Background: Post-acute COVID-19 syndrome (PACS) affects sleep and neuropsychiatric functions but treatment is limited. We aimed to assess the effects of faecal microbiota transplantation (FMT) in alleviating post-COVID insomnia and anxiety.

Methods: In this open-label pilot trial, patients with an Insomnia Severity Index (ISI) score of ≥ 8 at least 4 weeks after COVID-19 were allocated to the FMT group or the control group at 1:1 ratio. The FMT group received FMT via oesophagogastroduodenoscopy (OGD) at baseline, 2, 4, and 8 weeks, and via flexible sigmoidoscopy (FS) at baseline. The control group did not receive FMT. Primary outcome was insomnia remission, defined as a change in ISI from ≥ 8 (subthreshold to clinical insomnia) to < 8 (no clinically significant insomnia) by 12 weeks. Secondary outcomes were changes in Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Generalised Anxiety Disorder-7 (GAD-7) scores, blood cortisol or melatonin and gut microbiome. Multivariable stepwise logistic regression was performed to identify independent predictors of insomnia remission. Blood cortisol and melatonin were quantified by ELISA tests. Gut microbiome was profiled by shotgun metagenomic sequencing. ClinicalTrials.gov identifier: NCT05556733.

Results: Between September 2022 and June 2023, 60 subjects (mean age 46.6 ± 12.2 years, 57.6% female) with a mean ISI score of 16.5 (± 4.3) were recruited. At 12 weeks, a significantly higher proportion of subjects who received FMT achieved insomnia remission (37.9% vs 10.0%, p=0.018). Mean ISI score of the FMT group significantly improved from 17.1 (± 0.9) to 8.5 (± 1.0) at 12 weeks (p<0.0001). ISI scores were significantly lower in the FMT group (p=0.0001). On multivariable analysis, treatment with FMT was the only significant predictor of insomnia remission (OR: 5.500, 95% CI: 1.344-22.506, p=0.018). Subjects who received FMT also showed significant improvement in sleep quality [PSQI: 12.9 (± 0.7) to 6.8 (± 0.6), p<0.0001], daytime sleepiness [ESS: 11.3 (± 0.8) to 8.7 (± 0.8), p=0.0057], and anxiety [GAD-7: 9.8 (± 1.2) to 5.3 (± 0.9), p=0.0019]. No significant improvement was observed in ISI, PSQI, ESS, and GAD-7 scores in the control group (p>0.05). The FMT group showed significantly lower concentration of blood cortisol at 12 weeks (p=0.035). Faecal microbiome of the FMT group showed enrichment of Gemmiger formicilis, and depletion of Bacteroides xylanisolvens and microbial pathways producing menaquinol derivatives at 12 weeks.

Conclusion: Treatment with faecal microbiota transplantation (FMT) alleviates sleep disturbance and anxiety in patients with PACS. Further controlled studies are warranted to explore the effects on sleep and mental health.

This study was funded by the Hui Hoy & Chow Sin Lan Charity Fund Limited. The authors are partially supported by InnoHK, the Government of the HKSAR.

Kwok Tung Moses Li

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