Diagnosing chronic, post-acute inflammatory conditions – like Long COVID – remains a persistent challenge for researchers and healthcare professionals alike12. The variable presentation of symptoms – along with the allusivity of an exact cause – make these conditions difficult to pin down in the clinic. Current diagnostic approaches rely on highly speculative patient questionnaires; these, while useful, do not provide researchers or clinicians with accurate measures of symptomology – nor do they provide quantitative data to stratify disease severity or explore potential disease subtypes. The urgent need for accurate, improved diagnostics has led researchers to explore a variety of options when it comes to sample types – including stool and blood3.
In recent years, a research focus on the gut microbiome has led scientists to speculate whether stool samples may offer a convenient, non-invasive option for diagnosis and stratification – offering the opportunity to profile distinct microbial “signatures” reflective of disease status. Yet, with the exact cause of Long COVID still unknown, the jury is out on whether microbiome profiling will translate to the clinic; there remain no approved diagnostics using this approach. This article highlights some of the latest research into the Long COVID microbiota. It also explores the benefits and drawbacks of potential stool-based microbiome profiling compared to blood-based biomarker detection.
Long COVID (also known as “post-acute sequalae of COVID-19”, or “PASC”) is a chronic illness characterized by an array of variable, sometimes debilitating symptoms —from profound fatigue and cognitive impairment to cardiovascular symptoms and neuropathic pain4. It occurs in some (but not all) people who have experienced an acute SARS-CoV2 virus infection and can persist for many months, or even years, after the initial infection has cleared. While the exact causes of Long COVID remain unknown, research suggests that the gut microbiome may play a profound role in its ongoing symptomology5.
Gut dysbiosis is defined as an imbalance or disruption in the gut microbiome. It can be caused by a variety of factors, including viral infection, inflammation, stress and medication6. While it’s perhaps unsurprising that gut dysbiosis is a common effect of Long COVID, it is unclear whether such changes are symptomatic or causative7.
Several dysbiosis changes have been identified as disease ‘hallmarks’ in patients that have a verified Long COVID diagnosis. These hallmark changes include an increase in commensal pathogens (such as Clostridium, Micrococcus and Vellonella) alongside a decrease in the abundance of beneficial bacteria (Bifidobacterium, Faecalbacterium and Eubacterium). While the cause of such changes are yet to be fully understood, some experts believe that gut-immune system crosstalk could be, at least in part, responsible for this effect.
Some experts speculate that the aggressive induction pro-inflammatory cytokine signalling may potentiate the depletion of beneficial immunomodulatory bacteria – creating a feedback loop that sustains the pro-inflammatory environment. As bacterial metabolites – such as short-chain fatty acids (SCFAs) – are known to enhance the expansion and maturation of the immune system’s T cells, it is possible that this molecular crosstalk perpetuates immune dysregulation and contributes to the T cell dysfunction also observed in PASC patients8.
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In a 2022 scientific study published in Gut, researchers were able to effectively characterize PASC patients according to stool-based microbiome profiling 6 months after an initial SARS-CoV2 infection9. They also identified that non-PASC patients (who had also had COVID) displayed a recovered intestinal microbiota, highlighting the diagnostic potential of Long COVID specifically. While there is clear potential for microbiome profiling in PASC diagnosis and research, several challenges prohibit the implementation of this approach. Firstly, the inherent heterogeneity of the human microbiome presents a barrier to developing a one-size-fits-all solution10. In addition, the high cost of microbiome metagenomic sequencing means that routine stool sampling testing at this analytical depth is not economically viable in a healthcare setting. Hence, while diagnosing Long COVID using stool sampling is theoretically possible, it remains limited by bottlenecks.
Researchers have found that, like the microbiome, the adaptive immune system also reflects several, measurable hallmarks of Long COVID11. These hallmarks patterns include T cell dysfunction – an effect that is both cheaper and easier to measure than microbial dysbiosis. As such, blood-based sampling may offer several benefits in clinical applications; it may also facilitate easier research into PASC and PASC-related conditions.
While gut microbiome profiling can offer insights into the pathophysiology of Long COVID, the high cost of comprehensive sequencing and heterogeneity of sample types limit widespread clinical application. Conversely, research into blood-based biomarkers, particularly those reflecting adaptive immune system, is gaining traction. These blood-derived measurements present a more accessible and economically viable approach for both routine clinical assessment and large-scale research into Long COVID and other PAIS conditions.
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