Gastrointestinal Involvement in COVID-19: Research & Interventions

Understanding the connection between the health of the gut microbiome, the severity of COVID-19 infection, and persistent long-haul symptoms is an active area of research. Increasing evidence suggests that gastrointestinal (GI) health contributes to both the course and the severity of COVID-19.^1-5 Research studies continue to provide insight into the prevalence, etiology, and potential mechanisms of this viral infection in the GI tract crucial for defining prevention measures, clinical care, and treatment strategies.^1,4-7 Scientists are hopeful that therapeutic interventions to restore the gut microbiome may mitigate systemic inflammation and intestinal damage and even limit the effects on the central nervous system through the gut-brain axis⁸ in patients with acute and long COVID. 

What is the latest research exploring the COVID/GI health connection, and how can functional medicine clinicians harmonize the gut microbiome to promote healing in these patients?

(Video Time: 3 minutes) In the following video, Patrick Hanaway, MD, IFM educator and senior advisor to IFM’s CEO, discusses gastrointestinal involvement in COVID-19. Dr. Hanaway is a board-certified family physician who teaches on the clinical application of nutritional biochemistry, with an emphasis on digestion, immunology, mitochondrial function, and wellness. He is also the former medical director of the Center for Functional Medicine at the Cleveland Clinic.

The Gut Factor: COVID-19 Microbiome Studies

Research studies continue to underscore the potential importance of managing patients’ gut microbiota before, during, and after COVID-19 infection, as evidence suggests that the gut microbiome is likely to remain significantly altered, even after recovery from acute infections.^7,9,10 Dysbiosis in the gut contributes to a loss of beneficial microbes, the proliferation of potentially harmful microbes, and a reduction in microbial diversity.^1,9 A metagenomics analysis of 15 COVID-19 hospitalized patients revealed that their fecal microbiomes were deficient in beneficial commensals and abundant in pathogens.⁴ This can lead to epithelium breakdown and inflammation, which have been shown to increase levels of angiotensin-converting enzyme 2 (ACE2)—a protein target of SARS-CoV-2.^1,3 Furthermore, studies suggests that gut dysbiosis may persist even after clearance of SARS-CoV-2 infection or recovery from it.⁷

A 2023 prospective follow-up cohort study of 320 patients found that COVID-19 led to a significantly higher number of new-onset post-infection functional gastrointestinal disorders/disorders of gut-brain interaction (PI-FGID/DGBI) compared with healthy controls at three and six months of follow-up.⁶ Specifically, at one month, 11.3% of patients had developed post-infection functional gastrointestinal disorder (FGID) symptoms.⁶ Persistent symptoms were found in 27 (8.4%) at three months and in 21 (6.6%) at six months. After three months, eight (2.5%) had irritable bowel syndrome, seven (2.2%) had functional diarrhea, six (1.9%) had functional dyspepsia, three (0.9%) had functional constipation, two (0.6%) had functional dyspepsia–IBS overlap, and one had functional abdominal bloating/distention. Among those with symptoms, at three months, eight (29.6%) were positive for isolated carbohydrate malabsorption, one was positive for post-infection malabsorption syndrome, and one was positive for intestinal methanogen overgrowth. Healthy controls did not develop FGID up to six months of follow-up (P <.01). Investigators noted that severity of infection and presence of GI symptoms at time of infection were significant predictive factors.⁶ 

INFLAMMATORY CYTOKINES & MICROBIOME COMPOSITION

Gut dysbiosis causes pro-inflammatory bacterial products to leak out into systemic circulation, triggering inflammatory cascades,¹ commonly known as leaky gut. A 2020 study published in the Lancet revealed that intensive care unit patients with COVID-19, including those with acute respiratory disease syndrome (known to be caused by a cytokine cascade) had an abundance of proinflammatory cytokines, including IL-2, IL-7, IL-10, GCSF, IP10, MCP1, MIp1A, and TNFα, compared to non-ICU patients.^9,11 These inflammatory cytokines were said to correlate with a specific pattern of the gut microbiome.⁹

A 2020 pilot study on 15 patients with COVID-19 also found persistent alterations in fecal microbiota compared with controls.⁴ Specifically, the baseline abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi correlated with COVID-19 severity; there was an inverse correlation between abundance of Faecalibacterium prausnitzii (an anti-inflammatory bacterium) and disease severity.⁴ In another small study (n=15), SARS-CoV-2 RNA was detected in 46.7% of stool samples, regardless of the gastrointestinal symptoms.¹² That report also showed that the numbers of specific bacterial species (Collinsella aerofaciens and Morganella morganii) were increased in fecal samples with high SARS-CoV-2 active viral transcription compared with fecal samples with low-to-no SARS-CoV-2 infectivity.^9,12

More recently, scientists writing in BMJ Gut report that in a two-hospital observational study of 100 patients with confirmed SARS-CoV-2 infection, gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals and varied with disease severity, irrespective of whether patients had received medication, including antibiotics. Imbalances in the make-up of the microbiome may also be implicated in persisting inflammatory symptoms, or long COVID, the findings suggest.²

Disease severity of the patients was varied, ranging from mild to moderate, critical, and acute.² Specifically, researchers found that:

• Composition of the gut microbiota in patients with COVID-19 was concordant with disease severity and magnitude of plasma concentrations of several inflammatory cytokines, chemokines, and blood markers of tissue damage.² Other studies have reported increased concentrations of cytokines in the blood of hospitalized COVID-19 patients.¹³
• Without controlling for use of antibiotics, patients with COVID-19 were depleted in gut bacteria with known immunomodulatory potential, such as Faecalibacterium prausnitzii, Eubacterium rectale, and several bifidobacterial species.²
• The dysbiotic gut microbiota composition in patients with COVID-19 persisted for some time after clearance of the virus. To assess gut microbiota composition following recovery, 42 stool samples were collected from 27 patients up to 30 days after testing negative for SARS-CoV-2. Compared with non-COVID-19 subjects, gut microbiota composition of the 27 recovered patients remained significantly distinct, irrespective of whether they had received antibiotics.² (The study’s short follow-up period did not permit extrapolation of data for long-term persistent symptoms).

Because these findings indicate that gut microbiota composition of patients with COVID-19 may be correlated with plasma concentrations of several cytokines, chemokines, and inflammatory markers, this suggests that the gut microbiota could play a role in modulating host immune response and potentially influence disease severity and outcomes.²

Clinical Applications: Harmonizing the Gut Microbiome

Reformulating the gut microbiota may emerge as a new therapeutic strategy in the disease management of COVID-19.³ Since the gastrointestinal tract harbors immune system activity, it is essential to keep it nourished with the necessary nutrients for a healthy microbiome.¹⁴

Dietary fiber from whole, plant-based foods can be fermented by gut bacteria for energy, resulting in the production of short-chain fatty acids (SCFAs) that have pleiotropic effects, including positively influencing epithelial barrier function and reducing pathogen cytotoxicity from compounds produced by harmful bacteria.^7,15 Butyrate is one of these SCFAs with immune-modulating activities, including improving gut barrier function and innate immunity.¹⁶ High-fiber diets can directly modulate immune reactivity by increasing levels of SCFAs, which can activate the G protein–coupled receptors on various tissues, including immune cells.¹⁵ Recommendations for fiber intake are for a minimum of 14 grams per 1,000 kcal, or approximately 25-35 grams daily for most individuals.¹⁷

Fermented foods such as yogurt, kefir, kimchi, miso, and sauerkraut may provide microorganisms and secondary metabolites such as alkyl catechols¹⁸ that continue to be studied for their potential immune and other health benefits.¹⁹ Fermentation byproducts may impact specific viruses and may be important for targeted actions related to immune function. For example, a kefir containing six lactic acid bacteria strains resulted in increased natural killer cell activity and interferon-gamma secretion in response to tumor cells.²⁰

Other interventions being studied include the use of a “microbiome-based risk profile” to identify individuals at risk of severe disease,² and probiotics are also being considered as an adjunctive treatment for COVID-19 patients, with some research suggesting that probiotic supplements may significantly improve disease symptoms.²¹

With respect to interventions, the practice of functional medicine emphasizes the primacy of safety, validity, and effectiveness. Functional medicine practitioners are trained in providing personalized guidance to patients in the use of nutrition, nutraceuticals, and lifestyle to prevent, reverse, and decrease the burden of complex diseases such as COVID-19.