Interim Analysis of Microbiome Remodeling Effects of Adjunct Therapy with Polyherbal Formulation (PHF) in Type 2 Diabetes Patients

Introduction and Objective: Metformin gastrointestinal (GI) adverse effects are common in people with type 2 diabetes (T2D) and may limit therapy. Prior work links metformin intolerance to gut microbiome alterations and, to a lesser extent, variation in drug transporter genes (OCT1-3, MATE1/2-K, PMAT). We assessed whether a standardized multi-extract polyherbal formulation (PHF) modulates gut microbiome composition and functional pathways when co-administered with maximally tolerated metformin XR. Methods: Adults with metformin intolerance (N=27) were randomized 1:1 to PHF+metformin XR or placebo+metformin XR for 7 days in an ongoing randomized, placebo-controlled trial. Stool samples collected pre/post intervention underwent shotgun metagenomic sequencing with taxonomic/functional profiling. Results: In the first recruitment block, 7/27 participants reported mild GI symptoms (PHF 5; placebo 2). PERMANOVA identified PHF assignment as a significant factor explaining variation in microbiome composition (R2=0.04; P=4.01×10−2), alongside participant identity (R2=0.88; P=1.00×10−4). Differential abundance identified 10 pathways associated with PHF intake (FDR<0.25), with 8 decreased, including anhydromuropeptide recycling and methylglyoxal degradation. Alpha diversity did not change, but beta diversity shifted after PHF. Metagenomics showed selective enrichment of 6 Bifidobacterium species, including B. adolescentis and B. ruminantium; no similar enrichment occurred with placebo, suggesting a direct PHF effect on ecology. Conclusion: This interim analysis of a 7-day intervention phase indicates that PHF co-administered with metformin can rapidly and selectively remodel the gut microbiome in metformin-intolerant T2D. Although glycemic metrics were unchanged over this short period, compositional and functional shifts—particularly Bifidobacterium enrichment—support further evaluation of PHF to enhance metformin tolerability and potential longer-term efficacy. Disclosure: S. Sausa: None. A. Zodane: None. S. Kumar: None. M. Kakarla: None. S. Kistkins: None. L. Grima: None. V. Pirags: None. M. Briviba: None.