Researchers published in Nature found that beyond the initial 30 days of COVID-19 infection, patients experienced heightened risks and increased burdens of various gastrointestinal disorders even after one year. But there is hope.

This story does not include health advice. It is for information, inspiration, and awareness purposes.

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The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, has led to a worldwide health emergency. In 2022, both my immediate and extended family, including myself, contracted the virus. Thankfully, we all recuperated without any fatalities. Sadly, several elderly neighbors, grappling with cardiometabolic and respiratory conditions, succumbed to complications from the virus. My primary research focuses on neurological aspects, as almost everyone in my circles instantly experienced it.

To my surprise, all family members except for me began experiencing digestive problems and sought examination of their gastrointestinal (GI) tract. Some were diagnosed with motility disorders, while others had acid-related issues and appetite problems. Due to my strict eating habits like intermittent fasting, I remained unaffected, but I empathized deeply with their situation and intensely started reviewing the literature.

I have been aware of the gut-lung connection for a long time, but it wasn’t until mid-2022 that I received manuscripts from case studies in my inbox as a peer reviewer for several international journals. Unfortunately, some early case studies couldn’t be published due to insufficient literature reviews. Nonetheless, I assisted several medical doctors, allowing them to collaborate with postdoctoral scientists in my circles to publish their papers with extensive literature reviews successfully. We know we have a growing literature thanks to the well-documented biochemistry of the gut.

Some exciting research developments occurred in late 2022 and early 2023. One particularly notable paper was published in Nature and another in Frontiers. While there were many others, these stood out for their impact, inspiring more scientists and clinicians to investigate the issue further and innovate new solutions, including healthy lifestyles and pharmaceuticals to improve the digestive system.

Initially, some medical professionals dismissed the connection between the lung and the digestive system, attributing symptoms to other causes and delaying research. The rejection and retraction of some papers was disheartening. However, thanks to the pioneering work of courageous scientists, the undeniable truth of this link and its potential mechanisms has been revealed. Many physicians publicly like this one on YouTube openly admit the correlation. There are also educational videos like this for practitioners.

In this story, rather than citing hundreds of papers, I will mainly summarize the key points from papers published in Nature and Frontiers and link some relevant and supportive papers defending the ideas presented in those papers as supplementary and informative records for those interested in details.

One of my key goals is to discuss how changes in gut microbiota affect susceptibility to COVID-19 and the progression of the disease, highlighting the biochemistry of the gut. I will also explore how interventions targeting gut microbiota could be used to treat COVID-19 in the future based on growing literature.

Summary of 2023 Paper on Nature: “Long-term gastrointestinal outcomes of COVID-19”

This study published in Nature in 2023 highlights the need for a thorough assessment of gastrointestinal issues in the aftermath of COVID-19, particularly in the absence of comprehensive data.

Using data from the US Department of Veterans Affairs, researchers examined over 154,000 individuals with COVID-19 and found increased risks of various gastrointestinal disorders beyond the initial 30 days of infection.

These risks persisted across different severity levels of COVID-19 and were observed even in those not hospitalized during the acute phase. The findings highlight the importance of post-COVID care, which includes monitoring and addressing gastrointestinal health concerns.

The study involved three groups: COVID-19, contemporary control, and historical control, comprising 154,068, 5,638,795, and 5,859,621 participants, respectively. These groups were followed up for a median duration of 408 to 409 days, resulting in 14,064,985 person-years of follow-up. Supplementary tables in the original paper provided baseline demographic and health data for each group.

It reveals that beyond the initial 30 days of infection, COVID-19 survivors face heightened risks and burdens of gastrointestinal disorders across various categories, including motility disorders, acid-related disorders, functional intestinal disorders, acute pancreatitis, and hepatic and biliary disease.

These risks persist irrespective of hospitalization status during the acute phase and escalate with the severity of COVID-19 illness. Comparative analysis indicates increased gastrointestinal risks in COVID-19 patients compared to those with seasonal influenza.

The study highlights the importance of addressing gastrointestinal health in post-acute COVID-19 care and highlights the substantial impact on affected individuals and healthcare systems. However, limitations exist, including potential misclassification bias and residual confounding, urging further research to understand the mechanisms and implications of post-acute sequelae of SARS-CoV-2 infection.

The Impact and Implications of SARS-CoV-2 on Digestive System

In this section, I will summarize the key points from a paper published on Frontiers in May 2023. It is titled “The relationship between gut microbiota and COVID-19 progression: new insights into immunopathogenesis and treatment.”

This paper cited 135 papers I reviewed to improve my knowledge and understanding. Therefore, I will summarize the most critical points in simple terms to make this post helpful. The Frontier’s paper and most of the cited papers are publicly available.

Our immune system is crucial in fighting the virus and is linked to all other systems, organs, tissues, and cells. When it becomes dysregulated, it can lead to severe consequences. The paper mentioned that many studies suggest that the balance of microorganisms in our gut (microbiota) is vital for maintaining a healthy immune system and communication between the gut and lungs.

However, new studies indicate that SARS-CoV-2 infection can disrupt this balance, leading to gut dysbiosis. This imbalance can worsen COVID-19 by producing harmful substances, affecting immune responses, and worsening inflammation.

As the virus becomes more common, it is expected to stick around and cause seasonal respiratory infections. It spreads mainly through respiratory droplets and, to a lesser extent, through the fecal-oral route.

While respiratory symptoms like coughing and difficulty breathing are common, they also affect the digestive system, leading to symptoms like diarrhea and vomiting. Patients with gastrointestinal symptoms are more likely to develop severe complications.

This has led researchers to investigate the role of gut microbiota in COVID-19. Changes in gut microbiota (dysbiosis) have been linked to various diseases, and evidence suggests it may play a role in COVID-19 severity.

In the next section, I will discuss the connection between gut microbiota and COVID-19, highlighting how manipulating gut bacteria could be a potential treatment avenue.

Insights from 100+ papers I reviewed

The purpose of this longer section is to discuss the vital role of gut microbiota in immune homeostasis (balance) and the gut-lung crosstalk in the papers I reviewed.

The gut microbiota in COVID-19 patients shows significant imbalances, with an increase in potentially harmful bacteria like Actinomyces, Akkermansia, Collinsella, and Enterococcus and a decrease in beneficial microbes such as Bacteroides and Faecalibacterium.

This dysbiosis may contribute to illness severity, with Enterococcus potentially playing a role in worse outcomes. Additionally, COVID-19 patients might be more susceptible to secondary infections from opportunistic pathogens present in the gut.

Several studies, which I link below, suggest that specific bacteria levels are associated with immune markers and clinical symptoms in COVID-19, indicating a potential link between gut microbiota changes and the body’s response to the virus.

As initially confirmed in animal studies, gut microbiota dysbiosis in COVID-19 patients leads to changes in gut metabolome profiles, potentially affecting disease severity. Certain bacteria, like Blautia and Streptococcus, are associated with upregulated lipid (fat) metabolism, which could cause viral replication.

Diminished microbial diversity in people with COVID-19 is associated with worse outcomes. This imbalance stimulates the proliferation of opportunistic pathogens while diminishing beneficial bacteria. Consequently, this dysbiosis can disrupt metabolic processes and trigger systemic inflammation, worsening the disease.

I learned that SARS-CoV-2 can be detected in feces even after respiratory symptoms clear, suggesting potential intestinal infection and transmission routes. The gut microbiota of COVID-19 patients harbors opportunistic pathogens, while beneficial bacteria might help fight the virus.

Clinical and case studies indicate that gut microbiota richness tends to decrease during recovery, with persistent symptoms correlating with specific microbial compositions. However, the good news is that the gut microbiota can eventually be restored, potentially aiding disease resolution, as confirmed by several clinicians in my circles.

While reviewing fungi-related papers, I noticed that gut mycobiota dysbiosis is also observed in COVID-19 patients, with certain fungi being depleted or enriched, potentially impacting disease severity. The variation in gut microbiota composition due to Covid infection, and the potential effects of fungi like C. albicans and Aspergillus on disease progression, require further investigation.

SARS-CoV-2 infection may disrupt gut microbiota through ACE2 downregulation and other pathological variations, highlighting the need for further research into the mechanisms and long-term impacts. Understanding these dynamics could lead to new therapeutic strategies for COVID-19.

Several studies mentioned that gut microbiota can hinder SARS-CoV-2 infection and its effects and cause instabilities. Commensal bacteria may prevent the virus from attaching to cells by influencing heparin sulfate.

This means that without these bacteria, we might become more vulnerable to the virus. Understanding how changes in microbiota composition affect SARS-CoV-2 susceptibility could help predict infection risk and guide COVID-19 treatment strategies.

A review paper (retracted) mentioned that in COVID-19 patients, there is an increase in Bacteroidetes, which decreases after recovery. Bacteroidetes have been found to inhibit signaling pathways related to toll-like receptor 4 (TLR4) and ACE2, which could contribute to the body’s immune defense against the virus.

Certain Bacteroides species, like Bacteroides dorei and Bacteroides ovatus, might reduce ACE2 expression in the colon, correlating with lower levels of SARS-CoV-2 in feces. These bacteria may protect against SARS-CoV-2 infection by blocking the virus from entering cells through ACE2 receptors.

My favorite metabolite, butyrate, derived from intestinal microbiota, has shown potential in inhibiting SARS-CoV-2 infectivity. It works by reducing the expression of membrane ACE2 and inactivating the viral spike protein in the gut epithelium, thus hindering viral replication.

Butyrate also activates the TLR signaling pathway, possibly contributing to its antiviral effects. While promising, more research, including preclinical and clinical studies, is needed to confirm the role of butyrate in preventing SARS-CoV-2 infection. Several scientist friends in my circles have started investigating them, so I will report their findings.

Some studies found a negative correlation between intestinal Collinsella levels and COVID-19 mortality. Collinsella-derived ursodeoxycholate has shown potential in preventing SARS-CoV-2 infection by blocking viral attachment to ACE2 and downregulating pro-inflammatory cytokines like IL-1β, IL-2, IL-4, IL-6, and TNF-α.

This microbial product might also alleviate ARDS (Acute Respiratory Distress Syndrome) by suppressing cytokine storm syndrome. However, we need further investigation to determine the effectiveness of ursodeoxycholate against SARS-CoV-2 infection and COVID-19 progression.

Gut microbiota may play a role in determining our susceptibility to SARS-CoV-2 infection. Elderly people, who often exhibit reduced microbial diversity with specific bacteria like Alistipes and Parabacteroides being enriched and Firmicutes being underrepresented, are more vulnerable to COVID-19.

These differences in gut microbiota composition might contribute to their increased susceptibility to the virus. However, direct evidence linking gut microbiota composition to SARS-CoV-2 susceptibility in healthy people is lacking and requires further investigation.

In short, gut microbiota dysbiosis could heighten the risk of SARS-CoV-2 infection by affecting the expression of the virus’s entry receptor ACE2 in the gut. Alterations in specific bacteria, like Bifidobacterium longum, might influence ACE2 expression and, consequently, COVID-19 susceptibility.

Broad-spectrum antibiotics may influence the composition of gut microbiota and the expression of ACE2, which could potentially influence the infectivity of COVID-19. Additionally, severe cases of COVID-19 might involve secondary bacterial infections, and patients who have not previously taken antibiotics may exhibit elevated levels of opportunistic pathogens such as Actinomyces viscosus and Bacteroides nordii.

Studies on germ-free rats suggest that gut microbiota can affect systemic inflammation and metabolism by influencing ACE2 expression. Understanding the relationship between gut microbiota and ACE2 expression in COVID-19-susceptible and -resistant individuals could offer insights into new treatment approaches.

From a benefits perspective, certain gut bacteria, like Bacteroides, might hinder viral invasion by regulating heparin sulfate, indicating a potential link between these bacteria and SARS-CoV-2 susceptibility. Additionally, gut microbiota-derived signals can influence the immune system’s response to the virus, further impacting susceptibility.

Many studies indicated a notable link between the complexity of gut microbiota and the severity of COVID-19. Dysbiosis caused by SARS-CoV-2 infection may disrupt the intestinal barrier, allowing extra intestinal bacteria to enter the gut. Some bacteria like Eubacterium dolichum and Prevotella copri show a positive correlation with faecal SARS-CoV-2 levels, while others like Alistipes and Bifidobacterium show an inverse association.

COVID-19 severity is associated with an increase in Bacteroides and a decrease in Bifidobacterium and Roseburium. So, Bifidobacterium may play a role in inhibiting the cytokine storm induced by the virus. Additionally, pathogenic fungi like Aspergillus flavus and Candida albicans are enriched in COVID-19 patients, potentially worsening inflammation and disease progression.

In general, certain Firmicutes species like Coprobacillus, C. hathewayi, and C. ramosum appear to positively correlate with COVID-19 severity, possibly through mechanisms like increased ACE2 expression. Conversely, beneficial species like A. onderdonkii and F. prausnitzii show inverse associations with severity. Inflammatory biomarkers like CRP and WBC tend to increase with the abundance of certain bacteria like Alistipes finegoldii and Clostridium innocuum.

Gut microbiota might significantly influence host immune system development and functionality, potentially affecting COVID-19 severity through immune system modulation. However, the relationship between gut microbiota and systemic immunity in COVID-19 is complex and requires further research to understand its implications fully.

Conclusions and Takeaways

I learned that the interaction between gut microbiota and the immune system is bidirectional, with commensal (harmless) and pathogenic (harmful) microbes triggering immune responses via pattern recognition receptors. SARS-CoV-2-induced damage to the gut lining and dysbiosis can lead to systemic inflammation. Besides, the virus can also invade the gastrointestinal tract, causing cytokine release and dysbiosis.

COVID-19, beyond its well-known respiratory manifestations, impacts various bodily systems, in this case, notably the gastrointestinal (GI) tract, showing symptoms ranging from nausea, vomiting, diarrhea, abdominal discomfort to lack of appetite

These GI manifestations, surprisingly common, affect about half of those infected and often present as the sole indicators of COVID-19. The virus exploits ACE2 receptors abundantly present in the gut’s epithelial cells, setting the stage for inflammation and mucosal damage. Unfortunately, these GI symptoms can persist long after the acute phase, becoming integral to the enigmatic long COVID syndrome.

Overactive immune responses in COVID-19 patients may result in organ damage, with gut microbiota composition affecting blood inflammatory markers. Reductions in beneficial microorganisms can disrupt the immune balance, while metabolites from commensals (harmless bacteria or fungi) regulate immune cell function.

Gut dysbiosis may lead to immune dysfunction and increased susceptibility to infections, underlining the importance of maintaining intestinal flora balance. Thus, the association between indigenous gut microbes and susceptibility to SARS-CoV-2 infection requires serious investigation to understand how gut microbiota influences COVID-19 susceptibility and inform potential treatment strategies.

From multiple studies, I understand that the dynamic alterations of gut microbiota during COVID-19 necessitate collaborative/multidisciplinary investigation into the direct and indirect effects of SARS-CoV-2 infection, particularly in untreated patients, to understand the mechanisms behind gut microbiota dysbiosis.

The duration of altered gut microbiota, especially in convalescent patients (recovering from illness), requires exploration to guide nutritional interventions and assess long-term health risks. Gut microbiome signatures hold promise as biomarkers for risk assessment and prognostic prediction, although the impact of treatments on gut microbiota configuration warrants controlled clinical studies.

Understanding the relationship between gut microbiota, host cytokine responses, and COVID-19 pathogenesis is crucial for clarifying disease severity and identifying potential therapeutic strategies like fecal microbiota transplantation and tailored probiotics for patients.

Intriguingly, the gut microbiome emerges as a pivotal player in COVID-19 outcomes, with a diverse microbial ecosystem potentially protecting against severe manifestations. Many studies highlight the therapeutic potential of interventions to restore gut microbial balance with promising outcomes in relieving acute and long-term COVID-19 symptoms.

Novel interventions, ranging from probiotic supplementation to tailored synbiotic formulations, emerge as potential game-changers, offering hope in the battle against COVID-19’s multifaceted impact. Our knowledge is still limited, and this virus might cause more long-term impacts.

Therefore, lifestyle and dietary interventions are potent allies in strengthening the gut microbiome. For example, observational studies highlight the protective role of nutrient-dense foods, associating them with reduced COVID-19 severity and improved outcomes.

By solving the enigma between viral pathogenesis, gut microbiome dynamics, lifestyle interventions, and pharmaceuticals, researchers can create collaboratively innovative therapeutic modalities, offering a glimmer of hope for the turbulent landscape after the COVID-19 pandemic.

Thank you for reading my perspectives. I wish you a healthy and happy life.

If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.