EFFECTS OF GUT MICROBIOME MODULATION ON CLINICAL OUTCOMES AND GUT DYSBIOSIS AMONG ELDERLY AND DIABETES PATIENTS AFTER COVID-19 VACCINATION: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Background: Emerging evidence suggest that gut microbiota influence human health such as digestive functions and risk of sepsis. We hypothesize that using a novel oral microbiome formula (SIM01) can restore dysbiosis and reduce adverse clinical events among vulnerable individuals after COVID-19 vaccination.

Methods: In a single center, double-blind, randomized, parallel arm, placebo-controlled trial, we recruited COVID-19 vaccination-naïve subjects (elderlies aged ≥ 65 years and patients with type 2 diabetes). After receiving the first dose of COVID-19 vaccine (CoronaVac or BioNTech), eligible subjects were randomized in a 1:1 ratio to receive 3 months of SIM01 (containing 20 billion CFU of probiotics per day) or placebo (2 mg of vitamin C per day). Intervention (SIM01 or placebo) was initiated within 1 week of receiving COVID-19 vaccines to minimize confounding effects of COVID-19 infection. Follow-up assessments were arranged at 1 month and 3 months after second vaccine dose. Outcomes included (1) Adverse events (AEs), defined as new symptoms/diseases which exerted unfavourable impacts on subjects; and (2) Restoration of gut dysbiosis, defined as improvement in (i) gut microbiome composition and diversity; (ii) functional potential (i.e., MetaCyc pathway abundances); and (iii) proliferation of beneficial bacteria genus (i.e., bifidobacteria, eubacterium, roseburia and other short-chain fatty acids producers). Fecal microbiome analysis using shotgun metagenomic sequencing were performed at baseline and after 3 months. The study is registered in a clinical trial registry (NCT04884776).

Results: Between April 2021 and March 2022, of 497 subjects assessed for eligibility, we recruited 453 individuals (50.3% females; mean age 67.5 years). We randomly assigned 224 subjects to SIM01 and 229 to placebo. There was no difference in baseline characteristics between the two groups (Table 1). The incidence of AE (2.9% vs. 10.6%, p=0.002) and combined AE/serious AE (2.9% vs. 12.6%, p<0.001) were significantly lower in SIM01 group than placebo group at 1 month. Rates of AE (0% vs. 2.5%, p=0.053) and combined AE/serious AE (0% vs. 3.1%, p=0.025) remained significantly lower in SIM01 than placebo group at 3 months. Overall, 70.4%, 18.5%, and 11.1% of the AEs and serious AEs at 1 month included gastrointestinal disturbance, dermatological conditions and infections, respectively. Probiotics in SIM01 successfully colonized in the gut. SIM01, but not placebo, led to a significant increase in beneficial bacteria and butyrate producers in fecal samples, enterotype shift from bacteroides to bifidobacteria and a strengthened microbial ecology network at 3 months after second vaccine dose.

Conclusion: SIM01 restored gut dysbiosis, reduced adverse clinical outcomes and strengthened gut microbiome resilience in elderly people and diabetes patients after COVID-19 vaccination.