Beyond Weight Loss: Gut Microenvironment Modulation to Enhance Cardiometabolic Outcomes and Long-Term Adherence...

Area of Science:

• Endocrinology
• Gastroenterology
• Microbiome Research

Background:

• Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonists offer significant benefits for obesity and cardiometabolic diseases.
• Gastrointestinal (GI) adverse events are a primary reason for dose reduction, treatment interruption, and poor adherence to these therapies.
• Interactions between incretin-based drugs and the gut microenvironment are increasingly recognized as factors influencing GI tolerability and treatment persistence.

Purpose of the Study:

• To review the literature on the relationship between incretin-based therapies, gut microbiota, intestinal barrier function, and microbial metabolites.
• To explore potential gut-directed supportive strategies for improving GI tolerability during incretin therapy.
• To propose a conceptual framework, the Incretin-Microbiota Tolerance Axis (IMTA), linking gut homeostasis, GI tolerability, and treatment adherence.

Main Methods:

• Conducted a narrative literature review.
• Evaluated evidence from randomized clinical trials, observational studies, systematic reviews, and mechanistic investigations.
• Focused on the interplay between incretin pharmacology and the intestinal microenvironment.

Main Results:

• Preclinical and mechanistic data suggest bidirectional interactions between incretin drugs and the gut microenvironment, but direct human evidence is limited and inconsistent.
• While GLP-1 RAs can alter GI motility, human studies have not consistently shown significant changes in gut microbiota composition or fermentation.
• Partially hydrolyzed guar gum (PHGG) and SCFA-supportive nutrition may enhance beneficial microbiota and gut homeostasis; simethicone may alleviate gas discomfort.

Conclusions:

• Optimizing the intestinal microenvironment may be a complementary strategy to enhance GI tolerability and long-term adherence to incretin-based therapies.
• The proposed Incretin-Microbiota Tolerance Axis (IMTA) framework is biologically plausible and supported by emerging evidence.
• Prospective clinical studies are necessary to confirm if microbiota-targeted interventions improve treatment persistence and cardiometabolic outcomes.