ARDS is a common complication of COVID-19. After binding to angiotensin-converting enzyme-2 receptors (ACE2) and transmembrane protease serine 2 (TMPRSS2), SARS-CoV-2 enters the host cells and causes pneumonia with possible ARDS in the most severe cases. The histologic presentation of severe COVID-19 pneumonia includes a progressive thickening of the alveolar wall with infiltrates of mononuclear cells and macrophages, associated with endotheliitis (11). Edema, fibroblasts, and myofibroblasts thicken the alveolar septa, with interstitial inflammatory cell infiltrates. In the late and organizing stage, the lungs become consolidated, and fibroblasts and myofibroblasts proliferate and migrate, forming granulation tissue and fibrosis by accretion, with possible thickening of interlobular septum and bronchial walls, thus leading to diffuse alveolar damage (DAD) (11). In this state, patients with severe COVID-19 may need to be admitted to the ICU for endotracheal intubation and mechanical ventilation. The evolution to COVID-19-ARDS is characterized by pulmonary edema, hypoxemia and inflammation, which are associated with changes in the lung microbiome (12). The microbiota is defined as the overall community of microbes included in a population (13), and the genetic content of the microbiota is known as the microbiome. In healthy conditions, the composition of the microbiota is generally characterized by high abundance and diversity of microorganisms with preponderance of potentially beneficial species, a condition known as eubiosis (13).

The microbiota is primarily involved in the immune response and host defense against pathogens, as well as in gut maturation, nutrient uptake and metabolism, mucosal barrier function, intestinal motility, and modulation of the enteric nervous system (14). Moreover, mechanical ventilation, decreased bowel transit time, reduced oxygenation, multiple antibiotic usage, sedatives, analgesics, muscle relaxants, gastric protectors, and abnormal nutritional intake may affect the composition of microbiota, which may increase the risk of dysbiosis and inflammation (15–17). Mice treated with broad spectrum or targeted antibiotics impaired their response to systemic and respiratory infections (18). Most prominent among these are gram-negative bacteria (e.g., Proteobacteria), which can lead to severe gut-lung dysbiosis (9, 19).

Once affected the lungs' tissue, COVID-19 may extend to other organs by binding to ACE2 and TMPRSS2 (20, 21), which are broadly expressed in various tissues (22, 23). ACE2 are involved in the regulation of inflammation and microbial community, while regulating the host intestinal metabolism of tryptophan, which plays a key role in the composition of gut microbiota (24–26). Thus, ACE2 expression may alter both the lung and gut microbiomes in certain disease conditions (24–26). In fact, a down-regulation of ACE2 reduces the absorption of tryptophan in the gut, while reducing the secretion of antimicrobial peptides and triggering dysbiosis (27). Bacterioides dorei and other bacterial species down-regulate the expression of colonic ACE2, thus supporting the appearance of intestinal symptoms in some COVID-19 patients (28). SARS-CoV-2 infection of the intestinal tract impairs the absorption of nutrients altering the intestinal function and activation of the enteric nervous system, causing gastrointestinal manifestations (29). Recent findings confirmed the role of gut dysbiosis in the induction of ARDS and its importance in possibly determining tissue damage in SARS-CoV-2 infection (16, 30).

The gut microbiota regulates the function of the immune system and cellular homeostasis of both gut and lung tissues due to antimicrobial peptides and metabolites derived from intestinal commensals (18, 31). The enteric nervous system is composed of the myenteric plexuses, which control fluid movement and intestinal motility; and is influenced by the activation pattern recognition receptors (PRRs), especially toll-like receptors (TLRs) which recognize pathogens (32).

SARS-CoV-2 infection may promote intestinal inflammation, epithelial barrier disruption, and decreased production of antimicrobial peptides (AMPs), until developing secondary enteric infections. An increased inflammatory status of the gut induced by SARS-CoV-2 may alter gut permeability causing epithelial leakage, which may enhance bacterial translocation and trigger systemic inflammation and inflammatory response to other organs (22). Additionally, over-expression of fecal calprotectin is implied in gut inflammation in COVID-19 (33). The passage of gut bacteria from the intestinal to the lung tissues is regulated by the ability of gut tight junctions in maintaining epithelial permeability, and intestinal bacteria in preserving the intestinal barrier. Among the proposed mechanisms of alteration, products of commensal bacteria fermentation like butyrate and other short-chain-fatty-acids (SCFAs) are responsible of intestinal barrier function and regulation of tight junctions' permeability (34). Additionally, the alteration in the secretion of mucin by goblet cells can lead to impaired mucus layer, increasing susceptibility to increased gut permeability (35). Dysbiosis results in diminished production of microbial-associated molecular patterns including TLRs and nucleotide oligomerization domain (NOD)-like agonists and microbial metabolites such as SCFAs, thus reducing antibacterial pulmonary immunity (18). Hence, by altering the gut immune homeostasis, respiratory viral superinfection may occur. Gut bacteria were found in lung microbiome, suggesting possible translocation from the intestinal tract to the lungs via the hematic circulation (36). The abundance of gut-associated pathogens in the lungs is increased in non-COVID-19 ARDS patients, but little is known regarding ARDS associated with COVID-19. Patients with ARDS revealed a higher prevalence of Lechnospiraceae as a strong predictor of reduced survival (37). Some authors investigated the lung bacterial burden and diversity of patients with non-COVID-19 ARDS, concluding that the lung microbiota is reduced in term of diversity and is increased in terms of bacterial burden (38).

The multifunctional SARS-CoV-2 Envelope (E) protein, which interact with host tight junction protein ZO1, showed great contribution to virus assembly, while contributing to epithelial barrier damage, pathogenesis (binding to ACE2 receptor), and disease severity (39). Human intestinal epithelial cells (in the esophageal upper epithelia, gland cells, enterocytes of the ileum and colon) are potential target of viral replication, also promoting spreading of SARS-CoV-2 and immune response mediated by type III interferon (IFN) (40, 41). At lungs level, studies have highlighted the impact of gut microbiota on the lungs' production of type I IFN, which is implied in the control of viral infections (42, 43). Microbial metabolites such as desaminotyrosine and SCFAs are critical for microbiota homeostasis. For example, significant changes in the composition of gut microbiota have been identified in an experimental model of pulmonary influenza (44). Desaminotyrosine is produced by an anaerobe clostridium called Clostridium orbiscindens to protect the lungs and activate the innate immune response passing through the blood system against influenza infection. Desaminotyrosine implements type I IFN signaling of lungs' phagocytes by promoting genes transcription (45). Similarly, SCFAs result important in priming the pulmonary immune innate system (18, 31). The subsequent inflammatory response can promote and encourage local inflammation followed by endothelial and epithelial injury (Figure 1).

The inflammatory response of SARS-CoV-2 infection is very complex. In fact, SARS-CoV-2 may interfere with the innate antiviral immune response that is made up two different antiviral pathways.

Phagocytes are recruited to fight against local infections and to repair and regenerate the epithelium. As aforementioned, the manipulation of cytokines and IFNs may play an important role in the prevention of infections and mucosal protection. Particularly, IL-22 and IFN-λ act as mucosal defenders and upregulate antimicrobial peptides (46). The IFN regulatory factors increase transcription of type I and III IFNs, which stimulate natural killer cells and cluster differentiation (CD)8+ T lymphocytes, whereas the nuclear factor-kB (NF-kB) promotes the activation of monocytes and their differentiation into macrophages (type M1). Cytokines are therefore released, and T-cells activated (inflammatory T-cells Th1 and Th17). Notably, a “cytokine storm” appears to occur in cases of severe COVID-19, as demonstrated by increased levels of interleukin (IL)-2, IL-17, granulocyte-colony stimulation factor, IFN-γ, inducible protein 10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α (7). Previous studies found that IL-22 is substantially expressed during viral infections, and animals with deficiency of IL-22 were unable to repair and regenerate epithelial tissues (47). Moreover, IL-22 usually enhance the recruitment of other inflammatory cells, thus amplifying the systemic inflammatory response (46, 48), which along with the local damage may predispose COVID-19 patients to secondary bacterial infections, capillary leakage syndrome, and systemic bacterial translocation (49), thus enhancing the risk of multiple organ damage (20–22). Nevertheless, in the COVID-19 era the role of cytokines and interferons on epithelial integrity and systemic reaction is still not clear, and IL-22 and IFN-λ might be considered as further promising targets to maintain the COVID-19 lungs' integrity, but more evidences are urgently needed (50). This exaggerates cytokines and interleukins release may increase the expression of markers like programmed death-1, T-cell immunoglobulin, mucin domain-containing protein-3 while favoring lymphocyte apoptosis and necrosis. Lymphopenia is frequent and is associated with disease severity and inflammation (51). Lymphopenia in COVID-19 may be induced by several mechanisms, including direct infection of lymphocytes, viral aggression of lymphatic organs, or continuous inflammation with cytokines release that could induce lymphocyte deficiency (52–54). Additionally, lymphopenia may be associated with glucocorticoids treatment (51). Since gut microbiota is one of the key components of the host immune system, and primary responses to infections and other immune insults, lymphopenia due to SARS-CoV-2 infection may interfere and predispose to changes in the normal flora by opportunistic germs (52–55).

The age of patients with severe COVID-19 is commonly high, and populations of gut bacteria normally change with age. In the gut of the elderly, less Bifidobacteria have been identified, maybe because of reduced gut epithelial barrier function, reduced immune function, and increased inflammation (74). In addition, obesity seems to be a typical characteristic of COVID-19, and it is associated with higher levels of pro-inflammatory cytokines and a poorer gut barrier. These mechanisms may favor the passage of gram-negative bacteria with possible endotoxemia (75). Intestinal bacteria along with their products (like SCFAs) play a key role in the protection of the mucosal intestinal barrier, and in the maintenance of adequate permeability through tight junctions, that may be down-regulated by pro-inflammatory cytokines and chemokines (76). Low-grade systemic inflammation is also present in those with chronic cardiovascular disease, type II diabetes mellitus, arthritis, and cancer. This may increase the risk of infection and altered microbiota (77). A great proportion of COVID-19 patients has hypertension (78). SCFAs has a crucial role in regulating blood pressure, while trimethyl amine-n-oxide (TMAO) is involved in atherosclerosis, hypertension, and coronary artery diseases' pathogenesis (79).

COVID-19 patients who present type II diabetes mellitus are around 30%. Lactobacilli are higher in diabetic patients, while the abundance of Firmicutes is correlated with inflammation (80). This basal diversity should be kept in mind when approaching dysbiosis in a COVID-19 patient with both SARS-CoV-2 infection and type II diabetes mellitus. Finally, according to the CDC's weekly report, around 35% of critically ill COVID-19 patients have an underlying chronic lung disease, such as asthma (81). As previously explained, the direct lung damage may be responsible for microbiota dysbiosis and over-infections. The airway mucosal barrier may lose the critical defense against SARS-CoV-2 and other infections (46).

Probiotics are living micro-organisms which confer benefits to the host when administrated in adequate dose, and most used organisms include bifidobacteria, lactic acid bacteria, enterococci, and yeast (139). Probiotics usually have distinctive characteristics such as the ability of surviving under intestinal conditions, stimulating the immune system and acting against pathogens, also preventing health-care associated pneumonia (140). Furthermore, probiotics exert interesting properties by modulating cytokines production, interacting with TLRs, antagonizing pathogens in cell adhesion and mucin homeostasis, and by stimulating SCFAs production (141).

Probiotics act by enhancing epithelial barrier function and are anti-inflammatory, improving gut diversity and competing against opportunistic pathobionts for the same ecological niches in the gut (including competition for nutrients or cellular receptors on the mucosal surface). Specifically, they act by blocking or activating multiple signaling pathways (such as NF-kB and STAT1) and producing protective metabolites such as SCFAs. Gastrointestinal symptoms (including diarrhea) appear to be common in COVID-19, possibly reflecting alterations in the composition of gut microbiota (dysbiosis), inflammation and disruption of the epithelial barrier. In this context, administration of probiotics and/or prebiotics might be considered. As an example, Lactobacilli are well-known modulators of intestinal inflammation and immune response, so that their administration is recommended to counteract high level of inflammation, in prevention of diarrhea, and during infections sustained by enteric pathogens (139). Additionally, Bifidobacteria, are able to produce vitamins, enzymes, acetic and lactic acids, lowering the pH in the colon microenvironment and inhibiting (potential) pathogens (142). Evidence of beneficial effects, such as decreased infections frequency, shortening of the duration of episodes by 1–1.5 days, reduced shedding of rotaviruses or an increase in the production of rotavirus-specific antibodies, have been demonstrated for Lactobacillus rhamnosus GG (LGG), L. casei Shirota, L. reuteri, Bifidobacterium animalis ssp. lactis Bb-12, and a number of other probiotic strains (143).

Probiotics, prebiotics (formulation of nutrients exploited by probiotic bacteria), and symbiotics (a synergistic combinations of pro- and prebiotics) are currently used to improve gut dysbiosis, by favoring the proliferation of healthy protective bacteria in the intestine, ameliorating or preventing inflammation (balancing proinflammatory and immunoregulatory cytokines) and other intestinal diseases (144). The use of probiotics has also been associated with a reduction in the incidence and severity of VAP. Probiotics reduced the duration of mechanical ventilation in critically ill patients (145, 146). Specifically, use of the probiotic Streptococcus salivarius K12 has been proposed for patients with COVID-19 (146). Also, the presence of ACE2 was identified in certain probiotics strains. Oral delivery of human ACE2 through the probiotic species Lactobacillus paracasei increased ACE activity in the serum and tissues of mice. Similar results can be obtained with the bacteria-derived B38-CAP enzyme (147, 148). Recent research highlighted the role of mucin biopolymers as pivotal in regulating mucin production, which is implied in viral replication in the gut. Lactobacilli are known implementors of the mucus layer and glycocalyx, and inhibitors of pathogenic adherence, thus preventing intestinal inflammation (149). A recent network meta-analysis provided a rationale for the implementation of probiotics in preventing and treating COVID-19. They identified 90 genes potentially implicated in COVID-19 probiotics treatment. Moreover, the clearly shown that the application of probiotics could play a pivotal role on ACE2-mediated virus entry, activation of the systemic immune response, immunomodulatory pathways, lung tissue damage, cardiovascular complications, and altered metabolic pathways in the disease outcome (150). There are currently multiple lines of research with probiotics and numerous potential therapeutic indications, however studies with strong scientific evidence of therapeutic benefits are required.

Fecal microbiota transplantation (FMT) is gaining ground as a treatment option for certain changes in the gut microbiota. The mechanism of action of FMT requires a fecal suspension from a healthy donor deposited into the gastrointestinal tract of a patient by using an endoscope, nasal tube, or capsule. However, FMT is still considered “off label” except for recurrent or refractory Clostridium difficile infections, where reconstitution of the intestinal microbiota by FMT has proved extremely successful and has definitively confirmed the role of dysbiosis in the pathogenesis such infection. Only one study reported FMT in COVID-19 population (151). Because COVID-19 frequently presents with gastrointestinal symptoms (such as diarrhea), fecal transplantation could potentially contribute to spreading the virus. Therefore, the authors suggested careful identification of donors, considering typical symptoms and history of possible contacts, as well as donor testing for SARS-CoV-2 by real-time PCR (152). Eleven COVID-19 patients who received fecal microbiota transplantation resulted in altered peripheral lymphocyte subset, restored gut microbiota and alleviated gastrointestinal disorders (151). FMT efficacy may be affected by some microbial metabolites as primary bile acids (such as cholic acid and chenodeoxycholic acid), that are conjugated by the gut microbiota and bile salt hydrolase to form secondary bile acids (such as deoxycholic acid, lithocholic acid, and ursodeoxycholic acid) (153). The post-antibiotic expansion of C. difficile population was shown to be strongly associated with the depletion of secondary bile salts, consequently to an antibiotic-mediated depletion of microbial taxa mediating the conversion of primary into secondary bile acids (154). Primary and secondary bile acids may also exert anti-inflammatory properties and inhibit several viruses by modulating the cytokine-storm via NF-kB (influenza A, and other viruses) (155).

Most intriguingly, while the treatment's success of FMT mostly revolves around intestinal viable healthy bacteria that are transferred through fecal suspensions, it should be considered that the viable bacteria fraction may not be the only factor affecting the recipient's biology. Viruses, archaea, fungi, donor's colonocytes, immunoglobulin, protists, and a number of metabolites, made by the donor's commensal bacteria (as SCFAs) or intestinal cells, can be implanted, potentially triggering a plethora of functionally different effects (156).

In the acute phase of ICU admission, inflammation, energy expenditure, and catabolic metabolism are enhanced (157). During their stay in the ICU, patients often develop post-ventilation-acquired dysphagia and ICU-acquired weakness, which mean nutritional support has a pivotal role in maintaining the necessary muscular strength to help wean patients from the ventilator (158–160). Moreover, critical illness is considered to be a major environmental factor in influencing gut homeostasis and dysbiosis, and nutritional therapy could play an essential role in these processes. Among the various environmental factors, indeed, diet is a source of dominant variation of the whole gut microbial community (161). As an example, nutritional models based on plant-based foods were shown to promote a more favorable gut microbiota profile based on the high amount of dietary fiber and SCFA (162). Therefore, nutrition may exert different indirect effect on intestinal function by modulating the gut microbial composition. A recent study on fecal samples of patients with COVID-19 revealed a high abundance of bacterial species Collinsella aerofaciens, Collinsella tanakaei, Streptococcus infantis, Morganella morganii, and higher nucleotide de novo biosynthesis, amino acid biosynthesis, and glycolysis. These were distinct from fecal samples of patients without COVID-19 who had higher abundance of SCFAs-producing bacteria, including Parabacteroides merdae, Bacteroides stercoris, Alistipes onderdonkii, and Lachnospiraceae bacterium 1_1_57FAA (163). It is now well-recognized that SCFAs exert several beneficial effects, influencing a number metabolic (as the lipids, cholesterol and glucose metabolism) and inflammatory (as the butyrate-mediated inhibition of macrophagic NF-κB or inhibition of the LPS-induced cytokines IL-6 and IL-12p40) responses (164).

Colon bacteria respond to fermentable substrates provided by the diet to produce SCFAs and gases through anaerobic metabolism (165). Within this context, dietary intake is an essential factor for resilience of patients' gut microbiota and its impact on upper respiratory tract infections (145).

The use of early enteral nutrition has been associated with improved immunologic function, decreased bacterial translocation, and better mucosal integrity (111). Moreover, the composition of enteral nutrition has a great impact on intestinal homeostasis. The gut microbiota is normally preserved be feeding with various dietary components in different concentrations. With that in mind, an inadequate dietary composition may alter the composition of the intestinal microbiota, thus increasing the growth of opportunistic pathogens over commensals (111).

General nutritional consideration for ICU patients should be applied to COVID-19 patients (166). As COVID-19 is frequently associated with gastrointestinal symptoms, patients can be at high risk of refeeding syndrome. If this risk is present, SCCM/ASPEN guidelines recommend starting at ~25% of the target energy intake (whether enteral or parenteral) (166). The ESPEN guideline estimates around 27 kcal/kg body weight/day, based on total energy expenditure, for patients aged >65 years with multiple comorbidities, or 30 kcal/kg body weight/day, based on total energy expenditure, for severely underweight patients with multiple comorbidities and older adults (individually adjusted on the basis of nutritional status, physical activity, and disease status) (167). An energy goal of 15–20 kcal/kg actual body weight should be reached within the first week of nutritional support even in COVID-19 (166). Recently, in a prospective observational study Cereda et al. in mechanically ventilated COVID-19 patients who have been fed with a low caloric intake in the early phase of ICU admission, found a higher risk of death. Additionally, patients with mild obesity were associated with higher mortality, while those with moderate-severe obesity were more difficult to wean from the ventilator (168). Early overfeeding should be avoided, because aggressive caloric intake can cause hyperglycemia or the need for insulin therapy (169). In case of contraindications to oral and enteral nutrition, parenteral nutrition should be implemented and increased within 3–7 days (170, 171). In critically ill patients intolerant to enteral feeding, intravenous erythromycin should be considered as the first-line prokinetic therapy, followed by intravenous metoclopramide or a combination of both (170). Prone positioning is being used with increasing frequency to treat both typical ARDS and respiratory distress in severe COVID-19 pneumonia. Traditionally, this leads to forced periods of rest from enteral nutrition (172), although enteral nutrition has recently been demonstrated to be feasible and safe in the prone position as well (173). In patients at high risk of aspiration, post-pyloric enteral nutrition can be provided instead (170) to reduce the possible risks related to prone positioning and development of pneumonia.

The specific recommendations for nutritional management in COVID-19 (167) suggest that a high-energy, low-to-normal carbohydrate (based on diabetic status and glycemic control), normal-to-high protein diet should be considered. Contrasting findings are available concerning the optimal protein intake for critically ill patients (174). Protein intake can influence the catabolic response. During the catabolic phase, within the first 10 days of ICU admission, a reduction in muscle mass of up to 1 kg/day in patients with multiorgan dysfunction can occur (175). A recent RCT compared enteral feeding with high-intact-protein formula (VHPF) with a standard high-protein formula (SHPF). The VHPF facilitated feeding without increasing energy intake, which is consistent with previous ESPEN guidelines (176). However, early high protein intake is associated with a lower mortality rate only in patients with a low skeletal muscle area at hospital admission, not in those with a normal skeletal muscle area (177). Another study found that improvement in daily protein intake could reduce 3-month mortality after hospital discharge (178). A standard high-protein (>20%) isosmotic enteral formula may be used in the early phase of critical illness, with possible addition of fibers (if tolerated) for maintenance of gut microbiota function (166). Consider 1 g protein/kg body weight/day in older persons (individually adjusted on the basis of nutritional status, physical activity, disease status, and tolerance), and 1.2–2.0 g protein/kg body weight/day (166) in patients with multiple comorbidities (167). An isocaloric, high-protein diet is recommended for obese patients, especially guided by urinary nitrogen losses (170); if this measurement is not available, a protein intake of 1.3 g/kg should be considered. The latest ESPEN guidelines recommend a daily protein intake of 1.3 g/kg, delivered progressively (170). However, a great number of COVID-19 patients require continuous renal replacement therapy as part of the systemic multiorgan dysfunction that they manifest. Thus, specific consideration of protein intake during the use of such filters for renal depurations should have been counted by novel guidelines (179).

The amount of glucose, whether parenteral or via carbohydrates by enteral feeding, should not exceed 5 mg/kg/min (170). However, current guidelines in COVID-19 did not account that hypertension, obesity, and diabetes mellitus are the most prevalent comorbidities that may alter patients' metabolic profile (180). Similar consideration may be done for lipids administration in a population composed by a large number of obese patients, as COVID-19 population is (180). Indeed, guidelines recommend that intravenous lipids for parenteral nutrition should not exceed 1.5 g/kg/day (170). The intake of carbohydrates and fat should be adapted according to energy ratio of 50:50 from fat and carbohydrates for ventilated patients (167). Additionally, a ketogenic diet for obese or diabetic patients should be considered (181). Since COVID-19 often leads to liver and renal failure, parenteral Gln dipeptide should not be administered (170). Blood glucose should be measured at ICU admission and at least every 4 h for the first 2 days. Insulin therapy should begin when glucose levels exceed 180 mg/dL (170). Triglyceride levels should be considered in cases of prolonged sedation with propofol or prolonged administration of intravenous lipid emulsion for parenteral nutrition (166). Adequate intake of vitamins and minerals is paramount for the prevention of viral infections. Particularly, vitamins A, E, B6, B12, C, and D; zinc; selenium; iron; and omega-3 polyunsaturated fatty acids should be administered with a view to ameliorating clinical outcomes, as advised for other viral illnesses (167, 182). A recent RCT demonstrated that no mortality advantages were found in critically ill patients who received early implementation of vitamin D (183). In COVID-19, a serum 25-hydroxyvitamin-D level of around 30 mg/mL reduced the risk for adverse clinical outcomes (184), but further studies are needed to confirm these findings. General dietetic recommendations for critically ill patients with COVID-19-ARDS are depicted in Figure 3.

Other nutritional interventions have been proposed to modulate the cytokine storm in ARDS and COVID-19, but studies are lacking. Therefore, the following sentences represent an overview of nutritional treatments for immune and inflammatory dysfunctions in COVID-19 patients. ARDS is considered an overwhelming systemic inflammatory process. Patients with COVID-19 frequently present with hypoalbuminemia and lymphopenia, which may reflect malnutrition and hyperinflammation and have been associated with a negative prognosis (1). Although the albumin level should not be considered a nutritional marker in patients with active inflammation, prealbumin levels are associated with progression to ARDS (185). Patients who survived severe COVID-19 pneumonia often present significant functional limitations, and experience higher morbidity and mortality (186).