MODULATION OF GUT MICROBIOME ALLEVIATES POST-ACUTE COVID-19 SYNDROME: A RANDOMISED, TRIPLE-BLIND, PLACEBO-CONTROLLED TRIAL (RECOVERY STUDY)

Background: Gut dysbiosis is associated with persistent multi-system symptoms following SARS-CoV-2 infection, or post-acute COVID-19 syndrome (PACS). We performed a randomised controlled trial to assess the effects of gut microbiome modulation on alleviation of PACS symptoms.

Methods: This is a single-centre, triple-blind, randomised, placebo-controlled study in recovered COVID-19 patients who reported persistent PACS symptoms. Eligible subjects were randomly assigned at 1:1 ratio to receive either a novel oral microbiome immunity formula (SIM01, synbiotic) or placebo orally for 6 months. The primary outcome was the alleviation of PACS symptoms by month 6 as compared to baseline, assessed by a structured 14-item symptom questionnaire. Chi-squared test was used to evaluate the association between intervention and symptom alleviation. The secondary outcome was the reduction of gastrointestinal symptoms severity, evaluated by a self-report scale from 1 to 4 (1=none, 4=severe). Wilcoxon signed-rank test was used to compare the changes in severity scores between baseline and month 6. Bonferroni correction was applied to adjust for multiple comparisons of symptoms.

Results: A total of 463 subjects (mean age 49.4 ± 13.4 years, 65.4% female) were randomised at a median duration of 4 (IQR: 3-11) months since COVID-19 diagnosis. All subjects had at least one of 14 common symptoms of PACS at randomisation and were included in the intention-to-treat analysis. A significantly higher proportion of subjects who received SIM01 had improvements in fatigue (62.8% vs 42.6%, p<0.001), memory loss (42.0% vs 26.9%, p=0.002), difficulty in concentration (62.3% vs 38.5%, p<0.001), digestive problems (70.2% vs 54.1%, p=0.001), and general unwellness (77.3% vs 59.0%, p=0.001) by 6 months compared with the placebo group, after adjusting for multiple comparisons. Amongst 134 subjects who reported improvement in digestive problems after SIM01 intervention, we found significant reductions in severity score for 7 out of 8 gastrointestinal symptoms assessed, including diarrhoea (p<0.001), constipation (p<0.001), abdominal pain (p=0.003), epigastric pain (p<0.001), bloating (p<0.001), vomiting (p=0.005) and acid reflux (p<0.001), following Bonferroni correction.

Conclusion: This is the first randomised controlled trial showing that modulation of gut microbiome with a novel oral microbiome formula (SIM01) alleviates gastrointestinal and neuropsychiatric symptoms of PACS.

This study was funded by the Health and Medical Research Fund under the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, and Hui Hoy & Chow Sin Lan Charity Fund Limited. The authors are partially supported by InnoHK, the Government of the HKSAR.