17 features associated with glycohemoglobin reduction had a 0.96 diagnostic ability, based on area under the Receiveroperating characteristic (ROC) curve: Bacteroides dorei and Roseburia inulinivorans, the two microbes having immunomodulation effects, along with Lachnoclostridium sp. and Butyricicoccus sp., were positively correlated with glycemic reduction; Prevotella copri, the microbe related to insulin resistance, together with Ruminococcaceae sp., Bacteroidales sp., Eubacterium coprostanoligenes sp., Dialister succinatiphilus, Alistipes obesi, Mitsuokella spp., Butyricimonas virosa, Moryella sp., and Lactobacillus mucosae had negative correlation
Unique gut microbial signatures are associated with glycemic responses to GLP-RA treatment and reflect degrees of dysbiosis in T2D patients

Summary

Introduction

An increasing incidence of type 2 diabetes mellitus (T2D) is a severe health issue worldwide, causing high morbidity and mortality with resulting healthcare costs expected to reach US $825B annually by 2030 [1]. Glycemic control in T2D patients is critical to reduce diabetic complications, cardiovascular consequences, and costs [2]. Glucagon-like peptide-1 receptor agonist (GLP-1 RA) has pleotropic effects on pancreas, brain, and other target organs, acting through systemic or enteric neuroendocrine cell pathways [3]. Augmented GLP-1 actions include anti-inflammatory, potent glycemic and body weight reduction effects [4]; GLP-1 RA is highly recommended for T2D patients with cardiovascular risk factors [5]. Perhaps loss of efficacy is due to target cells becoming resistant to GLP-1 [9]. Risk factors for development of GLP-1 RA treatment failure are prolonged disease duration, previous insulin use, lower Cpeptide concentrations or positive islet autoantibodies, partially implicating b-cell failure [10, 11]. Regardless, apart from insulin deficiency, GLP-1 resistance has no specific marker

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Conclusion