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THE MAJOR FLAW IN EVIDENCE-BASING LONG COVID RESEARCH
In times of a pandemic, relying solely on evidence-based medicine (EBM) for treatment decisions presents significant challenges. The urgency of the situation clashes with the time-consuming nature of traditional research methodologies, hindering timely decision-making.
Moreover, the scarcity of evidence in the early stages of a pandemic complicates treatment choices, leaving clinicians to navigate uncertainty. The emergence of new viral variants creates further issues, as EBM struggles to keep pace with evolving strains. Resource constraints and ethical dilemmas surrounding treatment allocation add layers of complexity, while the diverse characteristics of affected populations challenge the generalisability of research findings.
In such dynamic circumstances, clinicians need freedom to explore innovative treatments beyond the scope of traditional EBM, as well as apply a common sense approach to what is being witnessed within clinical practice, balancing the need for evidence with the ability to act swiftly, safely and effectively.
Now that we are four years down the line, there are still limited recognised and effective treatments, for long COVID, although many research groups have come quite far in understanding some of the pathophysiology. The purpose of this post is not to present a complete pathophysiological picture of this disease. Instead, I aim to outline how I believe the gut microbiota ties into the overall clinical picture.
The findings I share here stem from my personal research, clinical tests, analysis of existing research, collaborations with other researchers in this field and 4 years of clinical experience working with long COVID sufferers. While my proposals are not definitive, or indeed set in stone, they reflect my current understanding.
I have organised this post so that the first sections cover basic concepts that are accessible to non-scientific readers, and the following sections provide explanation of the proposed underlying science and key mechanisms.
The gut microbiota phenotype of long COVID:
The decision to publicly disclose my findings and hypotheses regarding a long COVID microbiota phenotype has been a subject of extensive deliberation. The fundamental question of whether it is indeed feasible to define a distinct microbiota profile associated with long COVID remains to be properly assessed, I understand the complexities and the need for ongoing scientific scrutiny. However, my observations from clinical practice and the rapidly evolving research landscape have provided enough evidence to share my preliminary insights.
I present the current state of my investigations, with the aim of promoting further questioning and research within this area so that we can all advance our understanding of this complex health challenge.
The Long COVID Microbiome Phenotype:
Exacerbated by 6 major mechanisms:
Gut associated Viral persistence.
SARS-CoV-2 bacteriophage like activity
Gut derived toxic peptides through viral persistence
LPS translocation exacerbated by SARS-CoV-2
Industry produced probiotic contamination
Yet to be identified microbiota structures / entities
Results in:
Low levels of multiple stains of Bifidobacteria spp.
Low or very high levels of Akkermansia spp.
Disruption to various Lactobacillus spp.
Disruption to Oxalobacter formigenes that help to break down oxalates from the diet
Increased incidence of parasitic/fungal dysbiosis
High levels of gram-negative bacteria, methanogens, and/or hydrogen sulfide producers
Disruption to Short Chain Fatty Acid production
Tight junction protein displacement
Poor barrier function and intestinal hyperpermeability leading to:
Altered system behaviours connected to the gut-brain, gut-lung, gut-liver, gut-kidney axis.
Inappropriate immune system signals
Activation of inflammatory pathways
Increased potential for viral syncytia formation and activation of senescent cells
Activation of fibrin and clotting cascades
Additional evidence of a new microbiota structure to be further explored: Obelisks Viroid-like particles. Fig. 1.
PERSISTENT DISRUPTION COULD LEAD TO THE EMERGENCE OF A COMPLETELY NEW MICROBIOME STRUCTURE!
Fig 1 | Rachel Jessey: Long Covid Phenotype Schematic of Mechanisms
There is growing evidence that the SARS-CoV-2 spike protein can infect the vagus nerve. Fig. 2. Significantly, the vagus nerve forms a direct connection between the brain and the enteric nervous system - the nervous system of the gut. This important connection sends nerve signals to every organ in the gastrointestinal tract as well as the heart and lungs but also serves as an entry point allowing SARS-CoV-2 from the gut to initiate brain infection.
Common gastrointestinal complaints among those suffering from long COVID include small intestinal bacterial overgrowth, reflux, severe bloating, gastroparesis (delayed gastric emptying), and constipation or diarrhoea. In some cases, people have gone on to develop more severe gastrointestinal conditions such as inflammatory bowel disease, and a form of gastroparesis where normal eating becomes impossible and tube feeding and/or surgery becomes necessary. Part 3 of this blog series will explore specific gastrointestinal conditions observed in long COVID, along with practical and safe interventions.
Fig 2 | The Cranial Nerves: Cranial Nerve X is the vagus nerve. @Physiopedia
Key Concepts:
Delving deeper into the proposed mechanisms within the gut
Persistent viral infections in the gastrointestinal tract present complex challenges in both clinical practice and research. Research has shown that SARS-CoV-2, can persist in the gut for extended periods, potentially leading to chronic infection and ongoing health complications. This persistence is further complicated by asymptomatic shedding and viral reactivation, which contribute to disease progression and transmission. Hany M et al. (2024), through endoscopic examination and immunohistochemistry analysis of biopsy samples, demonstrated that gut mucosal tissues can retain SARS-CoV-2 viral particles for months after the initial infection.
Brogna C et al. (2023) has revealed that in vitro, SARS-CoV-2 RNA can replicate within bacteria in the gut. Fig. 3. This finding challenges conventional understanding of viral replication and should be prompting researchers to re-evaluate microbiological and virological knowledge.
Figure 3 | Brogna et al. Analysis of Bacteriophage Behavior of a Human RNA Virus, SARS-CoV-2, through the Integrated Approach of Immunofluorescence Microscopy, Proteomics and D-Amino Acid Quantification. Int J Mol Sci. 2023 Feb 15;24(4):3929. doi: 10.3390/ijms24043929. PMID: 36835341; PMCID: PMC9965620.
In addition, earlier findings from Brogna C et al. (2022) identified toxin-like peptides were being produced by the gut microbiota during acute stress induced by viral persistence of SARS-CoV-2. The role of these toxin-like peptides was uncovered through research on infected patient stool samples, with the peptide structures resembling conotoxin proteins known for their neurotoxic effects. These have been found to up-regulate or down-regulate neuronal genes in human neural stem cells. Moreover, phospholipase A2, another identified toxin-like peptide, may contribute to coagulation disorders and interact with the cholinergic system, affecting various processes in both clotting cascades and central and peripheral nervous systems.
Germ-free mice receiving microbiome samples from post-COVID-19 syndrome patients have shown increased susceptibility to pulmonary problems and cognitive deficits, highlighting the significant role of the microbiota in COVID-19 outcomes.
Possibly one the most interesting concepts that has been presented to me is by Marakhovski A (2020), that alerted me to the concept of industry originated probiotic contamination. The article presents the hypothesises that the widespread consumption of the probiotic bacteria Bifidobacterium animalis subspecies lactis, and lactobacillus acidophilus commonly used in dairy products and supplements, may have worsened the COVID-19 pandemic.
Chronic administration of industry produced probiotics may colonise the human gut when consumed over a long periods. This “probiotic contamination” could cause alterations to microbiota structures and increase susceptibility to SARS-CoV-2 infection by enhancing the virus's ability to enter cells and cause cytokine storms. Countries with high consumption of Bifidobacterium animalis and lactobacillus acidophilus from big manufacturers seem to correlate with more severe COVID-19 outbreaks according to observations. This theory would also make perfect sense when we start to understand SARS-Cov-2 as a bacteriophage and its apparent ability to take down keystone species in the gut.
The case for probiotic contamination and SARS-CoV-2 bacteriophage activity would also explain reported recoveries in many people who have taken antimicrobial as opposed to antiviral agents and why I am cautious around probiotic administration.
In addition to the above, a new 2024 study by Zheludev IN. et al. has introduced a novel class of circular viroid-like elements called "Obelisks" found in the human gut microbiome. These Obelisks persist in the microbiome and may interact with bacterial species. This discovery highlights that our current knowledge is likely still limited, and countless more revelations about the microbiome remain to be uncovered. As such, it is crucial to keep an open mind as our understanding of the microbiome's complexities and influences continues to evolve.
Key Concepts:
Delving deeper into the proposed mechanisms beyond the gut wall
In part 1, I introduced you to lipopolysaccharide (LPS) translocation from the gut due to dysbiosis and intestinal hyperpermeability. Translocated LPS is well known to activate inflammatory processes, but notably, LPS interaction with the SARS-CoV-2 spike protein appears to further intensify this process.
To explain further its role in inflammation, LPS binds to Toll-like receptor 4 (TLR4) on immune cells, which activates pro-inflammatory signalling and mast cell degranulation. This leads to the release of cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukins (ILs). At the same time, displacement of tight junction proteins, as discussed in part 1, and secretion of secretory phospholipase A2 (sPLA2) further contribute to gut barrier disruption, and in the case of sPLA2, generates pro-inflammatory lipid mediators, amplifying the inflammatory response and allows for the passage of spike fragments across the gut wall.
The pro-inflammatory cytokines, lipid mediators, toxic peptides, translocated LPS, and spike protein can activate the NLRP3 inflammasome, a multiprotein complex that cleaves and drives further production of pro-inflammatory cytokines. TNF-α also plays a crucial role in activating the NLRP3 inflammasome through direct binding or indirectly via mechanisms like reactive oxygen species (ROS) generation, potassium efflux, and lysosomal destabilisation.
The release of cytokines and other pro-inflammatory mediators triggers the recruitment and activation of neutrophils, which can undergo NETosis, leading to the formation of neutrophil extracellular traps (NETs). While NETs can trap and immobilise harmful substances crossing the gut into the systemic circulation, they can also promote fibrin formation, cellular senescence, and the formation of syncytia, exacerbating tissue damage and inflammation. In addition, SARS-CoV-2 can disrupt the body's ability to regulate blood clotting, leading to various abnormalities in the anticoagulant and fibrinolytic systems.
Deficiencies in key proteins, along with reduced levels of antithrombin, heighten the risk of clot formation. Endothelial dysfunction further exacerbates this risk by disrupting the balance of clot-preventing and clot-promoting substances in the blood vessels. Elevated levels of Plasminogen Activator Inhibitor-1 (PAI-1) hinder blood clot breakdown, while reduced activity of Tissue Plasminogen Activator (tPA) impedes clot dissolution. Elevated D-dimer levels can be a sign of increased blood clot formation and breakdown. however, if the mechanisms that hinder the breakdown of clots are inhibited, D-dimer levels will likely be within normal ranges even though clots continue to be formed.
Conclusion
I believe that the gut microbiota plays a vital role in the persistence of long COVID. The potential impact of the long COVID microbiome phenotype, include disruptions in microbial composition and metabolic activities, that extends far beyond the gut.
Despite significant advancements in microbiome research, our understanding remains limited. Scientists have compiled data on thousands of bacterial species, but there are still many unknowns, particularly concerning viral, fungal, and parasitic species and emerging novel entities like obelisks. Technological constraints further impede progress, with the study of viruses often overlooked due to their small size and the complexity of viral communities.
The dynamic nature of the gut microbiota adds another layer of complexity. Microbiome composition can vary widely between individuals and change over time due to factors such as diet, lifestyle, and environmental influences. This variability will continue to complicate future research efforts and makes it challenging to draw definitive conclusions. Despite these challenges, ongoing research will continue to shed light on the microbiota’s significance on long COVID and other chronic illnesses, we must always remain open minded.
Next week I will be uploading part 3 where I will be sharing some of the interventions, I have been using to support these mechanisms over the last 4 years.
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