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Fine mapping-based multi-omics analysis interprets the gut-lung axis function of SGLT2 inhibitors
Fengqin Yuan1, Tianlong Zhang2, Sixiang Jia3
1Department of Infection Control, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
Frontiers in Cellular and Infection Microbiology
|September 25, 2024
Summary
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show benefits for pulmonary diseases by influencing gut microbiota and metabolites. This research reveals SGLT2 inhibition’s potential role in reducing risks for interstitial lung disease, tuberculosis, pneumoconiosis, and asthma.
Area of Science:
- Pharmacogenomics and Microbiome Research
- Multi-omics Analysis in Pulmonary Medicine
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer benefits beyond glycemic control, impacting gut microbiota and circulating metabolites.
- Gut microbiota and metabolites are increasingly recognized for their role in the biological mechanisms underlying pulmonary diseases.
Purpose of the Study:
- To investigate the mediating roles of gut microbiota and metabolites in the association between SGLT2 inhibition and 10 pulmonary diseases.
- To utilize Mendelian randomization (MR) to explore causal relationships and identify potential biological pathways.
Main Methods:
- A two-sample, two-step Mendelian randomization (MR) study design was employed.
- Gene fine-mapping and annotation were performed using FUMA and Magma.
- Multi-omics MR analyses assessed causal associations, and Phenome-Wide Association Studies (PheWAS) evaluated potential side effects.
Main Results:
- SGLT2 inhibition was associated with reduced risk for Type 2 Diabetes Mellitus (T2DM), Interstitial Lung Disease (ILD), Pneumoconiosis, Pulmonary Tuberculosis, and Asthma.
- Specific gut bacteria (Enterobacteriaceae, Enterobacteriales, Alcaligenaceae, X-12719, Phascolarctobacterium) and metabolites (fatty acids, docosahexaenoic acid ratio, 4-androsten-3beta,17beta-diol disulfate 2) were linked to these diseases.
- Target genes were identified for four diseases, with six overlapping genes found for asthma via proteomic MR analysis.
Conclusions:
- This study provides strong multi-omics evidence for an association between SGLT2 inhibition and reduced risk of ILD, tuberculosis, pneumoconiosis, and asthma.
- Identified gut microbiota, metabolites, metabolic pathways, and target genes offer potential mechanistic insights into SGLT2 inhibition's pulmonary benefits.
- PheWAS analysis confirmed the comprehensive effects of SGLT2 inhibitors.
