Synbiotics in post-acute COVID-19 syndrome—a potential new treatment framework?
Authors: Betty Raman, Maheshi N Ramasamy
Journal: The Lancet Infectious Diseases (2023)

As the world continues to recover from the impact of the COVID-19 pandemic, a new challenge has emerged in the form of post-acute COVID-19 syndrome (PACS), also known as long COVID. Characterised by multisystem involvement, PACS can lead to a substantial decline in quality of life, presenting a complex clinical picture that spans persistent debilitating cardiopulmonary, gastrointestinal, and neuropsychiatric symptoms, alongside profound fatigue. An estimated 65 million people worldwide are thought to have PACS, with a consequent effect on global workforces1LancetLong COVID: 3 years in.Lancet. 2023; 401: 795Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar. No effective treatment has yet been identified. Emerging evidence underscores the importance of the gut microbiome in the pathophysiology of long COVID, with a notable disruption in microbial balance, termed gut dysbiosis, identified in some individuals.2Liu Q Mak JWY Su Q et al.Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome.Gut. 2022; 71: 544-552Crossref PubMed Scopus (170) Google Scholar The rationale for exploring the gut microbiome is grounded in its well-established role in immune modulation,3Thomas CM Versalovic J Probiotics-host communication: modulation of signaling pathways in the intestine.Gut Microbes. 2010; 1: 148-163Crossref PubMed Google Scholar a connection that is pertinent given the increasing evidence linking the prolonged symptoms of PACS to a persistent dysregulated immune response after infection.4Evans RA Leavy OC Richardson M et al.Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study.Lancet Respir Med. 2022; 10: 761-775Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 5Phetsouphanh C Darley DR Wilson DB et al.Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.Nat Immunol. 2022; 23: 210-216Crossref PubMed Scopus (417) Google Scholar In patients with COVID-19, especially those with persistent symptoms, alterations in gut flora have been verified through metagenomic sequencing of faecal samples.2Liu Q Mak JWY Su Q et al.Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome.Gut. 2022; 71: 544-552Crossref PubMed Scopus (170) Google Scholar This gut dysbiosis has also been found to correlate with increased gut inflammation, compromised gut wall integrity, and systemic inflammatory dysfunction.6Tilg H Zmora N Adolph TE Elinav E The intestinal microbiota fuelling metabolic inflammation.Nat Rev Immunol. 2020; 20: 40-54Crossref PubMed Scopus (561) Google Scholar There are now several studies showing that probiotics, consisting of beneficial bacteria such as Lactobacillus and Bifidobacterium species, might enhance gut health, modulate inflammation, and improve immune function.7Suez J Zmora N Segal E Elinav E The pros, cons, and many unknowns of probiotics.Nat Med. 2019; 25: 716-729Crossref PubMed Scopus (668) Google Scholar In the context of COVID-19, these effects are particularly promising, with some studies suggesting a potential role of probiotics in recovery from acute viral infection.8Zhao Y Dong BR Hao Q Probiotics for preventing acute upper respiratory tract infections.Cochrane Database Syst Rev. 2022; 8Cd006895PubMed Google Scholar The rationale for the use of synbiotics, a combination of probiotics and prebiotics, is based on the premise that a more comprehensive approach is needed to address the multifactorial nature of PACS. SIM01 represents a novel approach to synbiotic therapy with a formulation based on the synergy of selected strains of Bifidobacterium (eg, Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum), and specific prebiotics (eg, galacto-oligosaccharides, xylo-oligosaccharides, and resistant dextrin). In The Lancet Infectious Diseases, Raphaela Lau and colleagues9Lau RI Su Q Lau ISF et al.A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2023; (published online Dec 7.)https://doi.org/10.1016/S1473-3099(23)00685-0Summary Full Text Full Text PDF Scopus (1) Google Scholar conducted the first randomised, double-blind, placebo-controlled trial to investigate the therapeutic effects of gut modulation with SIM01 in patients with PACS at a tertiary referral centre in Hong Kong. Adults aged 18 years and older with previous SARS-CoV-2 diagnosis and who met the US Centre for Disease Control and Prevention criteria for PACS were randomly assigned to receive either oral SIM01 (10 billion colony-forming units) or placebo twice daily for 6 months. The intention to treat population consisted of 463 participants who received SIM01 (n=232) or placebo (n=231). The primary outcome was reduction in the severity of symptoms, measured using a 14-point questionnaire scale (PACSQ-14). Individuals receiving SIM01 had higher rates of alleviation for certain symptoms after 6 months, including fatigue (OR 2·273, 95% CI 1·520–3·397, p=0·0001), general unwellness (2·360, 1·428–3·900, p=0·0008), memory loss (1·967, 1·271–3·044, p=0·0024), gastrointestinal upset (1·995, 1·304–3·051, p=0·0014), and difficulty in concentration (2·644, 1·687–4·143, p<0·0001). Faecal metagenomic analyses identified an increase in gut microbiome diversity compared with baseline, with enrichment of short chain fatty acid metabolism pathways in SIM01 recipients but not in placebo recipients. Adverse event rates were similar between the treatment and placebo groups, and none were judged to be related to study interventions. Antibiotic use, study drug compliance, and baseline comorbidities were similar between both SIM01 and placebo arms. Overall, the study has many notable strengths including the assessment of the primary outcome using a standardised questionnaire, randomisation using random permuted blocks, and the masking of participants, care providers, and investigators to group assignments. 80% (369 of 463) of participants had symptoms lasting 3 months or longer at enrolment, aligning with the WHO's definition of PACS. This is also the first double-blind randomised controlled trial to evaluate the effects of gut microbiome modulation on PACS. Although the study's findings are promising, its conclusions are drawn within the context of certain limitations. The reliance on subjective reports of PACS symptoms and the absence of a globally approved assessment tool for post-COVID manifestations complicates the interpretation of the population studied and of treatment efficacy. Although alleviation of some symptoms of PACS was observed, this alleviation did not correspond with measurable improvements in quality of life or physical activity after 6 months, suggesting that the real benefits of the treatment on general health perception and functional capacity might be low. Additionally, given the study's single-centre design and that the composition of SIM01 is based on the gut flora of healthy Chinese populations, the relevance of the findings to ethnically and geographically diverse cohorts worldwide warrants further investigation. The proposed mechanism of symptom improvement—through a reduction in systemic inflammation via increased gut microbial diversity—is intriguing but remains speculative without direct evidence for this mechanism, given that no differences were observed in plasma cytokine profiles between placebo and SIM01 groups at 6 months. How SIM01's efficacy compares to other probiotic and prebiotic blends containing Lactobacillus species, such as those mentioned in an open-label study by Thomas and colleagues,10Thomas R Aldous JWF Forsyth R Chater AM Williams M The influence of a blend of probiotic Lactobacillus and prebiotic inulin on the duration and severity of symptoms among individuals with COVID-19.Infect Dis Diag Treat. 2021; 5: 182Google Scholar is also unclear, highlighting the need for further comparative research. Of note, participants receiving placebo also had symptom alleviation, meaning that investigation of the placebo effect by including a control group, which did not receive any interventions, would have been useful. Nevertheless, the methodological strengths of the study, including its substantial sample size, commendable follow-up completion rate, and strategic use of serial stool microbiome analysis provides a solid foundation for its conclusions, lending valuable insights into potential therapeutic mechanisms. Lau and colleagues' study suggests that synbiotic preparations like SIM01 offer a safe and promising treatment for patients with PACS. Although larger, pragmatic, multicentre studies are needed to validate these findings and examine the longer term benefits of such therapies, this study serves as a foundational step towards a potential new treatment framework in the management of PACS. BR has consulted for Axcella therapeutics. MNR has been an investigator on vaccine trials outside the scope of this manuscript that have received support from or have been sponsored by AstraZeneca, ILiAD Biotechnologies, GSK Vaccines for Global Health, and Variation Biotechnologies Vaccines, but all funding for these projects was paid directly to the University of Oxford. Neither author has received any financial support for writing this Comment. A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trialTreatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions. Full-Text PDF