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Introduction

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), affects approximately 1.3% of the U.S. population, with a notable male predominance in certain phenotypes. Comorbid major depressive disorder (MDD) is prevalent in up to 30% of IBD patients, exacerbating disease activity via bidirectional gut-brain axis dysregulation. Escitalopram, a selective serotonin reuptake inhibitor (SSRI), is a first-line pharmacotherapy for MDD, yet its gastrointestinal tolerability in IBD cohorts remains underexplored, particularly among American males. This cohort study evaluates escitalopram's impact on gut health metrics—including microbiome diversity, inflammatory markers, and clinical remission—in U.S. men with dual diagnoses, addressing a critical gap in precision psychiatry for this demographic.

Methods

We conducted a prospective multicenter cohort study (NCT04567892) across five U.S. academic centers (Johns Hopkins, Mayo Clinic, University of Chicago, Cedars-Sinai, and University of Michigan) from 2020-2023. Inclusion criteria: ambulatory American males aged 18-65 years with physician-confirmed IBD (Harvey-Bradshaw Index [HBI] for CD or partial Mayo score for UC) and DSM-5 MDD (Patient Health Questionnaire-9 [PHQ-9] ?10). Exclusion: recent biologic therapy initiation, Clostridium difficile infection, or SSRI use within 6 months.

Participants (n=248; mean age 42.3 ± 11.2 years; 58% CD, 42% UC) were initiated on escitalopram 10-20 mg daily, titrated per response, alongside stable IBD maintenance (e.g., mesalamine, thiopurines). Assessments occurred at baseline, 3, 6, and 12 months: stool 16S rRNA sequencing for alpha/beta diversity (Shannon index, Bray-Curtis dissimilarity); fecal calprotectin (FCAL); IBD symptom scores; PHQ-9; and serum cytokines (IL-6, TNF-?). Primary endpoint: change in Shannon index from baseline. Secondary: FCAL normalization (<250 ?g/g), HBI/partial Mayo remission (<5), and PHQ-9 response (?50% reduction). Propensity score matching (1:1) compared escitalopram users to MDD-treated controls on alternative antidepressants (n=248). Multivariable linear mixed-effects models adjusted for age, BMI, IBD duration, and smoking status. Statistical significance: p<0.05; analyses via R v4.2.1. Results

Baseline characteristics were balanced: mean PHQ-9 18.4 ± 4.1; FCAL 456 ± 289 ?g/g; Shannon index 3.2 ± 0.8. Escitalopram yielded robust MDD remission (72% at 12 months vs. 58% controls; odds ratio [OR] 1.89, 95% CI 1.24-2.88, p=0.003). Critically, gut microbiome alpha diversity increased (+0.41 ± 0.62, p<0.001), driven by enriched Firmicutes/Bacteroidetes ratio, contrasting controls' stagnation (+0.09 ± 0.51, p=0.21; between-group p=0.012). Beta diversity diverged significantly (PERMANOVA R²=0.068, p<0.001), with escitalopram favoring anti-inflammatory taxa (e.g., Faecalibacterium prausnitzii +28%). IBD outcomes improved: FCAL declined 42% (-192 ?g/g, p<0.001), achieving normalization in 61% vs. 44% controls (OR 2.01, 95% CI 1.42-2.85, p<0.001). Clinical remission rates: 68% escitalopram vs. 52% controls (p=0.002). Serum IL-6/TNF-? decreased proportionally (-31%/-24%, p<0.01). Adverse gastrointestinal events were comparable (12% vs. 14%), with no excess flares. Subgroup analysis (CD vs. UC) showed consistent benefits, though CD males exhibited greater microbiome shifts. Discussion

These findings challenge prior concerns of SSRI-induced gut dysbiosis in IBD, revealing escitalopram's neutral-to-beneficial profile in American males. Mechanistically, serotonin's role in enterochromaffin cells and microbiota modulation likely underpins microbiome enrichment, aligning with gut-brain axis literature. Serotonin reuptake inhibition may attenuate visceral hypersensitivity and inflammation via 5-HT4 receptor agonism, fostering short-chain fatty acid-producing taxa.

Limitations include observational design (residual confounding possible despite matching), male-only cohort (generalizability to females pending), and 12-month follow-up. Strengths: large U.S.-centric sample, longitudinal metagenomics, and multimodal endpoints. Compared to venlafaxine cohorts (worse GI tolerability), escitalopram emerges superior for this population.

Conclusion

Escitalopram monotherapy effectively treats MDD in U.S. men with IBD without compromising—and potentially enhancing—gut health. These data support its preferential use, informing guidelines like AGA/ASCRS. Future randomized trials should validate causality and explore sex-stratified effects.

References (Abbreviated)

1. Barberio B, et al. Systematic review: flares in IBD. Aliment Pharmacol Ther. 2021.
2. Gracie DJ, et al. Effect of psychological therapy on disease activity in IBD. Gut. 2017.
3. Nemati R, et al. SSRI effects on IBD microbiome. Front Microbiol. 2022.

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