key: cord-0885047-iua5rtqn
authors: Cortes, Gian Mario; Marcialis, Maria Antonietta; Bardanzellu, Flaminia; Corrias, Angelica; Fanos, Vassilios; Mussap, Michele
title: Inflammatory Bowel Disease and COVID-19: How Microbiomics and Metabolomics Depict Two Sides of the Same Coin
date: 2022-03-21
journal: Front Microbiol
DOI: 10.3389/fmicb.2022.856165
sha: 0a12181a56c694bd524d9c5c7f2078c7cf8e6f14
doc_id: 885047
cord_uid: iua5rtqn

The integrity of the gastrointestinal tract structure and function is seriously compromised by two pathological conditions sharing, at least in part, several pathogenetic mechanisms: inflammatory bowel diseases (IBD) and coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IBD and COVID-19 are marked by gut inflammation, intestinal barrier breakdown, resulting in mucosal hyperpermeability, gut bacterial overgrowth, and dysbiosis together with perturbations in microbial and human metabolic pathways originating changes in the blood and fecal metabolome. This review compared the most relevant metabolic and microbial alterations reported from the literature in patients with IBD with those in patients with COVID-19. In both diseases, gut dysbiosis is marked by the prevalence of pro-inflammatory bacterial species and the shortfall of anti-inflammatory species; most studies reported the decrease in Firmicutes, with a specific decrease in obligately anaerobic producers short-chain fatty acids (SCFAs), such as Faecalibacterium prausnitzii. In addition, Escherichia coli overgrowth has been observed in IBD and COVID-19, while Akkermansia muciniphila is depleted in IBD and overexpressed in COVID-19. In patients with COVID-19, gut dysbiosis continues after the clearance of the viral RNA from the upper respiratory tract and the resolution of clinical symptoms. Finally, we presented and discussed the impact of gut dysbiosis, inflammation, oxidative stress, and increased energy demand on metabolic pathways involving key metabolites, such as tryptophan, phenylalanine, histidine, glutamine, succinate, citrate, and lipids.

Since the onset of the pandemic outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it emerged that frailty, elderly, and pre-existing chronic diseases, such as chronic kidney disease, hypertension, cardiovascular disease, and diabetes, are risk factors for the development of severe and/or fatal coronavirus disease 2019 (COVID-19; March 2022 | Volume 13 | Article 856165 Cortes et al.

Metabolic Differences and Analogies IBD-COVID-19 Grasselli et al., 2020; Falandry et al., 2021) . Theoretically, patients with immune-mediated inflammatory diseases, such as inflammatory bowel disease (IBD), might be at increased risk of developing severe COVID-19. However, current knowledge on the pathophysiology of IBD and COVID-19 points out that patients with IBD are not at increased risk or have adverse outcomes for COVID-19 (Neurath, 2020) . Strong evidence supporting this conclusion emerge from clinical studies published elsewhere (Allocca et al., 2020; D'Amico et al., 2020) , including the discovery that biological therapies (e.g., monoclonal antibodies) may play a protective role against the cytokine storm observed in the course of the SARS-CoV-2 infection (Allocca and Craviotto, 2021) . IBD and COVID-19 may share many alterations in molecular mechanisms, microbial communities, and biochemical pathways; "omics" technologies may considerably contribute to decipher mechanisms inducing these alterations, improving patient care and outcome. Microbiome and metabolome were primarily investigated in IBD, and similar but relatively few studies were conducted in patients with  in this review, we examined analogies and differences in gut microbiota and body fluids metabolome between IBD and COVID-19 with the aim to identify microbial and metabolic hallmarks linking IBD, COVID-19 and SARS-CoV-2 infection.

IBD is an umbrella term encompassing a group of disorders, namely, Crohn's disease (CD), ulcerative colitis (UC), and inflammatory bowel disease, type unclassified (IBDU; Satsangi et al., 2006) . IBD is marked by chronic relapsing-remitting or continuously active idiopathic inflammation and bowel injuries; both adults and children exhibit an immunological dysregulation. The etiology of IBD is multifactorial, including the contribution of genetic, environmental, host factors and their reciprocal interactions (Flynn and Eisenstein, 2019) ; recent data indicate a worldwide 0.3% incidence and prevalence of IBD (Ng et al., 2017) . The therapeutic treatment of IBD with immunomodulators (Park et al., 2020) and biologics (Neurath, 2019 ) may activate a transient or persistent immunocompromised state inducing opportunistic infections, especially when multiple drugs are prescribed simultaneously (Bonovas et al., 2016; Shah et al., 2017; Irving et al., 2021) . Several research groups investigated whether patients with IBD may be or not more susceptible to developing SARS-CoV-2 infection (Monteleone and Ardizzone, 2020) , how they should be managed in the context of the COVID-19 pandemic, and the risks and benefits of the therapeutic treatment with immunomodulators, especially in the pediatric age (Dipasquale et al., 2020; Sultan et al., 2020) . An early analysis of data collected from the international registry Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) showed that among 525 pediatric and adult patients with IBD and confirmed COVID-19, 31% were hospitalized, 7% developed severe COVID-19, and 3% died (Brenner et al., 2021) . Data from the registry evidenced that among patients with IBD, corticosteroids treatment may be a key risk factor for severe COVID-19 (Brenner et al., 2020) , confirming results previously reported elsewhere (Mazza et al., 2020) . A recent multicenter study enrolling 1816 patients with IBD treated with biologic therapy over the first 2 months of the pandemic reported an overall COVID-19 incidence of 3.9 per 1,000 patients with a 57% hospitalization rate and 29% case fatality rate (CFR; Ardizzone et al., 2021) . In a cohort of 1912 patients with an IBD median duration of 17 years, the crude incidence rate of COVID-19 was at 6.2 cases per 1,000 patients, lower than that found in the general population (6.6 cases per 1,000 individuals); the mortality rate was 0.9 per 1,000 and 1 per 1,000 in patients with IBD and the general population, respectively (Taxonera et al., 2020) . Although the CFR for IBD cases with COVID-19 was higher than in the general population (16.7 vs. 13.2%, respectively), the statistical difference was not significant. Finally, a meta-analysis including 9,177 patients with IBD from eight studies reported an incidence of 0.3% for COVID-19; 8.6% required admission to the intensive care unit, and the mortality rate was 6.3% (Aziz et al., 2020) . In a cohort of patients with IBD, the rate of positive results for anti-SARS-CoV-2 antibodies (approximately 4.6% for IgG and IgM, and 6% for IgA) was found higher than that in healthcare professionals without inflammatory diseases (approximately 1.6% for IgG and IgM, and 1% for IgA); interestingly, no SARS-CoV-2-infected patients with IBD developed symptomatic COVID-19 (Łodyga et al., 2021) . Further studies reported similar results, confirming that SARS-CoV-2 seroprevalence among individuals with IBD is closely comparable to that in subjects without IBD (Norsa et al., 2020; Bertè et al., 2021) .

Gut microbiota plays a key role in health and disease; it actively impacts multiple host systems and organs. A balanced gut microbial ecosystem with high biodiversity is associated with the beneficial effects of a myriad of symbiotic interactions between intra-and inter-microbial species, genera, families, phyla, and between microbes and host systems and organs, such as the immune system , the brain, and the lung (Morais et al., 2021; Sencio et al., 2021) . Conversely, perturbations in gut microbial communities, namely, dysbiosis, induce detrimental effects on these networks and are associated with diseases (Durack and Lynch, 2019) . Gut dysbiosis can be defined as the loss of the overall microbial biodiversity with the imbalance between beneficial commensal and opportunistic pathogens, resulting in excessive production of pro-inflammatory mediators (Wei et al., 2021) . A large body of literature investigated and evaluated extensively gut dysbiosis in individuals with IBD; the most frequently observed alterations are the overgrowth of pro-inflammatory bacterial species (e.g., Escherichia coli) associated with the shortfall of anti-inflammatory species (e.g., Faecalibacterium prausnitzii). The latter are involved in the generation of short-chain fatty acids (SCFAs), namely, Frontiers in Microbiology | www.frontiersin.org butyrate, propionate, and acetate (Zuo and Ng, 2018; Khan et al., 2019; Aldars-García et al., 2021; Alshehri et al., 2021) .

Regrettably, data on gut microbiota composition are partially heterogeneous between studies, and results could be categorized as (a) fully concordant between studies; (b) roughly concordant with some exceptions; (c) discordant between studies. Table 1 recapitulates the most relevant data on gut dysbiosis in IBD, obtained from a great proportion of available studies from the literature (Favier et al., 1997; Seksik et al., 2003; Macfarlane et al., 2004; Martin et al., 2004; Ott et al., 2004; Gophna et al., 2006; Manichanh et al., 2006; Scanlan et al., 2006; Frank et al., 2007; Andoh et al., 2009; Kang et al., 2010; Rehman et al., 2010; Schwiertz et al., 2010; Willing et al., 2010; Joossens et al., 2011; Mondot et al., 2011; Rausch et al., 2011; Walker et al., 2011; Michail et al., 2012; Morgan et al., 2012; Nemoto et al., 2012; Vigsnaes et al., 2012; Fujimoto et al., 2013; Kabeerdoss et al., 2013 Kabeerdoss et al., , 2015 Kumari et al., 2013; Prideaux et al., 2013; Sha et al., 2013; Tong et al., 2013; Varela et al., 2013; Gevers et al., 2014; Hedin et al., 2014; Machiels et al., 2014; Walters et al., 2014; Wang et al., 2014; Hoarau et al., 2016; Jacobs et al., 2016; Mar et al., 2016; Takahashi et al., 2016; Chen et al., 2017; Halfvarson et al., 2017; Pascal et al., 2017; Santoru et al., 2017; Sokol et al., 2017; Vrakas et al., 2017; Zhang et al., 2017 Zhang et al., , 2021 de Meij et al., 2018; Laserna-Mendieta et al., 2018; Nishino et al., 2018; Franzosa et al., 2019; Heidarian et al., 2019; Lloyd-Price et al., 2019; Yilmaz et al., 2019; Alam et al., 2020; Ryan et al., 2020; Shahir et al., 2020; Clooney et al., 2021) . No specific pattern of dysbiosis in patients with IBD has been definitively established; nevertheless, there is a broad agreement between studies on the imbalance of gut bacterial abundance in IBD. In particular, most studies report the depletion of Clostridium genus, C. leptum (cluster IV), C. coccoides (cluster XIVa) groups, F. prausnitzii, E. rectale, R. bromii species, Ruminococcaceae, Lachnospiraceae families, and the overgrowth of Enterococcus and Fusobacterium genera, E. coli and F. nucleatum species, Enterobacteriaceae, Veillonellaceae families. Controversial results may derive from many variables affecting gut microbiota composition, including the pre-existence of chronic diseases, the intensive therapeutic treatment in critically ill patients, especially with antibiotics to prevent secondary bacterial infections, and sudden and radical changes to eating habits ( Table 2) . Gut microbiome composition in IBD is strongly influenced by complex interactions between microbial communities and genetically altered host functional pathways Knights et al., 2014) . In CD, gut dysbiosis is more pronounced than in UC and is marked by a lower microbial diversity, a more altered microbiome composition, and a more unstable microbial community (Pascal et al., 2017) . Microbial diversity and abundance significantly differ between feces and gut mucosa, as reported in early studies (Lepage et al., 2005; Gillevet et al., 2010; Morgan et al., 2012) and confirmed in more recently published papers (Lo Presti et al., 2019; Ryan et al., 2020) . In IBD, inflammation alters the mucosal barrier inducing bacterial translocation; in patients with CD, bacterial translocation is revealed by the increase in several bacterial families within the submucosa compared to the corresponding superjacent mucosa at the advancing disease margin (Chiodini et al., 2016) . Mucosal and fecal microbiome differences may explain, at least in part, some discrepancies between studies; for example, the increase in fecal F. prausnitzii (Table 1) corresponds to the decreased proportion of this bacterium at the mucosal surface (Walters et al., 2014) . Differences in the abundance of various bacterial species and families (e.g., Lactobacilli, C. leptum group, E. coli, and F. prausnitzii) were observed between ulcerated (inflamed) and non-ulcerated (non-inflamed) mucosa (Zhang et al., 2007; Li et al., 2012) as well as between patients with high clinical activity indexes and/or sigmoidoscopy scores and patients with low clinical activity indexes and/or sigmoidoscopy scores (Fite et al., 2013) .

Other studies reported no difference in microbiota composition and enrichment between inflamed and non-inflamed mucosa (Kabeerdoss et al., 2015; Nishino et al., 2018) . The abundance of some bacteria, such as the genus of Faecalibacterium and the family of Enterobacteriaceae, significantly differs between ileal CD and colonic CD (Dicksved et al., 2008; Naftali et al., 2016) ; for example, F. prausnitzii is markedly reduced in CD localized in the ileum compared with colonic localization (Willing et al., 2010) . Interestingly, in current smokers with CD, the abundance of Bacteroides-Prevotella genera is higher than in non-smokers with CD (Benjamin et al., 2012a) . Significant differences in several microbial taxa can be observed between young adults with IBD and IBD adults aged 60 years or older; in particular, Bifidobacterium genus decrease with age, and Bacteroides genus increase with age, probably reflecting body mass index and diet changes over time (Morgan et al., 2012) .

Researchers have a unanimous consensus on the E. coli overgrowth in IBD. E. coli overgrowth has been found in children with severe IBD (Schwiertz et al., 2010; Michail et al., 2012; Gevers et al., 2014; de Meij et al., 2018) and in adults with CD (Mondot et al., 2011) . In patients with CD, the high prevalence of E. coli strictly adhering to the ileal mucosa has led to the identification of a new group of E. coli strains (Nadalian et al., 2021) . This pathogenic group, called adherent-invasive E. coli (AIEC), has the ability to adhere and colonize enterocytes as well as to internalize into macrophages and replicate within their cytoplasm, inducing the release of tumor necrosis factor-α (TNF-α) and the cytotoxic response of Th17 and CD8 + (Lee et al., 2019) . Thus, AIEC is involved in the pathogenesis of IBD, specifically CD (Palmela et al., 2018; Chervy et al., 2020) , by promoting inflammatory diseases that originated from the adaptative evolution of the genome (Nash et al., 2010; Ellermann et al., 2015) . The recognition of AIEC is unusual in patients with UC; rather, UC is associated with the intestinal enrichment of a heterogeneous, diarrheagenic group of E. coli strains, termed diffusely adherent E. coli (DAEC); this group was found expressed not only in children and young adults with UC but even in those with CD (Walczuk et al., 2019) .

Although the lung is considered the main entry route for SARS-CoV-2, the gastrointestinal tract is equally a key target Frontiers in Microbiology | www.frontiersin.org 

Cortes et al.

Frontiers in Microbiology | www.frontiersin.org of the virus (Xiao et al., 2020; Qian et al., 2021) . Indeed, the brush border of human enterocytes exhibits the highest expression of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2; Qi et al., 2020) ; even the transmembrane serine protease 2 (TMPRSS2), mediating the entry of SARS-CoV-2, is expressed on the luminal surface of enterocytes from ileum and colon as well as on the epithelial and gland cells of the esophagus (Knyazev et al., 2021) . Thus, it is not surprising that SARS-CoV-2 infects human gut enterocytes (Lamers et al., 2020) , promoting gut mucosal inflammatory infiltration with activated immune cells and cytokines (Lehmann et al., 2021) . These findings support (a) the frequently observed gastrointestinal symptoms in patients with COVID-19, including severe abdominal pain, diarrhea, nausea, and vomiting (Devaux et al., 2021) ; (b) the persistence of viral RNA in patient's stool even after the virus clearance from oropharyngeal swab (Morone et al., 2020) ; (c) the likelihood of SARS-CoV-2 transmission by the fecal-oral route (Cheung et al., 2020; Guo et al., 2021) ; (d) gut dysbiosis in asymptomatic infected individuals and patients with COVID-19 (Yamamoto et al., 2021) . SARS-CoV-2 gut colonization significantly alters the gut microbial ecosystem, leading to dysbiosis; on the other hand, gut dysbiosis, due to aging, unhealthy lifestyle habits, and pre-existing chronic diseases (e.g., hypertension, type-2 diabetes, autoimmune diseases, and metabolic syndrome), is a key risk factor for developing COVID-19 (Magalhães et al., 2021) . In hospitalized patients with COVID-19, the reduction in gut microbiota diversity, the depletion of beneficial bacterial symbionts, and the enrichment of opportunistic pathogens closely correlate with the host immune response and, in turn, with the disease severity and the clinical outcome (Villapol, 2020) . The variety of the therapeutic treatment for COVID-19 may impact changes in gut microbiome composition, as highlighted in a recent review (Aktas and Aslim, 2021) . Gut dysbiosis continues after the clearance of the viral RNA from the upper respiratory tract and the resolution of clinical symptoms. These associations result from complex interactions between the gut and the lung microbiota, the so-called gut-lung axis (de Oliveira et al., 2021) . In particular, a balanced gut microbial ecosystem enhances the pulmonary defense against viral infections, for example, by stimulating the lung's synthesis of type I interferons (Cyprian et al., 2021) . Conversely, gut dysbiosis negatively influences the progression of the viral infection, COVID-19 development, and patient outcome (Hussain et al., 2021) . Since SCFAs inhibit the overgrowth of opportunistic pathogens, activate the adaptive immune response by enhancing antiviral immunity, and contribute to maintaining the integrity of the intestinal mucosal barrier, the depletion of SCFAs producer bacteria is closely associated with COVID-19 severity and adverse outcome; therefore, the number of SCFAs producer bacteria could predict the severity of the disease . Based on the observation that the Enterococcus/Enterobacteriaceae ratio is altered in approximately 74% of patients with severe/critical COVID-19, being significantly increased in non-survivors compared with survivors, it was proposed that this index may be useful to predict death in critically ill patients . However, a strong limitation may be the heterogeneity of this ratio. Enterococcus is a genus belonging to the Enterococcaceae family (Firmicutes phylum), while Enterobacteriaceae family belongs to Proteobacteria phylum. Despite the limited number of studies on the gut microbiome in patients with COVID-19, the pattern of gut dysbiosis associated with the disease has been partially defined ( Table 1) . When compared with non-infected individuals, gut dysbiosis in patients with COVID-19 is marked by the depletion of C. leptum (cluster IV) group, F. prausnitzii, and E. rectale species, Ruminococcaceae, and Lachnospiraceae families, in conjunction with the overgrowth of Enterococcus genus, Veillonellaceae, and Enterobacteriaceae families Tao et al., 2020; Zuo et al., 2020 Zuo et al., , 2021 Gaibani et al., 2021; He et al., 2021; Wu et al., 2021; Yeoh et al., 2021) . The abundance of Coprobacillus, C. ramosum, C. hathewayi , and Enterococcus (Gaibani et al., 2021) was found positively correlated with COVID-19 severity; conversely, an inverse correlation was observed between the disease severity and the abundance of C. leptum (cluster IV) group, Lactobacillus, Bifidobacterium, C. butyricum , Bilophila, Citrobacter (Tao et al., 2020) , Bacteroides (Gaibani et al., 2021) , F. prausnitzii, E. rectale Yeoh et al., 2021) , B. bifidum, and B. adolescentis . In addition, the abundance of some microbial taxa, including Erysipelotrichaceae bacterium 2_2_44A , P. copri, E. dolichum (Wu et al., 2021) , C. aerofaciens, C. tanakaei, S. infantis positively correlates with the fecal SARS-CoV-2 load. Conversely, the abundance of B. dorei, B. thetaiotaomicron, B. massiliens, B. ovatus , S. anginosus, Dialister, Alistipes, Ruminococcus, C. citroniae, Bifidobacterium, Haemophilus, H. parainfluenzae (Wu et al., 2021) , P. merdae, B. stercoris, A. onderdonkii, and Lachnospiraceae bacterium 1_1_57FAA was inversely correlated with the fecal viral load. The increased gut colonization of bacteria usually resident in the oral and respiratory tracts, such as Actinomyces Zuo et al., 2020; Gaibani et al., 2021; Wu et al., 2021) and Granulicatella (Wu et al., 2021) , is associated with COVID-19 and its severity, confirming the active interchange between the gut, oral, and respiratory tract microbiota. The close relationship between gut microbiota and the immune-mediate response to SARS-CoV-2 infection and COVID-19 progression and outcome is supported by the correlation between the abundance of some gut microbial taxa and biomarkers of inflammation. For example, in critical patients with COVID-19, a negative correlation was observed between serum C-reactive protein (CRP) levels and the gut abundance of C. butyricum and F. prausnitzii . Fecal inflammatory cytokine IL-18 concentration was positively correlated with the abundance of Peptostreptococcus, Fusobacterium, and Citrobacter in patients with COVID-19 (Tao et al., 2020) . Similarly, B. dorei and A. muciniphila abundance was found positively correlated with the serum level of IL-1β, IL-6, and C-X-C motif ligand 8 (CXCL8), whereas F. prausnitzii, E. rectale, and B. adolescentis were negatively correlated with serum level of TNF-α, IL-10, C-C motif ligand 2 (CCL2), and CXCL10 .

Frontiers in Microbiology | www.frontiersin.org

Metabolomics is an evolving "omic" discipline allowing the identification and the quantification of endogenous and exogenous products of the cellular metabolism, namely, metabolites, within a biological system in a high-throughput manner (Liu and Locasale, 2017) . The set of metabolites recognizable in a biological matrix is called metabolome or metabolic profile; it is a highly personalized readout of the current metabolism and metabolic activity that occurred in the past (Zamboni et al., 2015) . Qualitative and quantitative data on metabolites reveal basic information on changes and perturbations of metabolic pathways deriving from interactions between genome, environment, microbiome, nutrients, and the intake of drugs and toxicants in health and disease states (Ashrafian et al., 2020 ). An updated PubMed literature search, querying the keyword metabolomics, results in approximately 26,200 studies, including in vitro experimental studies, studies on animal models, and clinical studies on patients with various diseases (Kang et al., 2021) . Approximately 200 studies used the metabolomic approach in patients with IBD (Gallagher et al., 2021) and 25 in patients with COVID-19 . The most relevant findings are reported below.

Tryptophan (TRP) is an essential amino acid mainly derived from the diet and involved in serotonin, melatonin, and niacin biosynthesis, as detailed in Figure 1 . More than 95% of TRP is metabolized along the kynurenine pathway; in the liver, the enzyme tryptophan dioxygenase (TDO) converts tryptophan into kynurenine. In the brain and the immunocompetent cells, the conversion is catalyzed by indoleamine 2,3-dioxygenase (IDO-1 and 2; Gao et al., 2018; Agus et al., 2018) . Kynurenine can be converted either into neurotoxic metabolites, namely, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid, or neuroprotective metabolites, such as kynurenic acid, anthranilic acid, xanthurenic acid, and picolinic acid (Savitz, 2020) . Depending on gut microbiota composition, approximately 4-6% of tryptophan is converted into various intermediates. For example, the prevalence of Clostridium sporogenes and Ruminococcus gnavus spp. originates tryptamine (Williams et al., 2014) , whereas the prevalence of Lactobacillus, Bacteroides, and Clostridium genera originates indole derivatives (Roager and Licht, 2018) . Among bacterial metabolites, indoles play a crucial role in the regulation of gastrointestinal barrier function and integrity by their binding with the pregnane X receptor (PXR), also known as steroid and xenobiotic receptor (SXR; Venkatesh et al., 2014; Oladimeji and Chen, 2018) . Finally, 1-2% tryptophan is converted into serotonin (5-hydroxytryptamine), a neurotransmitter and key regulator of intestinal secretion and motility. More than 90% of serotonin is synthesized by the rate-limiting enzyme tryptophan hydroxylase (Tph/TPH) 1 within enterochromaffin cells of the gut (Stasi et al., 2019) ; notably, gut microbiota may considerably affect serotonergic regulation via microbiota-derived SCFA (Reigstad et al., 2015) .

Tryptophan and indole-3-acetic are decreased in the blood of patients with IBD (Table 3 ; Ooi et al., 2011; Kohashi et al., 2014; Nikolaus et al., 2017; Bosch et al., 2018; Lai et al., 2019) . Conversely, kynurenine and quinolinic acid are increased (Forrest et al., 2002; Yau et al., 2014; Nikolaus et al., 2017; Whiley et al., 2019) . In the urine and stool of patients with IBD, tryptophan is increased (Schicho et al., 2012; Bosch et al., 2018) . Kynurenic acid blood levels were increased in IBD (Forrest et al., 2002) ; similarly, picolinic acid was increased (Yau et al., 2014) . More recently, kynurenic acid and picolinic acid were found decreased in patients with IBD (Nikolaus et al., 2017; Whiley et al., 2019) . These alterations seem to be closely related to gut dysbiosis (de Meij et al., 2018) , promoting the massive activation of pro-inflammatory cytokines (e.g., INF-γ and TNF-α), and the upregulation of the IDO expression (Wu et al., 2018) . Gut dysbiosis significantly affects the conversion of tryptophan into indole derivatives, such as indole-3 acetic acid and indole-3-acetaldehyde. Low blood levels of indole-3-acetic acid have been associated with the overgrowth of Clostridium and Lactobacillus genera; both bacterial genera decarboxylate indole-3-acetic acid in 3-methylindole, also known as skatole. As a result, indole-3-acetic acid is metabolized with the concomitant accumulation of skatole. In patients with IBD, skatole blood levels were significantly increased . Most indole derivatives are ligands of the Aryl Hydrocarbon Receptor (AHR), a cytosolic ligand-dependent transcription factor widely expressed by cells of the immune system and involved in antimicrobial activity and gut immune homeostasis (Stockinger et al., 2014; Lamas et al., 2018) . The indole derivatives-induced AHR activation promotes the local synthesis of the anti-inflammatory cytokine IL-22 by the innate lymphoid cells (Monteleone et al., 2011; Qiu et al., 2012; Yang et al., 2020) ; IL-22 protects the mucosa integrity against fungal infection by Candida albicans, commonly observed in patients with IBD (Sokol et al., 2017; Gronke et al., 2019) . In healthy subjects with gut eubiosis, the activation of AHR modulates local IL-22 production; conversely, in IBD patients, the decrease of indole-3 acetic acid due to the imbalance of gut flora reduces the AHR activity and hence IL-22 synthesis, as observed in an animal model (Lamas et al., 2016) . In patients with COVID-19, most metabolomics-based studies reported a significant decrease in blood tryptophan level in conjunction with the significant increase of kynurenine, kynurenic acid, and downstream metabolites of the kynurenine pathway (Barberis et al., 2020; Fraser et al., 2020; Thomas et al., 2020; Lawler et al., 2021) . The decrease of tryptophan was inversely correlated with biomarkers of inflammation, such as IL-6 and CRP (Thomas et al., 2020) . The increase of kynurenine is significantly associated with the increase of several cytokines, including interferon γ-induced protein 10 (IP-10), the mitogen-inducible cytokine macrophage inflammatory protein-1 β (MIP-1-β), also known as CCL4, TNF-α, interleukin-1 receptor antagonist (IL-1RA), IL-7, IL-18, and IL-8 (Lawler et al., 2021) . Controversial results on indole-3-acetic acid in patients with COVID-19 have been published. On the one hand, it was found decreased (Lawler et al., 2021) , and this finding remains unclear. A possible explanation may be the decrease of indole-3 acetic acid produced by the host because of the upregulation of the kynurenine pathway. This assumption is plausible, taking into account that a fraction of indole-3 acetic acid is produced by mammalian cells . On the other hand, indole-3 acetic acid has been found increased (Blasco et al., 2020) ; this finding is coherent with gut dysbiosis marked by the prevalence of bacteria converting tryptophan into indoles.

Glutamine is an L-α gluconeogenic and proteogenic amino acid containing five carbons and two amino groups. L-glutamine is considered a conditionally essential amino acid; it is obtained mainly through the diet, as well as it is synthesized de novo from glutamate and ammonia in almost all the human cells by the activity of glutamine synthase (E.C.: 6.3.1.2.). In rapidly diving cells, such as enterocytes of the small intestine (Windmueller and Spaeth, 1974) , lymphocytes, neutrophils, macrophages, and tumor cells, as well as under catabolic stressed conditions, including severe infections and sepsis, the endogenous synthesis does not meet the energy cell demand and the amount deriving from digested food absorbed through the small intestine becomes vitally important (Cruzat et al., 2018) . Glutamine is involved in many cytoplasmatic and mitochondrial pathways, such as (a) the preservation of the reactive oxygen species (ROS) homeostasis, by contributing to the synthesis of the glutathione (Matés et al., 2002) ; (b) the biosynthesis of hexosamine, nucleotides, asparagine; and (c) the activation of glutaminolysis (Yoo et al., 2020) . In the gut, the role of L-glutamine is crucial (Kim and Kim, 2017) . Firstly, glutamine exerts an anti-inflammatory activity, preventing the expression of pro-inflammatory cytokines through the inhibition of both nuclear factor k light chain-enhancer of activated B cells (NF-kB) and signal transducer and activator of transcription (STAT) proteins (Kretzmann et al., 2008) . Secondly, L-glutamine enhances tight junction integrity, as demonstrated in animal models (Wang et al., 2016) , triggering the mitogen-activated protein kinase (MAPK) function (Basuroy et al., 2006; Perna et al., 2019) ; in addition, L-glutamine is pivotal for gut cells proliferation (Rhoads et al., 1997) . Finally, L-glutamine modulates NO synthetase expression Swierkosz et al., 1990) . Thus, it is not surprising that L-glutamine is the most abundant free amino acid in humans. L-glutamine provides energy as a substitute fuel to the tricarboxylic acid (TCA) cycle to produce adenosine triphosphate (ATP; Curi et al., 2005) ; recently, it was postulated that L-glutamine is the fuel for the immune system, generating the concept of immunometabolism . In IBD, L-glutamine plasma levels are decreased (Table 4) , especially during the acute exacerbation of CD (Sido et al., 2006; Bjerrum et al., 2010; Ooi et al., 2011; Scoville et al., 2018) . Supplementation improves inflammation (Sugihara et al., 2019) and the mucosal barrier integrity in patients with remissive CD (Benjamin et al., 2012b) . Glutamine is reduced in the blood of patients with non-severe COVID19 and much more in severe forms (Thomas et al., 2020; Doğan et al., 2021; Meoni et al., 2021;  Table 4 ). In patients with COVID-19, it was observed a 19% reduction in glutamine blood level compared to that before the onset of the disease . This finding may be related to higher consumption of gluconeogenic amino acids, especially in patients with severe forms, because of the significant scarcity of amino acids . A further possible explanation may be the increased conversion of L-glutamine into glutamate, supported by the blood Krebs cycle's intermediates elevation and by the increase in oxidative stress (Páez-Franco et al., 2021) .

Histidine is an essential amino acid playing a crucial role as a ROS scavenger and anti-inflammatory mediator (Son et al., 2005; Holeček, 2020) . The decarboxylation of histidine, catalyzed by histidine decarboxylase, originates histamine, a primary mediator in allergic diseases and a neurotransmitter involved in the control of food intake and sleep biorhythm. Histidine decarboxylase is expressed in bacteria of the large intestine and human muscle, liver, lung, and gastric mucosa (Moro et al., 2020) . Blood histidine has been found significantly decreased in patients with IBD (Bjerrum et al., 2010; Ooi et al., 2011; Dawiskiba et al., 2014; Kohashi et al., 2014; Bosch et al., 2018; Probert et al., 2018 ). An early study found that histidine was significantly decreased in a large cohort (n = 387) of IBD patients (Hisamatsu et al., 2012) ; interestingly, plasma histidine was significantly lower in patients with active disease than in those in remission. Furthermore, a significant inverse correlation was observed between plasma histidine and serum CRP in patients with UC and CD. Authors postulated that the decrease in plasma histidine may reflect chronic inflammation in patients with IBD, suggesting supplementation with histidine as a novel therapy. In a subsequent 1-year follow-up of patients with UC in clinical remission, the same research group found that the decrease in histidine plasma level over time was associated with the increased risk of clinical relapse (Hisamatsu et al., 2015) . Previous in vitro studies and in animal models suggested that low levels of histidine do not allow the effective suppression of NF-kB (Andou et al., 2009; Hasegawa et al., 2011) ; thus, LPS-induced TNF-α expression cannot be inhibited, resulting in the exacerbation of inflammation. This was confirmed by the amelioration of intestinal inflammation after oral administration of histidine. A recent metabolomics-based study on serum and stool samples in pediatric patients with IBD found controversial results. Compared with healthy controls, fecal histidine was significantly decreased in children with CD and significantly increased in those with UC (Kolho et al., 2017) . Moreover, in the group of children with UC, serum histidine inversely correlated with erythrocyte sedimentation rate (ESR). Histidine fecal levels have been positively associated with more extended disease in UC but not in CD pediatric patients (Jagt et al., 2021) . A possible explanation may be either the colonic leakage of histidine and other amino acids or malabsorption. However, the overgrowth of Bacteroides vulgatus in patients with UC leads to an increased fecal proteolytic and elastase activity (Galipeau et al., 2021) . Therefore, it is reasonable to assume that the increased proteolytic and elastase activity might be the main factor promoting the high concentrations of fecal histidine rather than the protein-losing enteropathy. Several studies found L-histidine significantly decreased in the serum/plasma of patients with COVID-19 (Table 4 ; Barberis et al., 2020; Bruzzone et al., 2020; Thomas et al., 2020) ; the magnitude of L-histidine decline correlated with the disease severity (Lawler et al., 2021; Meoni et al., 2021) . COVID-19 is marked by the activation of gluconeogenesis that is positively correlated with the severity of the disease. Tryptophan (blood) Decreased Ooi et al., 2011; Kohashi et al., 2014; Nikolaus et al., 2017; Bosch et al., 2018 Decreased Barberis et al., 2020; Thomas et al., 2020; Lawler et al., 2021 Tryptophan (urine) Increased Schicho et al., 2012 Tryptophan (stool) Increased Bosch et al., 2018 Kynurenine (blood) Increased Forrest et al., 2002; Nikolaus et al., 2017; Whiley et al., 2019 Increased Fraser et al., 2020 Thomas et al., 2020; Lawler et al., 2021 Quinolinic acid ( L-Glutamine (blood) Decreased Sido et al., 2006; Bjerrum et al., 2010; Ooi et al., 2011; Scoville et al., 2018 Decreased Bruzzone et al., 2020 Thomas et al., 2020; Meoni et al., 2021; Dogȃn et al., 2021 L-Glutamine (gut mucosa) Decreased Ooi et al., 2011 Histidine (blood) Decreased Bjerrum et al., 2010; Ooi et al., 2011; Hisamatsu et al., 2012; Kohashi et al., 2014; Dawiskiba et al., 2014; Bosch et al., 2018; Probert et al., 2018 Decreased Thomas et al., 2020; Barberis et al., 2020; Bruzzone et al., 2020; Kimhofer et al., 2020; Lawler et al., 2021; Meoni et al., 2021 Histidine ( In patients with COVID-19, it was observed a 16% reduction in L-histidine blood levels compared to those before the onset of the disease, similarly to glutamine . In COVID-19, low L-histidine serum levels may be related to the skeletal muscle breakdown (Kimhofer et al., 2020) .

Phenylalanine is an aromatic, hydrophobic essential amino acid involved in the biosynthesis of catecholamines (Matthews, 2007) . Phenylalanine is hydroxylated to tyrosine by phenylalanine 4-hydroxylase; this reaction primarily occurs in the liver and the kidney. In turn, tyrosine is hydroxylated to L-DOPA (3,4-Dihydroxyphenylalanine) by tyrosine-5 hydrolase, and the enzyme DOPA-decarboxylase converts L-DOPA into Dopamine. A restricted number of gut bacteria, mainly belonging to the phylum Firmicutes, such as Clostridium sporogenes and C. botulinum spp., metabolize aromatic amino acids tryptophan, phenylalanine, and tyrosine to their corresponding propionic acid derivatives, namely, phenylpropionic acid and 4-hydroxyphenylpropionic acid (Elsden et al., 1976 ). In C. sporogens, this metabolic pathway can produce nine metabolites; they accumulate in host serum and exhibit specificity by engaging receptors and altering host biology, especially systemic immunity and gut permeability (Dodd et al., 2017) . Although an early metabolomics-based study focused on amino acids did not report any data on phenylalanine level in stool samples from adults with IBD (Marchesi et al., 2007) , further studies found a significant increase of phenylalanine in serum Dawiskiba et al., 2014) , urine (Alonso et al., 2016) , and stools (Jansson et al., 2009; Kolho et al., 2017; Bosch et al., 2018) . Interestingly, the magnitude of fecal phenylalanine increase differed between CD and UC, and no correlation was found between the disease activity and fecal phenylalanine concentration (Bosch et al., 2018) . Given that the activity of phenylalanine-4-hydroxylase is impaired during immune activation and inflammation (Scholl-Bürgi et al., 2013) , it is reasonable to assume that the increase of phenylalanine in patients with IBD may originate from the accumulation of this amino acid. A further contribution to the fecal phenylalanine increase in IBD may be related to the microbial biosynthesis of aromatic amino acids via the shikimate pathway (Sprenger, 2006) . The condensation of phosphoenolpyruvate with erythrose 4-phosphate, deriving from the glycolysis pathway and the non-oxidative branch of the pentose phosphate pathway, respectively, yields 3-deoxy-d-arabino-heptulosonate-7-phosphate (DAHP), which is converted into chorismic acid and then into aromatic amino acids L-phenylalanine, L-tyrosine, and L-tryptophan. Approximately one-third of gut bacteria expresses all the transcripts coded from the genes of the shikimate pathway, including A. muciniphila (Mesnage and Antoniou, 2020) ; the remaining bacteria species do not exhibit a complete shikimate pathway, having lost either one enzyme (nearly 22%) or five or more enzymes (nearly 74%; Zucko et al., 2010) . In COVID-19, the considerable generation of ROS, due to cytokine activation, induces the irreversible non-enzymatic oxidation of 5, 6, 7, 8-tetrahydrobiopterin (BH4), a cofactor of phenylalanine 4-hydroxylase (PAH), the enzyme catalyzing the conversion of phenylalanine to tyrosine. BH4 shortage induces the loss of PAH activity, with the reduced biosynthesis of tyrosine and the accumulation of phenylalanine. Data on phenylalanine emerging from metabolomic studies in patients with COVID-19 are heterogeneous and discordant: both phenylalanine and tyrosine were decreased, especially in severe and fatal outcomes (Barberis et al., 2020) or increased (Kimhofer et al., 2020; Shi et al., 2021) . Interestingly, in non-survivors, phenylalanine serum levels are significantly higher than in survivors (Shi et al., 2021) . Moreover, the increase in phenylalanine was associated with the decrease in tyrosine . The role of phenylalanine in SARS-CoV-2 infection seems to be crucial. In a multicenter study on elderly patients with COVID-19, phenylalanine and tyrosine metabolisms were highly upregulated in 132 deceased patients (median age 74 years) compared with 91 survivors (median age 70 years), suggesting that these amino acids contribute as building blocks for the production of internal SARS-CoV-2 protein and its subsequent assembly into viral particles (Mei et al., 2021) .

Succinate and citrate are intermediates of the TCA cycle. Succinate is generated within mitochondria via the TCA cycle from succinyl-CoA; then, succinate is oxidized to fumarate by succinate dehydrogenase. Succinate is also a product of the glyoxylate cycle, a pathway active in many bacteria, plants, and fungi. Overall, succinate accumulation is a metabolic signature of anoxia, asphyxia, and ischemia; the dysregulation of succinate metabolism can lead to pathological conditions, such as malignant transformation, inflammation, and tissue injury. Metabolomics-based studies carried out in serum, plasma, and urine of patients with IBD found that succinate and citrate significantly decreased in CD and UC compared to non-IBD individuals (Schicho et al., 2012; Stephens et al., 2013; Dawiskiba et al., 2014) . Succinate and citrate are strongly involved in energy metabolism, and their depletion confirms the increased demand and the rapid utilization of cellular energy in IBD. In this context, citrate depletion may be associated with the increase in fatty acids biosynthesis. Indeed, citrate is essential for carrying acetyl-CoA from mitochondria to the cytosol. The significant increase in circulating triglycerides, observed in several studies on IBD, can be considered further evidence (Levy et al., 2000; Sappati Biyyani et al., 2010; Tefas et al., 2020) . Beyond the role of succinate as an energy supplier, this amino acid is an inflammation mediator; it selectively binds to and activates the succinate receptor-1 (SUCNR1), which promotes pro-inflammatory signaling pathways (Mills and O'Neill, 2014) . In patients with CD, hypoxia, inflammation, and necrosis promote the accumulation of succinate in gut inflamed areas, with a further activation and infiltration of macrophages and fibroblasts, the overexpression of pro-inflammatory cytokines, and ultimately the acceleration of fibrosis (Macias-Ceja et al., 2019) .

Data on succinate emerging from metabolomics-based studies in COVID-19 are controversial (Table 4) ; the concentration of this amino acid has been found increased (Barberis et al., Frontiers in Microbiology | www.frontiersin.org 2020; Bruzzone et al., 2020) decreased in moderate and severe disease , or unchanged (Thomas et al., 2020) . Differences between patients normo-oxygenate and patients undergoing intense respiratory treatment may affect results obtained in different studies. In the paper of Bruzzone, the increase in succinate and citrate (156 and 12%, respectively) has been associated with central carbon metabolism dysfunction . In severe COVID-19, the association of citrate decrease with succinate increase could be related to mitochondrial dysfunction due to hypoxia (Páez-Franco et al., 2021) . Hypoxia inhibits oxidative phosphorylation, and thus energy is supplied by the anaerobic glycolysis, which is activated by the accumulation of the hypoxia-inducible factor 1α (HIF 1α; Majmundar et al., 2010) . As a result, the TCA is blocked, with the consequent accumulation of succinate, depletion of citrate, and increased demand for glucose. In turn, the latter induces the decreased availability of gluconeogenic amino acids and oxaloacetate, being utilized as substrates for gluconeogenesis. Oxaloacetate is converted into glucose, whereas mitochondrial acetyl-CoA oxidation is drastically reduced, and acetyl-CoA is redirected to the synthesis of ketone bodies.

Ketone bodies are small lipid-derived molecules, namely, 3-β-hydroxybutyrate, acetone, and acetoacetate (Laffel, 1999) . During fasting or prolonged exercise, the liver converts fatty acids mobilized from adipocytes into ketone bodies; then, they enter circulation, serving as an energy source. Ketone bodies are crucial regulators of metabolic health and longevity; in fact, they are neuroprotective and cytoprotective , having the ability to inhibit histone deacetylase activity and thereby epigenetic gene regulation (Newman and Verdin, 2014) . On the one hand, ketone bodies were increased in the serum of patients with IBD (Table 5) , and this finding was correlated to the increased energy demand Dawiskiba et al., 2014; Kohashi et al., 2014; Keshteli et al., 2017) . On the other hand, ketone bodies may play a strategic role in IBD when supplemented with diet, thanks to their capacity to protect from toxic effects of chronic inflammation. An experimental study demonstrated that 3-β-hydroxybutyrate suppresses the activation of the NLRP3 inflammasome in response to urate crystals, ATP, and lipotoxic fatty acids (Youm et al., 2015) . Then, in a mouse model of NLRP3-mediated diseases, authors observed that 3-β-hydroxybutyrate attenuates caspase-1 activation and the release of pro-inflammatory cytokines IL-1β and IL-18 from macrophages, reducing in definitive the severity of NLRP3-mediated chronic inflammatory diseases. The same effect was obtained by applying a ketogenic diet or supplementing 3-β-hydroxybutyrate (Youm et al., 2015) . The accumulation of ketone bodies following a ketogenic diet strongly impacts gut microbiota composition; in vivo and in vitro experiments demonstrated that ketone bodies selectively inhibit the growth of several Bifidobacterial spp., with downstream consequences for gut immune cells, especially Th17, and induce the decrease in the relative abundance of Actinobacteria (Ang et al., 2020) . In an animal model of inflammatory colitis, it 3-β-hydroxybutyrate Increased Zhang et al., 2013; Dawiskiba et al., 2014; Kohashi et al., 2014; Keshteli et al., 2017 Increased Barberis et al., 2020; Bruzzone et al., 2020; San Juan et al., 2020; Páez-Franco et al., 2021; Meoni et al., 2021 Acetone Increased Keshteli et al., 2017 Increased Bruzzone et al., 2020 San Juan et al., 2020 Acetoacetate Increased Dawiskiba et al., 2014 Keshteli et al., 2017 Increased Bruzzone et al., 2020 San Juan et al., 2020 Glycerophospholipids Decreased Bjerrum et al., 2010 , 2017 Fan et al., 2015; Kolho et al., 2017; Scoville et al., 2018; Tefas et al., 2019 Tefas et al., , 2020 Decreased Barberis et al., 2020; Wu et al., 2020; Song et al., 2020; Shen et al., 2020; Schwarz et al., 2021 Lysophospholipids Decreased Increased Barberis et al., 2020; Song et al., 2020; Schwarz et al., 2021 Sphingolipids Decreased Fan et al., 2015 Kolho et al., 2017 Decreased Barberis et al., 2020; Shen et al., 2020; Schwarz et al., 2021 Increased Song et al., 2020 Decreased Esteve-Comas et al., 1992; Scoville et al., 2018; Lai et al., 2019; Manfredi et al., 2019 Increased Barberis et al., 2020; Schwarz et al., 2021; Thomas et al., 2020 Arachidonic acid (stools) Increased Jansson et al., 2009 Frontiers in Microbiology | www.frontiersin.org was observed that the ketogenic diet alters gut microbiota and serum metabolome, alleviating colitis (Kong et al., 2021) . In particular, Akkermansia, Roseburia, and Ruminococcaceae genera were enriched. After colitis induction, the ketogenic diet protected intestinal barrier function and reduced the presence of RORgt + CD3 − group 3 innate lymphoid cells and related inflammatory cytokines and Ccl4) . As a result, the ketogenic diet in patients with IBD may substantially contribute to control inflammation and shape gut microbiota. Ketone bodies accumulate in the serum of patients with COVID-19, mimicking diabetic ketoacidosis . Further studies confirmed the elevation of circulating ketone bodies in COVID-19 ( Table 5) , suggesting their role as an alternative energy source during SARS-CoV-2 replication (Barberis et al., 2020; Bruzzone et al., 2020; San Juan et al., 2020; Meoni et al., 2021; Páez-Franco et al., 2021) . The increase in 3-β-hydroxybutyrate could interfere with viral replication by upregulating the expression of antioxidant genes, the cytoplasmic NADPH, and directly scavenging free radicals (Stubbs et al., 2020) . In addition, 3-β-hydroxybutyrate may induce the closing of mitochondrial permeability transition pore, apoptosis, and the inhibition of glycolysis. It was postulated that ketone bodies inactivate the extracellular virions (Shaheen, 2021) . Ketone bodies have carbonyl groups reacting with the ε-amino group of lysine to form a Schiff base. Given that SARS-CoV-2 spike protein contains approximately 4.5% lysine residues, almost equally distributed between the two subunits, the reaction between the ketone body, mainly acetoacetate, and the lysine residues of the spike protein forms Schiff bases, altering the conformation of the spike protein. This change promotes the separation of the spike protein from the virion, either by the separation between S1 and S2 subunits or promoting its bending. As a result, acetoacetate induces protein conformational changes by altering the secondary structure, namely, reducing the α-helix content (Bohlooli et al., 2016) . The sum of these researches has raised the question of whether or not it may be effective to induce ketosis both in asymptomatic individuals infected with SARS-CoV-2 and in patients with COVID-19 (Bradshaw et al., 2020) .

Glycerophospholipids, commonly termed phospholipids, their by-product lysophospholipids, and sphingolipids are key components of the cellular membrane; remarkably, phospholipids are involved in the metabolism of cell signaling. Phospholipids are essential for the biosynthesis of lipoproteins. As reported in Table 5 , in patients with IBD, circulating phospholipids were found decreased in various studies (Bjerrum et al., 2010 (Bjerrum et al., , 2017 Fan et al., 2015; Kolho et al., 2017; Scoville et al., 2018; Tefas et al., 2019 Tefas et al., , 2020 . Factors, such as the compromised integrity of the intestinal mucosa, TNF-α, NF-kB, mitogenactivated protein kinase (MAPK) pathway, and peroxisome proliferator-activated receptor (PPAR) signaling, seem to be closely implicated in phospholipids depletion. Glycerophosphocholine was significantly decreased in two subsequent studies (Bjerrum et al., 2010 (Bjerrum et al., , 2017 ; more recently, in patients with extensive UC and colonic CD, tetracosanoic acid, phosphatidylcholine, (PC) lysophosphatidylcholine (LPC), sphingomyelin (SM), and diacylglycerol were found decreased compared with healthy controls; interestingly, saturated LPC (18:2) was found decreased whereas polyunsaturated LPC (20:4) and LPC (22:6) increased (Tefas et al., 2019 (Tefas et al., , 2020 . It is likely that the anti-inflammatory polyunsaturated LPC effectively antagonized the pro-inflammatory activity of saturated LPC. Two studies found sphingolipids significantly reduced in patients with IBD (Fan et al., 2015; Kolho et al., 2017) . The significant depletion in sphingolipids may be the result of the increased activity of sphingomyelinases, which are activated in IBD by the combined action of TNF-α, NF-kB, and IFN-γ (Schütze et al., 1992) .

Phospholipids metabolism is strongly influenced by COVID-19 and by the severity of the disease ; data emerging from the literature suggest that SARS-CoV-2 infection promotes the downregulation of most phospholipids and sphingolipids (Table 5) , while various lysophospholipids are either overexpressed or unchanged (Barberis et al., 2020; Shen et al., 2020; Song et al., 2020; Wu et al., 2020; Schwarz et al., 2021) . The downregulation of phospholipids may originate from the liver impairment in patients with severe COVID-19, whereas lysophospholipids upregulation is the result of the increased activity of phospholipase A 2 . Low-risk infected patients are well discriminated from non-infected individuals by high levels of phosphatidylcholine (PC38:8), phosphatidylethanolamine (PE38:4), and phosphatidylglycerol (PG20:5). In patients with COVID-19, the predominance of inflammation over the macrophage-driven anti-inflammatory response leads to the underexpression of sphingosine 1-phosphate (Shen et al., 2020; Song et al., 2020) . The considerable number of lipids belonging to any lipid class gives a limited value to the definition of upregulation and downregulation of phospholipids, lysophospholipids, and sphingolipids in COVID-19; recently, a targeted lipidomic analysis measured a considerable number of phospholipids (n = 90), lysophospholipids (n = 14), and sphingolipids (n = 15), discovering that certain lipids decrease and other increase within the same lipid class (Caterino et al., 2021) .

Arachidonic acid is a 20-carbon chain belonging to the ω-6 (n-6) polyunsaturated fatty acids (PUFAs); it is obtained from food and then incorporated in phospholipids (Tallima and El Ridi, 2017) . Arachidonic acid is the primary precursor for the biosynthesis of eicosanoids, a complex family of lipid signaling mediators including but not limited to leukotrienes, prostaglandins, thromboxane, and prostacyclin A 2 (Calder, 2020) . By the cleavage of arachidonic acid from membrane phospholipids, phospholipases A 2 -IID, -IIF, -III, and -X initiate the arachidonic acid cascade and eicosanoid production (Murakami et al., 2020) . Eicosanoids are generated by three main pathways, namely, cyclooxygenases, lipoxygenases, and cytochrome P-450 epoxygenase pathways (Dennis and Norris, 2015) . Beyond their crucial role in a broad range of physiological processes, eicosanoids are involved in the pathogenesis of IBD (Alhouayek et al., 2021) . During the acute phase of the disease, their concentration significantly increases within the inflamed intestinal mucosa (Wallace, 2019) . In patients with IBD, arachidonic acid was increased in feces (Jansson et al., 2009) and decreased in the blood (Table 5) ; these variations were often associated with the exacerbation of the disease activity (Esteve-Comas et al., 1992; Scoville et al., 2018; Lai et al., 2019; Manfredi et al., 2019; Gallagher et al., 2021) . Based on current knowledge, the decrease of circulating arachidonic acid in IBD might be related to the increased synthesis of eicosanoids in the gut (Shores et al., 2011) . SARS-CoV-2 infection induces the overexpression of phospholipase A 2 , especially in macrophages, T, and B cells; as a consequence, the biosynthesis of arachidonic acid is upregulated in patients with COVID-19 ( Table 5 ). The arachidonic acid upregulation positively correlates with the IL-6 concentration and the disease's severity (Barberis et al., 2020; Thomas et al., 2020; Schwarz et al., 2021) . In patients with COVID-19 and severe liver injury, however, arachidonic acid may be downregulated (Shen et al., 2020) . Arachidonic acid is a potent antiviral PUFA that can inactivate the enveloped viruses, including SARS-CoV-2 (Hoxha, 2020); human cells infected by HCoV-229E and MERS-CoV are inhibited by arachidonic acid (Yan et al., 2019) . The increased activity of the cytosolic phospholipase A 2 α (cPLA 2 α) in cells infected by SARS-CoV-2 generates the overproduction of lysophospholipids that are essential for the viral replication (Casari et al., 2021) ; the pharmacological inhibition of cPLA 2 α in human Huh-7 cells infected with coronavirus 229E drastically reduces the viral RNA synthesis, blocking an early step in the replication cycle (Müller et al., 2018) . This finding opens new perspectives on the effective treatment of SARS-CoV-2 infection. A recent study performed a targeted lipidomic analysis of bronchoalveolar lavages fluids (BALs) from patients with severe COVID-19 (Archambault et al., 2021) . The most relevant finding was the significant increase in several bioactive lipids, such as thromboxane, leukotrienes, and 15-lipoxygenase metabolites derived from linoleic acid, linolenic acid, and dihomo-γ-linolenic acid ( Table 5) . During the early stage of inflammation, the enzymatic oxygenation of essential fatty acids, including arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid, generates a class of bioactive lipids, the so-called specialized pro-resolving mediators (SPMs; Serhan et al., 2000) . This class includes lipoxins, resolvins, maresins, and protectins (Basil and Levy, 2016) . Interestingly, BALs from patients with severe COVID-19 were also marked by the increase in SPMs. Increased levels of pro-inflammatory bioactive lipids and anti-inflammatory SPMs have also been reported in serum samples collected from hospital inpatients with a confirmed diagnosis of COVID-19 (Turnbull et al., 2022) .

IBD and COVID-19 are characterized by gut dysbiosis associated with impaired gut barrier function and immune-mediated chronic inflammation. However, COVID-19 can rapidly evolve to multisystemic organ damage due to a dysregulated, fulminant inflammatory response, the so-called "cytokine storm" (Jain, 2020; Hu et al., 2021) . The evident imbalance between the number of studies on gut microbiota in IBD and that in SARS-CoV-2 does not exclude a reliable data analysis; we noticed more similarities than differences in gut microbial alterations between IBD and COVID-19 ( Table 1) . The depletion in F. prausnitzii, E. rectale, R, bromii, Lachnospiraceae, C. leptum (cluster IV) , and the overgrowth of Enterococcus, E. coli, Shigella, P. mirabilis, Fusobacterium, Veillonellaceae are common patterns of dysbiosis, playing a key role in the severity and clinical outcome of IBD and COVID-19. An intriguing dissimilarity between IBD and COVID-19 is the abundance of A. muciniphila (Table 1) , a Gram-negative bacterium belonging to the Verrucomicrobia phylum. A. muciniphila colonizes the mucus layer close to gut epithelial cells and is able to degrade mucin sugars and the protein backbone by specific enzymes, such as sialidases and fucosidases, providing carbon and nitrogen for bacteria unable to produce these enzymes (van Passel et al., 2011) . Mucus degradation by A. muciniphila generates SCFAs, which are strongly involved in promoting host metabolic health. Therefore, A. muciniphila has several beneficial effects on host health by reducing inflammation, stimulating mucin biosynthesis and mucus thickness, preserving the integrity of the mucosal barrier, increasing the expression of tight junction proteins (e.g., occluding), and modulating the intestinal adaptative immune response (Ottman et al., 2017; Ansaldo et al., 2019; Ashrafian et al., 2019; Liu et al., 2021) . The depletion of A. muciniphila in IBD (Table 1) , reported by several studies, confirms the well-known inverse relationship between this bacterium and IBD (Rajilić-Stojanović et al., 2013) ; on the other hand, the enrichment in A. muciniphila in patients with COVID-19 has been associated with that of opportunistic pathogens, such as Enterococcus, Staphylococcus, Serratia, Collinsella, Actinomyces, and many others (Gaibani et al., 2021) . Concerns emerge about results on the probiotic strains Lactobacilli and Bifidobacteria, especially in patients with COVID-19 (Table 1) . These strains are Gram-positive, non-spore-forming, lactic acid producer bacteria with the antiviral activity performed by various mechanisms, including the synthesis of antiviral inhibitory metabolites, the upregulation of the protective immune responses, and by competing for nutrients and colonization sites with the virus and, more extensively, with pathogens (Kesika et al., 2021) . Five studies reported Lactobacillus enrichment in patients with COVID-19 (Table 1) , confuting the general notion that gut dysbiosis due to severe infections promotes the depletion of these strains (Harper et al., 2021) . Very few data support the depletion of Lactobacillus and Bifidobacterium in patients with COVID-19. Two articles cited in the PubMed library, written in Chinese with the same English abstract and the same digital object identifier (doi), described gut dysbiosis in "some patients" with COVID-19 marked by the decrease in Lactobacillus and Bifidobacterium abundance (Xu et al., 2020a,b) . Clearly, these data are unreliable. Therefore, further studies are required to elucidate the significance of Lactobacillus and Bifidobacterium enrichment in COVID-19.

Metabolomics reveals considerable similarities in the tryptophan metabolism between IBD and COVID-19 (Table 3) . In IBD, the increase in quinolinic acid is associated with the Frontiers in Microbiology | www.frontiersin.org decrease in picolinic acid, a non-selective metal ion chelating agent with antimicrobial, antiviral, and antifungal activity formed by a non-enzymic cyclization of aminomuconic acid semialdehyde. In COVID-19, the increase in quinolinic acid is associated with the increase of kynurenic acid; the biochemical mechanism underlying this unusual association should be clarified. In fact, quinolinic acid and kynurenic acid are closely related to each other by an inverse relationship that becomes imbalanced in various diseases. In COVID-19, the increase in picolinic acid reflects the activation of the enzymatic conversion of 2-amino-3-carboxymuconate-6-semialdehyde (ACMS) to 2-aminomuconic-6-semialdehyde. In turn, the latter undergoes either non-enzymatic cyclization to form picolinic acid or enzymatic transformation to 2-aminomuconic acid, yielding acetyl-CoA (Badawy, 2017) . It is unclear why picolinic acid is increased in COVID-19, taking into account the alteration of brain functions during the disease (Chou et al., 2021; Marshall, 2021) . It is reasonable to assume that the limited number of metabolic differences between IBD and COVID-19 (Tables 4, 5), for example, blood arachidonic acid, originates from the acute systemic damage and impairment of organs, tissues, and biological systems (e.g., coagulation) in COVID-19, while IBD remains a chronic disease localized in the gastrointestinal tract with a broad spectrum of extraintestinal symptoms and comorbidities (Argollo et al., 2019) . Emerging evidence indicates the role of the microbiome in modulating the immune response to vaccination and the role of metabolic profile in predicting vaccination outcome (Hagan et al., 2019; Alexander et al., 2021) . Therefore, microbiomics and metabolomics may be considered powerful tools for the early identification and monitoring of individuals at risk of adverse events, for example, fragile individuals or patients with severe chronic diseases. Since the COVID-19 pandemic is far from over, SARS-CoV-2 vaccination is the mainstay for preventing the COVID-19 spread. As a result, there is the need to extend SARS-CoV-2 vaccination to any adult or young subject, even if affected by pre-existing chronic diseases, such as IBD (Alexander et al., 2021) . Therefore, deciphering the individual metabolic and microbial fingerprint in IBD is crucial to define an effective strategy for the safe administration of the vaccine (e.g., to discover any metabolic/microbial alteration induced by recent steroid or rituximab therapy), to manage vaccinated individuals, and to avoid any possible adverse effect in individuals at risk . On the other hand, deciphering the individual metabolic and microbial fingerprint in patients with IBD with COVID-19 may considerably improve the therapeutic approach, preventing the risk of adverse outcomes.

GC and FB contributed to the conception and design of the study. VF conceptualized and performed the modeling. GC wrote the first draft of the manuscript. MM supervised the manuscript and wrote the final version of the paper. All authors contributed to the article and approved the submitted version.

Frontiers in Microbiology | www.frontiersin.org

Gut microbiota regulation of tryptophan metabolism in health and disease

Neuropathy in COVID-19 associated with dysbiosis-related inflammation

Microbial imbalance in inflammatory bowel disease patients at different taxonomic levels

Systematic review: the gut microbiome and its potential clinical application in inflammatory bowel disease

SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD clinical research group position statement

Bioactive lipids in inflammatory bowel diseases -From pathophysiological alterations to therapeutic opportunities

Patients with inflammatory bowel disease are not at increased risk of COVID-19: a large multinational cohort study

Low risk of severe COVID-19 in patients with inflammatory bowel disease: keep calm and take stock

Urine metabolome profiling of immunemediated inflammatory diseases

Dysbiosis of gut microbiota in inflammatory bowel disease: current therapies and potential for microbiota-modulating therapeutic approaches

Faecal microbiota profile of Crohn's disease determined by terminal restriction fragment length polymorphism analysis

Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages

Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells

Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis

High levels of eicosanoids and docosanoids in the lungs of intubated COVID-19 patients

Lower incidence of COVID-19 in patients with inflammatory bowel disease treated with non-gut selective biologic therapy

Comorbidities in inflammatory bowel disease: a call for action

Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice

Metabolomics: The stethoscope for the twenty-first century

The incidence and outcomes of COVID-19 in IBD patients: A rapid review and meta-analysis

Tryptophan availability for kynurenine pathway metabolism across the life span: control mechanisms and focus on aging, exercise, diet and nutritional supplements

Large-scale plasma analysis revealed new mechanisms and molecules associated with the host response to SARS-CoV-2

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

MAPK interacts with occludin and mediates EGF-induced prevention of tight junction disruption by hydrogen peroxide

Smokers with active Crohn's disease have a clinically relevant dysbiosis of the gastrointestinal microbiota

Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn's disease: a randomized controlled trial

Seroprevalence of SARS-CoV2 in IBD patients treated with biologic therapy

Metabonomics in ulcerative colitis: diagnostics, biomarker identification, and insight into the pathophysiology

Metabonomics uncovers a reversible proatherogenic lipid profile during infliximab therapy of inflammatory bowel disease

The specific metabolome profiling of patients infected by SARS-COV-2 supports the key role of tryptophan-nicotinamide pathway and cytosine metabolism

The role of acetoacetate in Amadori product formation of human serum albumin

Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis

Fecal amino acid analysis can discriminate De novo treatment-Naïve pediatric inflammatory bowel disease from controls

COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm

SECURE-IBD database public data update

Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry

SARS-CoV-2 infection dysregulates the metabolomic and lipidomic profiles of serum

Dissecting lipid metabolism alterations in SARS-CoV-2

Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19

Partners of patients with ulcerative colitis exhibit a biologically relevant dysbiosis in fecal microbial metacommunities

Adherent-invasive E. coli: update on the lifestyle of a troublemaker in Crohn's disease

Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: systematic review and meta-analysis

The predominant site of bacterial translocation across the intestinal mucosal barrier occurs at the advancing disease margin in Crohn's disease

Global incidence of neurological manifestations Among patients hospitalized With COVID-19 -a report for the GCS-NeuroCOVID consortium and the ENERGY consortium

Ranking microbiome variance in inflammatory bowel disease: a large longitudinal intercontinental study

Glutamine: metabolism and immune function, supplementation and clinical translation

Molecular mechanisms of glutamine action

SARS-CoV-2 and immune-microbiome interactions: lessons from respiratory viral infections

Systematic review on inflammatory bowel disease patients with coronavirus disease 2019: it is time to take stock

Serum and urine metabolomic fingerprinting in diagnostics of inflammatory bowel diseases

Variability of core microbiota in newly diagnosed treatment-naïve paediatric inflammatory bowel disease patients

Microbiota modulation of the gut-lung axis in COVID-19

Eicosanoid storm in infection and inflammation

New insights into the physiopathology of COVID-19: SARS-CoV-2-associated gastrointestinal illness

Molecular analysis of the gut microbiota of identical twins with Crohn's disease

Challenges in paediatric inflammatory bowel diseases in the COVID-19 time

A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites

Understanding the pathophysiological changes via untargeted metabolomics in COVID-19 patients

The gut microbiome: relationships with disease and opportunities for therapy

Adherent-invasive Escherichia coli production of cellulose influences iron-induced bacterial aggregation, phagocytosis, and induction of colitis

The end products of the metabolism of aromatic amino acids by clostridia

Plasma polyunsaturated fatty acid pattern in active inflammatory bowel disease

Risk factors associated with day-30 mortality in patients over 60 years old admitted in ICU for severe COVID-19: the senior-COVID-Rea multicentre survey protocol

Lipidomic profiling in inflammatory bowel disease: comparison Between ulcerative colitis and Crohn's disease

Seven secrets of COVID-19: fever, ACE2 receptors, gut-lung axis, metabolomics, microbiomics, probiotics, diet

Fecal beta-D-galactosidase production and bifidobacteria are decreased in Crohn's disease

How to manage COVID-19 vaccination in immune-mediated inflammatory diseases: an expert opinion by IMIDs study group

Longitudinal analyses of gut mucosal microbiotas in ulcerative colitis in relation to patient age and disease severity and duration

Inflammatory bowel disease presentation and diagnosis

Purine, kynurenine, neopterin and lipid peroxidation levels in inflammatory bowel disease

Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases

Gut microbiome structure and metabolic activity in inflammatory bowel disease

Metabolomics profiling of critically ill coronavirus disease 2019 patients: identification of diagnostic and prognostic biomarkers

Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn's disease

The gut microbiota of critically ill patients With COVID-19

Novel fecal biomarkers That precede clinical diagnosis of ulcerative colitis

Metabolomic analysis in inflammatory bowel disease: a systematic review

Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism

The treatment-naive microbiome in new-onset Crohn's disease

Quantitative assessment of the human gut microbiome using multitag pyrosequencing

Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region

Interleukin-22 protects intestinal stem cells against genotoxic stress

Alterations of the gut microbiota in patients with coronavirus disease 2019 or H1N1 influenza

Potential intestinal infection and faecal-oral transmission of SARS-CoV-2

Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans

Dynamics of the human gut microbiome in inflammatory bowel disease

Viral infections, the microbiome, and probiotics. Front

Amino acids exhibit antiinflammatory effects in human monocytic leukemia cell line, THP-1 cells

Fecal multi-omics analysis reveals diverse molecular alterations of gut ecosystem in COVID-19 patients

The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine

Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings

Altered fecal bacterial composition correlates with disease activity in inflammatory bowel disease and the extent of IL8 induction

Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease

Decreased plasma histidine level predicts risk of relapse in patients with ulcerative colitis in remission

Bacteriome and Mycobiome interactions underscore microbial dysbiosis in familial Crohn's disease

Histidine in health and disease: metabolism, physiological importance, and use as a supplement

What about COVID-19 and arachidonic acid pathway?

The cytokine storm and COVID-19

Multi-omics analysis of inflammatory bowel disease

Role of gut microbiome in COVID-19: An insight into pathogenesis and therapeutic potential

Risk of common infections in people with inflammatory bowel disease in primary care: a population-based cohort study

A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients

Fecal amino acid analysis in newly diagnosed pediatric inflammatory bowel disease: a multicenter case-control study

Effect of COVID-19 on the organs

Metabolomics reveals metabolic biomarkers of Crohn's disease

Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives

Alterations of mucosal microbiota in the colon of patients with inflammatory bowel disease revealed by real time polymerase chain reaction amplification of 16S ribosomal ribonucleic acid

Clostridium leptum group bacteria abundance and diversity in the fecal microbiota of patients with inflammatory bowel disease: a case-control study in India

Dysbiosis of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray

Using updated PubMed: new features and functions to enhance literature searches

Dietary and metabolomic determinants of relapse in ulcerative colitis patients: a pilot prospective cohort study

The antiviral potential of probiotics-a review on scientific outcomes

Alteration of gut microbiota in inflammatory bowel disease (IBD): cause or consequence? IBD treatment targeting the gut microbiome

The roles of glutamine in the intestine and its implication in intestinal diseases

Integrative modeling of quantitative plasma lipoprotein, metabolic, and amino acid data reveals a multiorgan pathological signature of SARS-CoV-2 infection

Complex host genetics influence the microbiome in inflammatory bowel disease

Endocytosis and Transcytosis of SARS-CoV-2 across the intestinal epithelium and other tissue barriers

A novel gas chromatography mass spectrometry-based serum diagnostic and assessment approach to ulcerative colitis

Faecal and serum metabolomics in paediatric inflammatory bowel disease

Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome

Effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS-induced colitis

Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India

Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes

Serum metabolomics identifies altered bioenergetics, signaling cascades in parallel with exposome markers in Crohn's disease

Aryl hydrocarbon receptor and intestinal immunity

CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

SARS-CoV-2 productively infects human gut enterocytes

Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in Crohn's disease and ulcerative colitis

Systemic perturbations in amine and kynurenine metabolism associated Frontiers in Microbiology | www

with acute SARS-CoV-2 infection and inflammatory cytokine responses

Characteristics and pathogenic role of adherent-invasive Escherichia coli in inflammatory bowel disease: potential impact on clinical outcomes

Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8+ T cells

Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD

Altered lipid profile, lipoprotein composition, and oxidant and antioxidant status in pediatric Crohn disease

COVID-19 infection may cause ketosis and ketoacidosis

Molecular-phylogenetic characterization of the microbiota in ulcerated and non-ulcerated regions in the patients with Crohn's disease

Metabolomics: A primer

Transcriptomics and metabolomics reveal the adaption of Akkermansia muciniphila to high mucin by regulating energy homeostasis

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

Fecal and mucosal microbiota profiling in irritable bowel syndrome and inflammatory bowel disease

Inflammatory bowel disease is associated with higher seroprevalence rates of antibodies against SARS-CoV-2

Chemotaxonomic analysis of bacterial populations colonizing the rectal mucosa in patients with ulcerative colitis

A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis

Succinate receptor mediates intestinal inflammation and fibrosis

Gut microbiota dysbiosis is a crucial player for the poor outcomes for COVID-19 in elderly, diabetic and hypertensive patients

Hypoxia-inducible factors and the response to hypoxic stress

Integrated serum proteins and fatty acids analysis for putative biomarker discovery in inflammatory bowel disease

Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach

Disease severity and immune activity relate to distinct Interkingdom gut microbiome states in ethnically distinct ulcerative colitis patients

Rapid and noninvasive metabonomic characterization of inflammatory bowel disease

COVID and the brain: researchers zero in on how damage occurs

Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer

Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death

An overview of phenylalanine and tyrosine kinetics in humans

A fatal case of COVID-19 pneumonia occurring in a patient with severe acute ulcerative colitis

Survival factors and metabolic pathogenesis in elderly patients (≥65) with COVID-19: A multi-center study

Metabolomic/lipidomic profiling of COVID-19 and individual response to tocilizumab

Computational modelling provides insight into the effects of glyphosate on the shikimate pathway in the human gut microbiome

Alterations in the gut microbiome of children with severe ulcerative colitis

Succinate: a metabolic signal in inflammation

Highlighting new phylogenetic specificities of Crohn's disease microbiota

Are patients with inflammatory bowel disease at increased risk for Covid-19 infection?

Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract

The gut microbiotabrain axis in behaviour and brain disorders

Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

Histidine: a systematic review on metabolism and physiological effects in human and different animal species

Incidence and persistence of viral shedding in COVID-19 post-acute patients With Negativized pharyngeal swab: a systematic review

Inhibition of cytosolic phospholipase A2α impairs an early step of coronavirus replication in cell culture

Updating phospholipase A2 biology

Could metabolomics drive the fate of COVID-19 pandemic? A narrative review on lights and shadows

Prevalence of the pathobiont adherent-invasive Escherichia coli and inflammatory bowel disease: a systematic review and meta-analysis

Distinct microbiotas are associated with ileum-restricted and coloninvolving Crohn's disease

Genome sequence of adherent-invasive Escherichia coli and comparative genomic analysis with other E. coli pathotypes

Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis

Targeting immune cell circuits and trafficking in inflammatory bowel disease

COVID-19 and immunomodulation in IBD

Ketone bodies as signaling metabolites

Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies

Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases

Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease

Asymptomatic severe acute respiratory syndrome coronavirus 2 infection in patients with inflammatory bowel disease under biologic treatment

PXR: more than just a master xenobiotic receptor

GC/MS-based profiling of amino acids and TCA cyclerelated molecules in ulcerative colitis

Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease

Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function

Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients

Adherent-invasive Escherichia coli in inflammatory bowel disease

An immune therapy model for effective treatment on inflammatory bowel disease

A microbial signature for Crohn's disease

The role of glutamine in the complex interaction between gut microbiota and health: a narrative review

Impact of ethnicity, geography, and disease on the microbiota in health and inflammatory bowel disease

Plasma nuclear magnetic resonance metabolomics discriminates between high and low endoscopic activity and predicts progression in a prospective cohort of patients with ulcerative colitis

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

Direct evidence of active SARS-CoV-2 replication in the intestine

The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells

Phylogenetic analysis of dysbiosis in ulcerative colitis during remission

Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (secretor) genotype

Transcriptional activity of the dominant gut mucosal microbiota in chronic inflammatory bowel disease patients

Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells

L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases

Microbial tryptophan catabolites in health and disease

Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

Abnormal concentration of porphyrins in serum from COVID-19 patients

A. Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients

Dyslipidemia and lipoprotein profiles in patients with inflammatory bowel disease

The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications

The kynurenine pathway: a finger in every pie

Cultureindependent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn's disease

Quantitative metabolomic profiling of serum, plasma, and urine by (1)H NMR spectroscopy discriminates between patients with inflammatory bowel disease and healthy individuals

Chronic immune stimulation may cause moderate impairment of phenylalanine 4-hydroxylase

TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown

Cutting edge: severe SARS-CoV-2 infection in humans is defined by a shift in the serum lipidome, resulting in dysregulation of eicosanoid immune mediators

Microbiota in pediatric inflammatory bowel disease

Alterations in lipid, amino acid, and energy metabolism distinguish Crohn's disease from ulcerative colitis and control subjects by serum metabolomic profiling

Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon

The lung-gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing

The biodiversity and composition of the dominant fecal microbiota in patients with inflammatory bowel disease

Risk for overall infection with anti-TNF and antiintegrin agents used in IBD: A systematic review and meta-analysis

Can ketone bodies inactivate coronavirus spike protein? The potential of biocidal agents against SARS-CoV-2

Crohn's disease differentially affects region-specific composition and aerotolerance profiles of mucosally adherent bacteria

Proteomic and metabolomic characterization of COVID-19 patient sera

The serum metabolome of COVID-19 patients is distinctive and predictive

New insights into the role of fatty acids in the pathogenesis and resolution of inflammatory bowel disease

Low intestinal glutamine level and low glutaminase activity in Crohn's disease: a rational for glutamine supplementation?

Fungal microbiota dysbiosis in IBD

Histidine inhibits oxidative stress-and TNF-alpha-induced interleukin-8 secretion in intestinal epithelial cells

Omics-driven systems interrogation of metabolic dysregulation in COVID-19 pathogenesis

Aromatic amino acids

The relationship Between the serotonin metabolism, gut-microbiota and the gut-brain axis

Urinary NMR metabolomic profiles discriminate inflammatory bowel disease from healthy

The aryl hydrocarbon receptor: multitasking in the immune system

Investigating ketone bodies as immunometabolic countermeasures against respiratory viral infections

The role of dietary nutrients in inflammatory bowel disease

Review of inflammatory bowel disease and COVID-19

L-glutamine inhibits the release of endothelium-derived relaxing factor from the rabbit aorta

Reduced abundance of butyrate-producing bacteria species in the fecal microbial Community in Crohn's disease

Arachidonic acid: physiological roles and potential health benefits -a review

Clinical significance of the correlation between changes in the major intestinal bacteria species and COVID-19 severity

Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18

2019 novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases

The potential of metabolic and lipid profiling in inflammatory bowel diseases: A pilot study

Lipidomic signatures of colonic inflammatory bowel diseases: a pilot study

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease

Serum levels of pro-inflammatory lipid mediators and specialised pro-resolving molecules are increased in SARS-CoV-2 patients and correlate with markers of the adaptive immune response

The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes

Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4

Gram-negative bacteria account for main differences between faecal microbiota from patients with ulcerative colitis and healthy controls

Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome

Intestinal bacteria composition and translocation of bacteria in inflammatory bowel disease

The prevalence of mucosa-associated diffusely adherent Escherichia coli in children with inflammatory bowel disease

High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease

Eicosanoids in the gastrointestinal tract

Analysis of gut microbiome and diet modification in patients with Crohn's disease

Increased proportions of bifidobacterium and the lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease

An evolutionary perspective on immunometabolism

L-glutamine enhances tight junction integrity by activating CaMK kinase 2-AMP-activated protein kinase signaling in intestinal porcine epithelial cells

Determining gut microbial dysbiosis: a review of applied indexes for assessment of intestinal microbiota imbalances

Ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionization quantification of tryptophan metabolites and markers of gut health in serum and plasma-application to clinical and epidemiology cohorts

Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine

A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes

Uptake and metabolism of plasma glutamine by the small intestine

Altered oral and gut microbiota and its association with SARS-CoV-2 viral load in COVID-19 patients during hospitalization

Indoleamine 2, 3-dioxygenase regulation of immune response (review)

Plasma metabolomic and lipidomic alterations associated with COVID-19

Evidence for gastrointestinal infection of SARS-CoV-2

Management of corona virus disease-19 (COVID-19): the Zhejiang experience

Management of COVID-19: the Zhejiang experience. Zhejiang Da Xue Xue Bao Yi Xue Ban

The human microbiome and COVID-19: A systematic review

Characterization of the Lipidomic profile of human coronavirus-infected cells: implications for lipid metabolism remodeling upon coronavirus replication

Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms

Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity

Bimodal plasma metabolomics strategy identifies novel inflammatory metabolites in inflammatory bowel diseases

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19

Microbial network disturbances in relapsing refractory Crohn's disease

Glutamine reliance in cell metabolism

The ketone metabolite b-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease

Defining the metabolome: size, flux, and regulation

Correlation between intestinal flora and serum inflammatory factors in patients with Crohn's disease

Endogenous Indole pyruvate pathway for tryptophan metabolism mediated by IL4I1

Elucidation of Proteus mirabilis as a key bacterium in Crohn's disease inflammation

1H NMRbased spectroscopy detects metabolic alterations in serum of patients with early-stage ulcerative colitis

Structural shifts of mucosa-associated lactobacilli and Clostridium leptum subgroup in patients with ulcerative colitis

Interaction between microbiota and immunity in health and disease

Global genome analysis of the shikimic acid pathway reveals greater gene loss in host-associated than in free-living bacteria

Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19

The gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease

Alterations in gut microbiota of patients With COVID-19 during time of hospitalization

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.