Abstract Background Gut microbial enterotypes are distinct community structures dominated by specific bacterial taxa and often reflect host health status. However, their geographical variability and relevance in inflammatory bowel disease (IBD) remain underexplored. This study investigates the association between gut enterotypes, lifestyle factors, and disease status across healthy Indian and US individuals and patients with IBD. Methods Gut microbiome profiles were analyzed from 359 healthy US individuals (Arivale dataset, PRJNA826648), 342 healthy Indian and 48 Indian IBD patients. Detailed questionnaire comprising of demographic, dietary, social and lifestyle habits were collected from all Indian participants. Sequence data (16s-V4 region) were processed followed by ASV-taxonomic assignment (SILVA database). Genus-level abundances were normalized (TSS) and clustered into enterotypes using Partitioning Around Medoids with Jensen–Shannon distances. Enterotype stability was evaluated using silhouette scores across multiple distance metrics. Differential taxa were identified via LEfSe, and host lifestyle associations were examined through correlation analyses. Results Principal coordinate analysis revealed clear geographic segregation among the two healthy cohorts, with broader dispersion among Indian samples. Distinct enterotypes were observed for each cohort dominated by Bacteroides while the IBD cohort additionally had Streptococcus (Fig1). Using other distance metrics (Bray-Curtis, Euclidean or Jaccard) did not change the enterotype classification in the US Healthy Cohort; however the Indian healthy cohort also showed the abundance of Bifidobacterium or Blautia as the third enterotype. Silhouette validation confirmed clustering robustness. Top 10 genera from each enterotype comprised of SCFA producers in both healthy cohorts, while pro-inflammatory and mucin degraders dominated IBD enterotype (Fig2). LEfSe identified enrichment of beneficial taxa (Akkermansia, Faecalibacterium, Bifidobacterium) in healthy cohorts, whereas IBD samples were enriched in opportunistic bacteria (Streptococcus, Veillonella). A fold-enrichment of beneficial taxa Faecalibacterium, Akkermansia was associated with fiber-rich & active lifestyles, while Streptococcus, Veillonella, and the Ruminococcus torques group taxa correlated with increased smoking, alcohol use, and sedentary lifestyle. Conclusion Distinct enterotype distributions across populations highlight geographic, dietary and lifestyle influences on gut ecology. IBD is marked by enterotype shifts toward pro-inflammatory taxa, highlighting microbiome–lifestyle interactions in disease susceptibility. Conflict of interest: Gunala, Nikhil: No conflict of interest Raghunathan, Nalini: No conflict of interest Thakur, Manisha: No conflict of interest Mekala, Dhanush: No conflict of interest Patel, Rajendra: No conflict of interest Dr. Banerjee, Rupa: RB has received grants/research support from Asian Healthcare Foundation, and the Leona M and Harry B Helmsley Charitable Trust Advisory board fees from Abbott, AstraZeneca, Abbvie, Cadila, Cipla,, Dr Reddy Labs, Eli Lilly, Emcure, Ferring Pharma, Hetero Drugs, Janssen, MSN Labs, Mankind Pharma, Menarini, Micro Labs, Pfizer, Sun Pharmaceuticals, Takeda Pharmaceuticals, Torrent, Waterley, and Zydus.
Gunala et al. (Thu,) studied this question.