Introduction

COVID-19, a disease caused by the novel coronavirus (SARS-CoV-2), has drastically changed the landscape of day-to-day life and, particularly, the healthcare field. The virus rapidly spread across the global landscape with the first cases being reported in December of 2019 and an official pandemic declaration by the World Health Organization (WHO) occurring only a few months later in March 2020 [1, 2]. Since then, the WHO reports an estimated 600 million infections globally with nearly 6.5 million deaths [1], The public health repercussions including lockdowns, border closures, and mask and vaccine mandates created significant social and economic impact on citizens around the world. Given the impact of the COVID-19 pandemic, efforts to better understand this novel pathogen, slow/stop its transmission, and improve the outcomes of those already infected surged, leading to an inundation of scientific information, societal recommendations, and purported remedies with varying degrees of accuracy. As the pandemic evolved, clear risk factors for COVID-19 progression were described including increased severity in patients with obesity and/or diabetes [3, 4]. In addition, while traditionally a respiratory pathogen, COVID-19 was found to be associated with significant gastrointestinal (GI) symptoms including diarrhea, abdominal pain, and anorexia [5,6,7]. With this described connection with metabolic comorbidities and GI symptoms, a particular area of interest and controversy that emerged was that of COVID-19’s interaction with the gut and the role of nutrition (and nutritional supplementation) in the prevention and treatment of the disease. Our goal is to provide the most recent and accurate scientific evidence available regarding COVID-19’s interaction with the human gut and the role of nutrition/nutritional supplementation in the prevention and treatment of the disease.

COVID-19 Pathogenesis

SARS-CoV-2 is a single-stranded RNA virus that is transmitted through aerosols and droplets. The virus is made up of a framework of proteins: envelope, membrane, nucleocapsid, and spike proteins [8]. Each protein in this framework serves a specific function in the pathogenesis of SARS-CoV-2. Specifically, the spike protein mediates the binding of SARS-CoV-2 to the ACE2 receptor of the host cells. Binding of the spike protein to the ACE2 receptor of host cells is what ultimately leads to membrane fusion and infection/viral replication [9]. Subsequently, this infection of host respiratory epithelial cells leads to local inflammation and, ultimately, the classic symptoms of COVID-19 which include cough, rhinorrhea, and fever. However, SARS-CoV-2 can also infect cells outside of the respiratory tract. In fact, the ACE2 receptor is expressed extensively throughout the body in tissues such as the small intestine, vascular endothelium, kidneys, heart, and the central nervous system [10, 11]. Systemic infection and subsequent inflammation is what leads to more severe cases of COVID-19 which are driven by “cytokine storm,” membrane permeability, sepsis, and acute respiratory distress. The presence of ACE2 receptors outside the respiratory tract will also become important when later considering GI symptoms of COVID-19 as well as discussing the management of post-COVID-19 complications.

Nutrition and Viral Infections/Immune System

Interest in the connection between diet, nutrition, and micronutrient/trace element supplementation preceded the COVID-19 pandemic. Adequate nutrition and dietary components are known to be critical to the healthy function of the immune system. For example, it is well established that protein poor diets are associated with a higher risk of infection. In this same way, multiple vitamins (vitamin A, vitamin D, vitamin C, vitamin E, etc.) and trace elements (zinc, selenium, iron, etc.) are known to serve as critical co-factors in immune-related enzymatic function [12]. In addition to their direct impact on immune function and infection prevention, many of these components are also postulated to have concurrent anti-inflammatory and anti-oxidative properties that could impact the treatment of COVID-19.

Further, a healthy gut helps to mount and maintain a robust immunological response which helps contain the SARS-CoV-2 virus in the upper airway and may assist in the prevention of invasion of the lung parenchyma and progression of COVID-19 [13]. Gastrointestinal manifestations of COVID-19 are associated with gut dysbiosis which is associated with immune dysregulation and delayed clearance of SARS-CoV-2. Similar patterns of gut dysbiosis have been associated with increased mortality in other respiratory infections and thus present probiotics as an attractive therapeutic option [13].

As mentioned earlier, severe COVID-19 is marked by widespread, systemic inflammatory reaction. Thus, both dietary components (vitamins, minerals, trace elements, etc.) and complete dietary patterns (Mediterranean, ketogenic, plant-based, etc.) that are associated with anti-inflammatory effect have also been postulated to assist in the prevention and treatment of severe COVID-19. We explore each of these subjects in detail throughout this review.

COVID-19 and the Gut

While classically a respiratory illness, COVID-19 can have a dramatic impact on the gut. In fact, a meta-analysis of over 18,000 patients worldwide displayed that nearly one-third of all COVID-19 sufferers experienced GI symptoms. Of all GI symptoms, diarrhea (11.5%), nausea and vomiting (6.3%), and abdominal pain (2.3%) were the most commonly reported [6]. The rate of GI symptoms rises to nearly 75% when solely considering critically ill patients, specifically, with the most common manifestations being elevated transaminases (67.3%), intolerance of feeding (46.2%), and ileus (55.8%) [7]. In fact, a recent meta-analysis demonstrated that gastrointestinal symptoms are associated with an increased risk of severe COVID-19 with an odds ratio of 2.8 [14]. This association of gastrointestinal symptoms with severe COVID-19 did not translate into increased mortality per another recent meta-analysis [15].

Gastrointestinal symptoms were also found to persist beyond the resolution of acute COVID-19 symptoms with 16% of patients reporting persistent GI symptoms (abdominal pain, diarrhea, and constipation) even 100 days after classically defined recovery [16]. While some of these symptoms could be attributed to general illness, it is believed that COVID-19 directly accounts for at least a portion of the described gastrointestinal toxicity. This is supported by a matched comparison study in which COVID-19 sufferers displayed nearly double the rate of gastrointestinal manifestations when compared with equally ill patients who were not COVID-19 positive [17]. There are two major theories to explain the prevalence of GI symptoms in COVID-19 sufferers. The first postulate, which we have already discussed, is that SARS-CoV-2 virus infects enterocytes via the ACE2 receptor which is known to be expressed in the GI tract. Direct infection and inflammation of the gastrointestinal lining could explain many of the GI manifestations of the virus and would also account for why these symptoms appear early in the disease course [18, 19]. This theory may explain why GI symptoms persist as well, as studies have reported cases of SARS-CoV-2 antigen detection in enteric biopsies up to 3 months after COVID-19 infection [20]. The second theory is that COVID-19 infection disrupts the gut microbiome, leading to the described symptoms. Multiple studies have displayed distortion of the microbiome in the setting of COVID-19 infection, and some have postulated that this alone could account for the acute gastrointestinal symptoms as well as the persistent symptoms seen in those with longstanding COVID-19 complications.

COVID-19 and the Microbiome

The human gut is the largest immunological organ system in the body, and the microbiome that the gut houses plays a pivotal role in immune response [21]. Significant effort has been made to further understand the role that the gut microbiome is playing in COVID-19 disease progression and recovery. Microbiome surveys of COVID-19 sufferers versus healthy individuals as well as severe COVID-19 versus milder cases have displayed a change in both microbiome diversity and have identified specific organisms that may be associated with severity [22,23,24]. Specific genera of bacteria such as Streptococcus, Prevotella, and Rothia (traditionally opportunistic and inflammatory organisms) were found more abundantly in the feces of COVID-19 patients, whereas Faecalibacterium (considered an anti-inflammatory organism) was found more abundantly in the feces of healthy controls [24, 25••, 26]. Overall, there appears to be significant evidence for decreased microbiome diversity, depletion of favorable commensals, and an increase in opportunistic GI pathogens in the setting of COVID-19 infection [25••]. These compositional changes in the GI microbiome have been directly associated with increased inflammation with COVID-19 infection—elevated cytokine levels, C-reactive protein, transaminases, and lactate dehydrogenase—which further supports the immunologic role of the gut [27•].

Probiotics

With the described alternations of the gut microbiome in the setting of COVID-19, probiotics have been considered as a potential intervention for both disease treatment and prevention. The results of current studies have been variable, but there does appear to be some benefit to probiotic use in the setting of COVID-19 infection and exposure. Specifically, a retrospective cohort study displayed significant reduction in hospitalization length, time to clinical improvement, and time to COVID-19 negativity in those who received a probiotic [28]. Multiple studies have also shown a shortened duration of diarrhea in those who are treated with probiotic after testing positive for COVID-19 [29, 30]. Probiotics are well-tolerated medications without significant side effects or adverse reaction profiles. For this reason, there appears to be an argument for probiotic use in the setting of COVID-19 infection. However, probiotic use in the setting of COVID-19 prevention remains under investigation with several pending clinical trials directed at this question specifically.

Fecal Microbiota Transplant

In a similar fashion to probiotics, fecal microbiota transplantation (FMT) has been considered as a treatment option for COVID-19-related gut dysbiosis. FMT is most commonly used to treat recurrent or severe Clostridioides difficile infections; however, its benefits have also been seen in other instances of dysbiosis. So far, only a few small studies/case studies of FMT in COVID and post-COVID patients have been undertaken and do show some promise [31, 32]. Future clinical studies will be needed to further investigate the safety and efficacy of COVID-19 treatment with FMT versus other less invasive alternatives such as probiotic treatment [33].

Diet Styles

It is well established that nutritional status plays an important role in immune function and that specific metabolic conditions (e.g., obesity and diabetes) are associated with an increased risk of severe COVID-19 sequela. It is reasonable to consider the role that daily dietary composition plays in the risk of COVID-19 infection and severity. We will review the most common implicated dietary patterns and the rationale behind their proposed protective or deleterious impact on COVID-19 immune response.

Healthy Plant-Based Diet

There is not a single, accepted definition or criteria for a “healthy plant-based diet” Ranging from the exclusion of all animal products to simple optimization of plant-based ingredients and high-quality whole foods, the plant-based spectrum is quite wide. For this purpose, and in the most pertinent literature, vegan, vegetarian, and more general plant-based patterns are all included. As a whole, plant-based diets have been associated with prevention and treatment of type 2 diabetes, coronary artery disease, and hypertension [34, 35]. A recent study, comprised mostly of healthcare workers, suggested that those following a plant-based diet had a 73% lower odds ratio of moderate-to-severe COVID-19. This same study also reported that individuals following a plant-based diet had a lower odds ratio of COVID-19 infection (defined as a positive PCR or antibody test) [36]. While there is certainly risk for confounding, particularly with other healthy behaviors likely practiced by this population, this study does provide signal to support the impact of diet on viral infection and severity.

Ketogenic Diet

The ketogenic diet (KD) is a dietary pattern that is characterized by reduced consumption of carbohydrates while relying heavily on dietary fats for energy. This dietary pattern is aimed at the development of metabolic ketosis. The proposed role of KD in the prevention and treatment of COVID-19 is twofold with the first mechanism being secondary to its weight loss benefits. As previously discussed, obesity is a major risk factor for COVID-19 and disease severity. The ketogenic diet has been touted as a successful diet for weight loss and, therefore, may reduce COVID-19 risk and severity. KDs have also been supported for their potential anti-inflammatory impact [37]. Specifically, KD could reduce airway lipid droplet formation and subsequent inflammation as well as dampening inflammasome response to reducing systemic complications [38, 39]. However, clinical trial data to support these propositions are lacking. In fact, there may be data favoring other dietary patterns over KD including, but not limited to, a purely plant-based diet [36].

Mediterranean Diet

The Mediterranean diet is rich in whole grains, legumes, vegetables, fruits, nuts, and other whole foods. This diet includes olive oil as the primary fat additive and seafood/fish as the primary protein. Overall, this is quite like a pescatarian diet, but dairy and poultry are also included, however, in moderation. Similar to the previously discussed dietary patterns, the Mediterranean diet has been associated with positive outcomes such as weight loss, cardiovascular health, and diabetes prevention/treatment [40]. The Mediterranean diet has also been associated with decreased inflammatory markers [41] as well as reduction in the risk of respiratory infections [42]. In regard to COVID-19 specifically, it appears that individuals who are adherent to the Mediterranean diet have a lower risk of COVID-19 infection [43, 44]. The Mediterranean diet is also the most common recommended diet for those suffering with extended, long-COVID-19 symptoms.

Overall, no single dietary pattern has been found to be superior to the rest when it comes to COVID-19 prevention or treatment. However, there does seem to be a benefit to balanced diets that are high in whole-food content and lower in processed ingredients. There is no need for extreme dietary changes, but focusing on a balanced intake that avoids processed and high-fat foods appears to bring health benefits both inside and outside the realm of COVID-19.

Nutritional Support in Critically Ill COVID-19

Severe COVID-19 is marked by progressive respiratory failure, ARDS, and necessitation of mechanical ventilation. These patients often have prolonged hospitalizations and intensive care unit stays. Management of nutrition in these critically ill patients is paramount to the acute treatment and long-term recovery from COVID-19. Most of these critically ill patients require enteral nutrition (EN) to meet their energy requirements. EN in COVID-19 patients has posed several challenges. Early in the pandemic, there was a reported trend of avoiding EN to reduce nursing burden and provider infection exposure as EN required a higher bedside presence [45]. However, studies have since shown the EN is overall well tolerated and does not pose an increased risk to those involved [46]. EN is preferred over parenteral nutrition (PN) as it is more physiologic and decreases risk of gut dysfunction [47]. A recent systematic review and meta-analysis of critically ill patients found a preference for early adoption of enteral feeding in COVID-19 patients. This study utilized the American Society of Parenteral and Enteral Nutrition definition for early enteral nutrition as feeding that is commenced within 24 to 36 h of ICU admission or 12 h of mechanical ventilation. Early nutrition was found to significantly reduce the risk of mortality with a relative risk reduction of 11%. However, when comparing early EN and late enteral EN or PN, there was no significant difference in the length of stay or length of ventilation [48•]. Overall, in the treatment of critically ill patients with COVID-19, we support the early adoption of EN if it can be tolerated.

Vitamin Supplementation

Vitamin C

Vitamin C, or ascorbic acid, has long been known to have anti-inflammatory benefits and has previously been used in the setting of severe sepsis. Vitamin C became a popular daily supplement early in the COVID-19 pandemic for this same reason. However, as more clinical trials and systematic reviews have become available, the benefit of vitamin C in COVID-19 prevention and treatment remains uncertain and controversial. Depending on the specific endpoint in question, randomized control studies have found evidence to support vitamin C supplementation in critically ill patients [49, 50]. However, these results have been inconsistent, often confounded by adjunctive therapies, and even contradicted by other studies [51,52,53,54]. Ultimately, consistent consensus data to support the use of vitamin C supplementation in COVID-19 prevention or treatment, regardless of disease severity, is lacking.

Selenium and Zinc

It has been noted that patients with lower levels of selenium and zinc are at higher risk of developing COVID-19, and deficiency of these minerals has further been associated with increased severity of COVID-19 [55, 56]. An interesting ecological study from China demonstrated increased severity of COVID-19 infection with selenium deficiency in the topsoil of the region of patient origin [57]. Another study correlated deficiency of selenium and zinc with increased severity of COVID-19 and elevated levels of CRP [58]. While there are described associations between selenium and zinc deficiency and risk of developing COVID-19, there are no clinical trials at this time that support the use of either zinc or selenium supplementation as a treatment for COVID-19.

Vitamin D

Vitamin D plays multiple modulatory roles in the immune system. In fact, studies have shown an association between low serum 25-hydroxyvitamin D and an increased risk of respiratory tract infections. It was only natural, therefore, that vitamin D supplementation be considered as both prophylaxis and treatment of COVID-19 [59, 60]. A multitude of randomized control trials have attempted to answer these questions, with varied methods and results. Regarding prophylaxis, the results have been mixed. A study with a short-term follow-up (1 month) showed a modest benefit against infection with vitamin D supplementation [61]. However, the largest study to date, performed in the UK, involved over 6000 participants with suboptimal vitamin D levels at baseline and found no benefit to a test-and-treat model for vitamin D deficiency and COVID prophylaxis [62•]. This negative result was further supported by a Scandinavian study of low-dose vitamin D/cod oil supplementation that also displayed negative results [63]. The studies of vitamin D in COVID-19 treatment have showed similar, varied results. A small, open-label study from Spain concluded that vitamin D supplementation significantly reduced the risk of ICU admission [64]. Meanwhile, other randomized control studies have shown benefit in the same clinical setting with similar endpoints. With the inconsistent results in both the treatment and prevention of COVID-19 with vitamin D supplementation, no national or international body currently recommends supplementation in either setting. Future well-designed randomized control studies with caution for confounding variables (risk factors, vaccination study, adjunct therapies, etc.) will be needed to advance the knowledge in this realm.

Conclusion

The medical impact of COVID-19 extends far past the pulmonary system with significant impact noted on the gastrointestinal system with differences noted with varied nutritional approaches. There was significant interest early in the pandemic about the role of nutritional approaches in the treatment of COVID-19, but the purported impact of these approaches was not realized. For those interested in adopting lifestyle modifications to prevent severe COVID-19 infection/side effects, focus should be placed on the interventions that are supported by evidence-based practice and have been shown to be safe and effective. Unfortunately, despite being 2.5 years into the pandemic, there is still a tremendous need for high-quality research on these topics. Based on our review, we would recommend adoption of a well-balanced nutritional model that is low in processed foods (such as a Mediterranean-style diet), daily exercise directed at cardio-pulmonary health and weight management, and vaccination against COVID-19. For those who become infected, specific focus should remain on maintaining nutritional quality, regardless of disease severity, and a compelling argument can be made for an oral probiotic for preservation/restoration of the microbiome. Lastly, we would recommend against high-dose vitamin supplementation and only support vitamin supplementation that is directed at rectifying a recorded deficiency (including micronutrients such as selenium and zinc).