Rapid and selective gut microbiome modulation by polyherbal formulation in type 2 diabetes.

Background: Metformin, the first-line treatment for type 2 diabetes, often induces gastrointestinal side effects, affecting treatment adherence. Recent research suggests that the gut microbiome mediates both the efficacy and tolerability of metformin. This study evaluates the effect of a polyherbal formulation, used as an add-on to metformin, on the gut microbiota in patients with type 2 diabetes and metformin intolerance. Methods: We report preliminary findings from the first 7-day intervention phase of an ongoing randomized, placebocontrolled, crossover trial (NCT06846138) in 27 adults with type 2 diabetes. Participants received either polyherbal formulations or a placebo alongside metformin for 7 days. Stool samples were collected pre- and post-intervention for shotgun metagenomic sequencing. Microbial diversity, composition, and pathway functions were analyzed using Kraken2, Bracken, and HUMAnN3. Continuous glucose monitoring was used to assess glycemic metrics. Results: No significant alpha-diversity changes were observed; however, beta-diversity differed significantly between arms (PERMANOVA R ² = 0.04, P = 0.04). In the polyherbal formulation group, 17 species changed post-treatment (FDR < 0.25), with significant increases in six Bifidobacterium spp. (e.g., B. adolescentis, B. ruminantium). In contrast, the placebo group showed no major microbial shifts. Polyherbal formulation also altered ten microbial pathways (FDR < 0.25). Continuous glucose monitoring revealed no short-term changes in glycemic levels. Conclusion: Short-term polyherbal formulation co-administration significantly modulates gut microbiota, promoting beneficial taxa, such as Bifidobacterium in metformin-treated type 2 diabetes patients. This supports the potential role of the polyherbal formulation in microbiome-targeted strategies to improve metformin tolerability and effectiveness.