Background: The Mediterranean diet (MED) is hypothesized to play a protective role in Crohn’s disease (CD) etiology, yet the underlying mechanisms remain unclear. Here we explored the association between adherence to MED, CD course, clinical and inflammatory markers, and microbial and metabolite composition in patients with newly diagnosed CD.
Methods: Patients with newly diagnosed CD were recruited and prospectively assessed. Food frequency questionnaires (FFQ) were collected each visit and assessed for adherence to MED, using a predefined IBDMED score, alongside validated MED adherence screeners. The Crohn’s disease activity index (CDAI) was used to evaluate clinical activity and serum and fecal samples collected for fecal calprotectin, C-reactive protein (CRP), and microbial composition using 16S rRNA sequencing. Baseline serum and fecal metabolomics were analyzed using a targeted quantitative metabolomics approach. Patients were classified as having a complicated course if during follow-up, they were steroid dependent, switched ≥2 biologics, hospitalized or underwent CD-related surgery.
Results: We recruited and prospectively observed 271 consecutive patients with newly diagnosed CD (52% males, average age- 31±12 years, inflammatory phenotype, B1- 75%) and collected 636 FFQs (range 1-5 FFQ per patient). Adherence to MED was associated with a non-complicated course and was inversely correlated with CDAI, fecal calprotectin, CRP and microbial dysbiosis index (all p<0.05). Increasing adherence to MED over time was associated with decreasing CDAI and fecal calprotectin in patients with complicated and non-complicated courses (p<0.05). Diet microbial interactions revealed two microbial clusters, showing that adherence to MED and intake of its recommended foods positively correlated with commensals and short-chain fatty acid producers including Faecalibacterium. Conversely, adherence to MED inversely correlated with a cluster of members of the Proteobacteria and also included Ruminococcus gnavus. Diet metabolomics interactions revealed two clusters showing that adherence to MED positively correlated with multiple serum and fecal organic compounds, vitamin derivatives, plant metabolites, amino acids and tryptophan metabolites and inversely associated with fecal triglycerides, ceramides and cholic acid, the major primary bile acid (FDR<0.1).
Discussion: Adherence to MED is associated with lower levels of primary bile acids and microbial dysbiosis and with a beneficial microbial and metabolite composition in patients with newly diagnosed CD. This may drive the inverse association of MED with clinical activity, inflammatory markers and complicated course. Microbial and metabolite-targeted dietary approaches like MED, should play a role in CD management.

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