Targeted Microbial Shifts and Metabolite Profiles Were Associated with Clinical Response to an Anti-Inflammatory Diet in Osteoarthritis

<b>Introduction:</b> Osteoarthritis (OA) is a chronic degenerative joint disease with limited treatment options focused primarily on symptom management. Emerging evidence suggests that dietary interventions may influence inflammation and pain through modulation of the gut microbiome and metabolome. <b>Methods:</b> We conducted a 4-week open-label pilot trial evaluating the effects of an anti-inflammatory dietary intervention (ITIS diet) in 20 patients with knee OA (ClinicalTrials.gov ID: NCT05559463, registered prior to enrollment; sponsor: University of California, San Diego; responsible party: Monica Guma; study start date: 1 October 2021). The following were assessed before and after the intervention: (1) clinical outcomes; (2) gut and salivary microbiomes; and (3) salivary, stool, and plasma metabolomes. Responders were defined as patients achieving ≥30% reduction in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scores. <b>Results:</b> The ITIS diet was well-tolerated, with good adherence (66.2%) and a significant improvement in clinical outcomes, including reduced pain and improved overall health measured with the visual analog scale (VAS). Responders (<i>n</i> = 8) showed distinct gut microbiome and metabolome profiles compared to non-responders (<i>n</i> = 12). Notably, taxa within the <i>Lachnospiraceae</i> family exhibited dynamic, bidirectional shifts post-intervention: <i>Anaerostipes</i> and <i>Limivivens</i> were enriched among responders and negatively correlated with pain scores, while <i>Oliverpabstia</i> and <i>Fusicatenibacter</i> were depleted following dietary intervention. These taxa also showed strong correlations with anti-inflammatory metabolites, including hydroxydecanoic acid derivatives and pyridoxine. Furthermore, subsequent network analysis revealed more structured and selective microbiome-metabolome interactions in responders, specifically post-intervention. <b>Conclusions:</b> This pilot study shows that a short-term anti-inflammatory dietary intervention was associated with meaningful changes in the gut microbiome and metabolome. Members of the Lachnospiraceae family emerged as key taxa associated with pain reduction and anti-inflammatory metabolite production. Our findings suggest that specific microbial responses-rather than global diversity changes-may underlie dietary responsiveness in OA. Although exploratory and limited by sample size, our results support further investigation into personalized, microbiome-informed nutritional strategies for OA management.