insights

Updated On: 8/07/2023

Read Time: 3 Minutes

Many patients who contract a SARS-CoV-2 infection will fall on two distinct ends of the disease spectrum: those with severe or fatal illness and those who are able to fully recover at home with therapeutic support. However, a significant number of COVID-19 patients may experience long-term problems—even if they are not particularly ill initially.¹ Data from a University of Arizona Health Sciences longitudinal study shows that an estimated 67% of people with mild or moderate infection develop post-acute sequelae of SARS-CoV-2 infection (PASC), with symptoms that last more than 30 days after a positive test.¹ The condition, commonly known as long COVID, long-haul COVID, post-acute COVID-19, or chronic COVID, may also develop in patients with breakthrough infections after vaccination.²

A 2021 study in The New England Journal of Medicine found that among 1,497 fully vaccinated healthcare workers in Israel, 39 SARS-CoV-2 breakthrough infections were documented.² 19% of patients with breakthrough infections still had symptoms six weeks later.² Patients with long COVID report prolonged, multisystem involvement and significant disability.³ By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden.³

Persistent symptoms are numerous and varied; one systematic review and meta-analysis identified up to 55 different long-term effects,⁴ while other studies have identified up to 74 persistent symptoms.³ Lopez-Leon et al identified the five most common symptoms as fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). This study, which is just one of many and has not yet been peer reviewed, also found that approximately 16% of people still experienced nausea and vomiting after recovering, while 12% continued to experience digestive disorders.³

Increasing evidence suggests that the gastrointestinal (GI) tract may influence the severity and outcome of COVID-19, particularly the gut microbiome.^5-9 An online survey of 3,762 patients published on July 15, 2021, in the Lancet found that 84% to 86.6% of patients with long COVID experience gastrointestinal distress, including diarrhea, loss of appetite, vomiting, abdominal pain, nausea, constipation, and gastroesophageal reflux.³ Studies like these are ongoing and provide insight into the prevalence, etiology, and potential mechanisms of COVID-19 in the GI tract crucial for defining prevention measures, clinical care, and treatment strategies.¹⁰ 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 brain-gut axis¹¹ in patients with acute and long COVID.

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. Specifically, at one month, 11.3% of patients had developed post-infection functional gastrointestinal disorder (FGID) symptoms.¹² Persistent symptoms were noted in 27 (8.4%) at three months and in 21 (6.6%) at six months. At 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 (0.3%) had functional abdominal bloating/distention. Among symptomatic individuals at three months, eight (29.6%) were positive for isolated carbohydrate malabsorption, one (3.7%) was positive for post-infection malabsorption syndrome, and one (3.7%) was positive for intestinal methanogen overgrowth. None of the healthy controls developed FGID up to six months of follow-up (P <.01). Predictive factors at three and six months were severity of infection (P <.01) and presence of gastrointestinal symptoms at the time of infection (P <.01).¹²

The Gut Factor: COVID-19 Microbiome Studies

Understanding the connection between the gut microbiome, the severity of COVID-19 infection, and persistent long-haul symptoms is an active area of research. The most recent studies suggest that the gut microbiome contributes to both the course and the severity of COVID-19.^13-15 Dysbiosis in the gut contributes to a loss of beneficial microbes, the proliferation of potentially harmful microbes, and a reduction in microbial diversity.^5,13 A metagenomics analysis of 15 COVID-19 hospitalized patients revealed that their fecal microbiomes were deficient in beneficial commensals and abundant in pathogens.¹⁵ 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.^5,7 Furthermore, research suggests that gut dysbiosis may persist even after clearance of SARS-CoV-2 infection or recovery from it.¹⁵

Gut dysbiosis also causes pro-inflammatory bacterial products to leak out and circulate systemically, triggering inflammatory cascades, commonly known as leaky gut.⁵ 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.^13,16 These inflammatory cytokines were said to correlate with a specific pattern of the gut microbiome.¹³

A 2020 pilot study on 15 patients with COVID-19 also found persistent alterations in fecal microbiota compared with controls.⁸ 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.⁸ In another report, SARS-CoV-2 RNA was detected in 46.7% of stool samples, regardless of the gastrointestinal symptoms.¹⁷ 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.^13,17

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.⁶

Disease severity of the patients was varied, ranging from mild to moderate, critical, and acute.⁶ 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.⁶Other studies have reported increased concentrations of cytokines in the blood of hospitalized COVID-19 patients.^18,19
• 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.⁶
• 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.⁶(The study’s short follow-up period did not permit extrapolation of data for long-term persistent symptoms).

Because the new 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.⁶ However, another paper reported that although COVID-19 patients in their study had lower lymphocyte counts and increased interleukin and TNF-α levels compared with the healthy cohort, the differences in gut microbiota abundance, diversity, and structure were not significantly significant between patients with mild and severe COVID-19.²⁰

A more recent study suggests that gut dysbiosis may also be associated with the recovery process following SARS-CoV-2 infection, perhaps linking it to long COVID risks.²¹ Chen et al conducted this prospective study to longitudinally monitor alterations of gut microbiota in patients with COVID-19 using 16S rDNA sequencing. Fecal microbiota was monitored at three timepoints: acute phase (from illness onset to viral clearance), convalescence (from viral clearance to two weeks after hospital discharge), and postconvalescence (six months after hospital discharge). The small study found that microbiota diversity was not restored to normal levels after six-month recovery. Patients with lower postconvalescence diversity showed higher levels of C-reactive protein and illness severity during the acute phase, suggesting close correlations between the inflammatory response and gut dysbiosis in COVID-19. Patients with lower postconvalescence diversity showed higher levels of hs-CRP and illness severity during the acute phase, suggesting close correlations between inflammatory response and gut dysbiosis in COVID-19, as illustrated in previous studies. The authors hypothesize that the persistent reduction of gut microbiota diversity may have long-term biological influence.²¹

Together, this research underscores the potential importance of managing patients’ gut microbiota before, during, and after infection, as research suggests that the gut microbiome is likely to remain significantly altered, even after recovery from COVID-19.¹³ Reformulating the gut microbiota may emerge as a new therapeutic target in the disease management of COVID-19. Since the gastrointestinal tract harbors a majority of immune system activity, it is essential to keep it nourished with the necessary nutrients for a healthy microbiome.²²

Clinical Applications: Harmonizing the Gut Microbiome

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.^15,23 Butyrate is one of these SCFAs with immune-modulating activities, including improving gut barrier function and innate immunity.²² 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.²³ Further, SCFAs have epigenetic effects, which could ultimately alter immune cell function.²⁴ Recommendations for fiber intake are for a minimum of 14 grams per 1,000 kcal, or approximately 25-35 grams daily for most individuals.²⁵

Fermented foods such as yogurt, kefir, kimchi, miso, and sauerkraut may provide microorganisms and secondary metabolites such as alkyl catechols²⁶ that may help with immune response and even reduce the incidence and duration of respiratory infections.²⁷ Lactic acid, which is a byproduct of fermentation, has been shown to reduce pathogen growth in the oral cavity, oropharynx, and esophagus.²⁸ Furthermore, specific strains of microorganisms 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.²⁹ In general, probiotic microorganisms within the Lactobacillus and Bifidobacterium species have been demonstrated to exhibit numerous beneficial effects on immunity through their interactions with macrophages, enterocytes, and dendritic cells, as well as Th1, Th2, and regulatory T (Treg) cells.^15,30 For more information about plant-derived compounds, plant dietary diversity, and immunity, please visit IFM’s Patient Education Tools: Lifestyle Practices for Strengthening Host Defense. 

Other interventions being studied include the use of a “microbiome-based risk profile” to identify individuals at risk of severe disease⁶ and the use of fecal microbiota transfers, which involves delivery or infusion of stool from a healthy donor to a patient with the disease of interest and presumed gut dysbiosis.³⁰ Probiotics are also being considered as an adjunctive treatment for COVID-19 patients, with some research suggesting that large doses of probiotics may significantly improve disease symptoms, reduce inflammation, and help the gut microbiota recover from abnormalities caused by COVID.^15,32,33 In the future, significantly more high-quality randomized controlled trials are necessary to achieve precise understanding of the clinical functions of probiotics as adjunctive treatments in novel diseases like COVID-19.³³

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, chronic diseases like long COVID. IFM has assembled a wealth of resources for functional medicine clinicians, including clinical recommendations and mechanisms of action; virus-specific nutraceuticals and botanical agents, nutrition, and lifestyle practices for strengthening host defense; practice considerations; testing; and vaccines.

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