Review Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2021; 27(13): 1255-1266
Published online Apr 7, 2021. doi: 10.3748/wjg.v27.i13.1255
Coronavirus disease–2019 and the intestinal tract: An overview
Gabriela Gama Freire Alberca, Rosa Liliana Solis-Castro, Maria Edith Solis-Castro, Ricardo Wesley Alberca
Gabriela Gama Freire Alberca, Department of Microbiology, Institute of Biomedical Sciences-University of São Paulo, São Paulo 05508-000, Brazil
Rosa Liliana Solis-Castro, Departamento Académico de Biología Bioquímica, Facultad de Ciencias de la Salud, Universidad Nacional de Tumbes, Pampa Grande 24000, Tumbes, Peru
Maria Edith Solis-Castro, Departamento Académico de Medicina Humana, Facultad de Ciencias de la Salud, Universidad Nacional de Tumbes, Pampa Grande 24000, Tumbes, Peru
Ricardo Wesley Alberca, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
ORCID number: Gabriela Gama Freire Alberca (0000-0002-3467-5562); Rosa Liliana Solis-Castro (0000-0002-1813-8644); Maria Edith Solis-Castro (0000-0001-5514-849X); Ricardo Wesley Alberca (0000-0002-3602-3306).
Author contributions: All authors contributed to the conception, writing, and review of the article and approved the submitted version.
Supported by RWA holds a fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), No. 19/02679-7.
Conflict-of-interest statement: The authors declare having no conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ricardo Wesley Alberca, PhD, Academic Research, Research Fellow, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, 455-Cerqueira César, São Paulo 01246-903, Brazil. ricardowesley@gmail.com
Received: January 20, 2021
Peer-review started: January 20, 2021
First decision: February 9, 2021
Revised: February 10, 2021
Accepted: March 8, 2021
Article in press: March 8, 2021
Published online: April 7, 2021

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can progress to a severe respiratory and systemic disease named coronavirus disease–2019 (COVID-19). The most common symptoms are fever and respiratory discomfort. Nevertheless, gastrointestinal infections have been reported, with symptoms such as diarrhea, nausea, vomiting, abdominal pain, and lack of appetite. Importantly, SARS-CoV-2 can remain positive in fecal samples after nasopharyngeal clearance. After gastrointestinal SARS-CoV-2 infection and other viral gastrointestinal infections, some patients may develop alterations in the gastrointestinal microbiota. In addition, some COVID-19 patients may receive antibiotics, which may also disturb gastrointestinal homeostasis. In summary, the gastrointestinal system, gut microbiome, and gut-lung axis may represent an important role in the development, severity, and treatment of COVID-19. Therefore, in this review, we explore the current pieces of evidence of COVID-19 gastrointestinal manifestations, possible implications, and interventions.

Key Words: COVID-19, SARS-CoV-2, Gastrointestinal, Microbiota, Antibiotics

Core Tip: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can progress to a severe respiratory and systemic disease named coronavirus disease–2019 (COVID-19). Nevertheless, SARS-CoV-2 can also generate a gastrointestinal infection. In this review, we explore the impact of COVID-19 on the gastrointestinal system, gut microbiome, and the gut-lung axis and the severity and possible implications and interventions in COVID-19 patients.



INTRODUCTION

The coronavirus disease–2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Coronaviruses (CoVs) are a family of single-stranded ribonucleic acid (RNA) viruses; currently six subtypes of CoVs can infect humans. Two CoVs, the Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), are the etiologic agents of the previous epidemics and have caused over 2000 deaths worldwide[1,2].

COVID-19 can cause a systemic and respiratory infection that can lead to death[3]. Since November 2019, SARS-CoV-2 has infected over 80 million people and killed over 1.5 million people worldwide, being declared a pandemic by the World Health Organization[4]. Several comorbidities have been postulated as risk factors for severe COVID-19, such as high age[5], smoking, chronic obstructive pulmonary disease[6], obesity[7], pregnancy[8], and co-infections[9].

SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) to invade the host’s cells. ACE2 and TMPRSS2 are expressed in many different organs in the human body, such as the lungs, heart, liver, kidney, and brain, intestine luminal cells, colonic epithelial cells, and small intestinal enterocytes[10-13]. In addition, SARS-CoV-2 infection has been described in multiple organs, including the lungs, pharynx, heart, liver, brain, kidneys, and gastrointestinal tract[14,15].

COVID-19 AND THE GASTROINTESTINAL TRACT

Gastrointestinal infections have been reported[16] (Table 1), with a lower frequency in comparison with the previous SARS-CoV-1 infection[17]. Nevertheless, SARS-CoV-2 can remain positive in fecal samples after nasopharyngeal clearance and may remain infective[18].

Table 1 Manuscripts describing patients with severe acute respiratory syndrome coronavirus-2 ribonucleic acid detection in rectal swabs or fecal samples.
COVID-19 respiratory manifestations
COVID-19 gastrointestinal clinical manifestations
Percentage of patients with gastrointestinal clinical manifestations
Rectal swabs or fecal samples positive for SARS-CoV-2
Ref.
YesYes65.38%53.42%[16]
YesYes60%50%[122]
YesYes80%90%[123]
YesYes11%22%[124]
YesYes33%80%[125]
YesYesNo data39%[126]
Yes (89 only respiratory/69 respiratory and gastrointestinal)Yes (48 only gastrointestinal/69 respiratory and gastrointestinal)56%54% of a cohort of 22 individuals[127]
YesYesNo data29%[128]
YesYes31%55%[24]
YesYesNo data83%[129]
YesYesNo data25%[130]

The most frequent gastrointestinal symptoms in COVID-19 are diarrhea, nausea, abdominal pain, and lack of appetite[19]. After a viral gastrointestinal infection, some patients may develop alterations on the gastrointestinal microbiota such as an increase of Proteobacteria and a simultaneous reduction of Bacteriodetes[20]. A recent report by Zuo et al[21] identified alterations in the intestinal microbiota of hospitalized patients with COVID-19, with a reduction in beneficial commensals bacteria and an increase in opportunistic pathogens[21]. In addition, Gupta et al[18] verified a reduction in the community richness and microbial diversity in COVID-19 patients with and without diarrhea. The intestinal tissue and feces may also be acting as a reservoir; recent reports have identified that even after negative nasopharyngeal and oropharyngeal swabs test for SARS-CoV-2 RNA, patients could still possess SARS-CoV-2 RNA in the stool samples[16,22]. Another report identified that the duration of COVID-19 symptoms was prolonged in patients with diarrhea and that the stool samples from patients with diarrhea were more frequently positive for virus RNA[23].

Although is not clear the mechanisms responsible for the development of diarrhea in COVID-19, the current hypothesis is that the direct viral infection on the intestinal tissue and local immune response to the virus may be involved. In fact, the detection of SARS-CoV-2 RNA in stool COVID-19 patients may indicate the possibility of fecal-oral transmission[24].

In addition to the SARS-CoV-2 impact on the gut immune response, bacterial co-infections and secondary infection could also occur in COVID-19 patients, implicating the necessary usage of antibiotics[25]. Nevertheless, even in the absence of bacterial co-infections in COVID-19 patients some reports highlighted that the usage of antibiotics is a common clinical practice in COVID-19 patients[25,26], which could also disrupt the gastrointestinal microbiome. Bacterial communities are present in numerous body sites such as the gut, the respiratory system, and skin; therefore, the unnecessary usage of antibiotics may predispose COVID-19 patients to opportunistic infections inside and outside of the gastrointestinal environment.

GUT MICROBIOTA

The microbiota is influenced by environmental factors, food, drugs, and infections[27]. Each microbiota possesses unique characteristics[28,29], differing its composition according to the site in the human body. Many factors influence the microbiome composition such as local pH, temperature, and nutrients[30]. Microorganisms can be found in nearly every niche of the human body[31], but the gastrointestinal tract is the largest interface between the host and microorganisms in the human body. There are approximately 1013-1014 microorganisms in the gastrointestinal tract, with greater genomic content than in the human genome[32].

Microbes and humans have a symbiotic relationship. Commensal microbes are crucial for human health, regulating many physiological functions, degradation of substances, production of metabolites, and immune response[33]. Microorganisms can activate and stimulate the differentiation of T helper cells (Th) 1, Th2, Th17, and T regulatory cells (Treg), which in consequence can regulate the immune response[34,35]. A low-diversity in the intestinal microbiota can increase the susceptibility to local[36] and pulmonary disorders[37].

The microbiome's environment is in constant regulation, modulated by external microorganisms and other non-bacterial compounds, for example, food in the intestinal microbiota and viruses. An abrupt change in the microbiota can generate an imbalance in the commensal bacteria and/or increase opportunistic microbes, increasing the susceptibility to diseases[38,39].

The microbiota is essential for the development of the human immune system and can influence both local and non-local immune responses, such as the gut-lung axis[40]. It is well established that alterations in the gut microbiota can modulate the development of respiratory disease[41].

In patients with gut dysbiosis such as patients with an established intestinal inflammatory disease or obese patients, the intestinal microbiota may be a secondary risk factor for the development of severe COVID-19[7]. Besides, patients with COVID-19 may develop a dysbiosis in the gastrointestinal microbiota[21] and a reduction in short-chain fatty acid-producing bacteria[42].

GUT MICROBIOTA DYSBIOSIS

Disruption of the gut microbiota can trigger inflammatory events that are associated with metabolic dysfunction, obesity, cancer, and neurological disorders[43,44]. The proliferation or reduction in certain microorganisms can increase the stimulation of innate immune receptors, like nucleotide-binding oligomerization domain-like receptors and Toll-like receptors[45]. The stimulation of this receptor triggers several pro-inflammatory signals and the production of cytokine and chemokine, which modulate the adaptive immune system, influencing both local and systemic immune response[43,44].

The activation of Toll-like receptors on immune cells by the microbiota can generate a low-grade systemic inflammation in the host that is associated with a change in metabolic and immunological responses[46]. Alterations in the microbiome are related to the development of diseases such as obesity, inflammatory bowel disease, and cancer[47]. Therefore, SARS-CoV-2 gastrointestinal infections and alteration of gut homeostasis may be implicated in the development of disease and impact immune response to oral vaccines and medicines and the pathogen immune response[48,49].

NUTRITIONAL INTERVENTION

Several reports have highlighted the potential role of nutrients in the modulation of the immune response to SARS-CoV-2 or a direct anti-viral and/or anti-SARS-CoV-2 properties[50-53]. During this pandemic, nutritional aspects such as obesity[7,54], malnutrition[55], and micronutrient deficiency[56,57] have been postulated as risk factors for severe COVID-19. Nevertheless, the composition of the human microbiota is influenced by many factors, including dietary components[41]. Some bacteria can ferment nondigestible carbohydrates (prebiotics), like soluble fibers, to produce short-chain fatty acids (SCFAs). SCFAs can stimulate the growth and/or activity of commensal bacteria and are associated with health benefits. SCFAs can induce the regulation of the intestinal barrier, reduce oxidative stress, control diarrhea, and modulate intestinal motility and also induce a local and systemic anti-inflammatory effect[58,59].

High-fiber diets can induce the proliferation of beneficial commensal microbes, such as Lactobacillus spp. and Bifidobacterium spp. in the gastrointestinal tract[60]. In fact, high-fiber diets may increase immunoglobulin A production and modulate the secretion of interferon-gamma and interleukin (IL)-10[61-63], which could aid in the control of gastrointestinal infections.

Prebiotics may alter the microbiota composition by a mechanism called cross-feeding, when the product of a prebiotic’s fermentation by a microorganism in the microbiota can be used as a substrate by another microorganism[64-66]. Another mechanism that prebiotics can alter the microbiota is through pH alterations. The fermentation products are predominantly acids, which may cause a decrease in the intestinal pH, restraining the growth of acid-sensitive bacteria, such as Bacteroides spp., and promoting butyrate-producing bacteria[67].

SCFAs are divided into acetate, propionate, and butyrate. All SCFAs have potential anti-inflammatory effects with the reduction of prostaglandin E2 and inflammatory cytokines[68]. Acetate can curb the activation of the NLR family pyrin domain containing 3 inflammasome[69]; propionate can inhibit histone deacetylase and reduce lipopolysaccharide-induced inflammation[70]. Butyrate has been associated with anti-cancer properties and reduces pulmonary inflammation[71,72].

Overall, research has demonstrated a potential anti-inflammatory role for SCFAs in both local (intestinal) and non-local inflammation via direct anti-inflammatory effects or modulation of the microbiota[71,73,74].

SCFAs can induce the release of anti-inflammatory cytokines such as IL-10[75,76], promoting the regulation of Th cells and inflammatory diseases[77], including inflammatory bowel disease[78].

Another intervention for the modulation of the gastrointestinal microbiome is via the consumption of probiotics. Probiotics are bacteria that can be ingested and provide a beneficial interaction to the host[79]. Several studies have investigated the effects of probiotics on the gut microbiota[80], with conflicting results involving their ability to graft on the commensal microbiota[81-84]. However, probiotics can produce metabolites that can modify and influence the commensal microbiota, intestinal barrier, and immune system[85,86].

Probiotics can also aid in the prevention or treatment of bacterial[87] and viral infections[88]. The administration of probiotics increases the survival of mice infected with the influenza virus[87]. Besides the influenza virus, studies have demonstrated beneficial protection against respiratory syncytial virus infection[89].

The heath benefit of probiotics in respiratory viral infections is due to the modulation of cytokine production and oxidative stress[90]; therefore, they may possibly be an adjuvant treatment for the aberrant release of pro-inflammatory cytokines, chemokines, and oxidative stress during severe COVID-19[91].

The most used probiotics are Lactobacillus, Bifidobacterium, and Enterococcus[92]. Although there is extensive research demonstrating their health benefits, currently there is a gap in knowledge involving the ideal dosage and comparison among strains of probiotics[93].

DISCUSSION

COVID-19 is a potentially deadly disease, which can infect intestinal cells[13]. SARS-CoV-2 gastrointestinal infections[16] can generate diarrhea, pain, and vomiting[19]. To date, few reports have investigated the possible consequences of gastrointestinal infection by SARS-CoV-2; nevertheless, viral infections can alter the gastrointestinal microbiota[20]. A report by Xu et al[94] identified a reduction in Lactobacillus and Bifidobacterium in fecal samples from COVID-19 patients[94]. Also, the microbiome of COVID-19 patients can be disturbed by the necessary or unnecessary use of antibiotics[34].

Yeoh et al[95] identified that the alteration on the gastrointestinal microbiome in COVID-19 patients was independent of medications. The alterations on the gut microbiome included a reduction in Faecalibacterium prausnitzii, Eubacterium rectale, and bifidobacteria for up to 30 d after SARS-CoV-2 clearance[95].

The microbiota dysbiosis in COVID-19 may be involved in the inflammatory response and may be a persistent problem after COVID-19 resolution, indicating a possible role for nutritional interventions to curb the inflammatory response and reestablish the gastrointestinal homeostasis of COVID-19 patients.

Dietary and nutritional intervention can modulate the immune response, increasing or dampening the anti-viral response[59-62]. Western-style diets (low fiber content) can increase Bacteroidetes and reduce Firmicutes[96] and are linked to the development of obesity[97], a risk factor for severe COVID-19[7]. Although reports have identified an increase in SCFAs in fecal samples from obese individuals[96], SCFAs have been associated with control of appetite[98] and increase energy expenditure[99].

In addition, very low fiber-diets can lower mucus production on the intestine and increase the susceptibility to gastrointestinal infections[39]. Importantly, a change in diet can modify the microbiota composition[100]. The microbial communities are in constant change and are also affected seasonally by food consumption[101]. In fact, a reduction in the consumption of fiber can change the microbiota in as little as 1 d, reducing SCFAs production[102].

In opposition, high fiber-diets increase Firmicutes and Actinobacteria on the gut microbiota[103] and increase the production of SCFAs, which can aid in the reduction of pulmonary inflammation, via the gut-lung axis[41,104,105] and promote a local and systemic anti-inflammatory response via IL-10 production and Treg cells[75,76,106]. The ingestion of probiotics may stabilize or alter the gastrointestinal microbiome, especially after a perturbation of the microbiota such as post usage of antibiotics or gastrointestinal infections[107].

Probiotic treatments with Bacillus subtilis and Enterococcus faecalis have been demonstrated to reduce ventilator-associated pneumonia[108]. Treatment with Lactobacillus rhamnosus can reduce ventilator-associated pneumonia and Clostridium difficile-associated diarrhea in mechanically ventilated patients[109], making it a possible addition to the treatment of patients with severe COVID-19 in intensive care units with assisted mechanical ventilation. Treatment with Lactobacillus may be of particular importance, because respiratory infections may cause a reduction in Lactobacillus, and an increase in Enterobacteriaceae and intestinal IL-17 inflammation[110].

Targeting IL-17 has been postulated as a treatment for COVID-19[111] because of the increase in IL-17 in severe COVID-19 patients compared to moderate COVID-19 patients[111]. IL-17 and IL-17-producing T helper cells (Th17), type three innate lymphoid cells, invariant natural killer cells, and γδ T cells are involved in the immune response of COVID-19[112]. IL-17 receptor is expressed on the surface of many different cells such as neutrophils, eosinophils, epithelial cells, keratinocytes, and fibroblasts[112]. In addition, IL-17 can directly influence the expression of ACE2, SARS-CoV-2 entry’s receptor[113].

The usage of IL-17 blockade, such as monoclonal antibodies against IL-17A and/or IL-17 receptor A, may represent a possible therapeutic option for COVID-19[112]. Nevertheless, IL-17 is an important cytokine in the immune response against Streptococcus pneumoniae and Pseudomonas aeruginosa, common pathogens in respiratory and intestinal tract infections[112,114]. Secondary bacterial infections can occur in the respiratory system following SARS-CoV-2 infection, especially in patients with invasive mechanical ventilation[34]. IL-17 is especially important for intestinal homeostasis[115]. Therefore, treatment with anti-IL-17 should consider the possible risk for an increase in susceptibility for bacterial infections both respiratory and intestinal.

COVID-19 patients may also develop a cytokine storm syndrome, which may induce multi-organ failure and lead to death or long-term consequences[91]. In this context, probiotics or prebiotics treatment have been previously demonstrated anti-inflammatory effects in respiratory infections via the increase in SCFAs[71,73,74,88,116].

SCFAs production and health benefit can be increased by the ingestion of highly fermentable fiber diets[117], probiotics[73], oral administration of drugs like tributyrin (a prodrug of butyrate)[118], or SCFAs directly[119-121].

In this context, the intake of prebiotics and/or probiotics can represent a significant prophylactic intervention and/or recovery of COVID-19 patients.

CONCLUSION

The SARS-CoV-2 infection on the gastrointestinal tract and the long-term consequences of COVID-19 in gastrointestinal homeostasis still needs further investigations. It is clear that SARS-CoV-2 can infect the gastrointestinal tract and impact the intestinal immune response and the gut microbiome. Currently, there is no specific treatment for COVID-19, but investigations on the impact of nutritional intervention via modulation of the immune response or via microbiota are been investigated and may represent a significant prophylactic intervention and/or recovery of COVID.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: Brazil

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P-Reviewer: Khan MKA S-Editor: Fan JR L-Editor: Filipodia P-Editor: Ma YJ

References
1.  V'kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 2021;19: 155-170.  [PubMed]  [DOI]
2.  Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, Liu W, Bi Y, Gao GF. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 2016;24:490-502.  [PubMed]  [DOI]
3.  Alberca GGF, Fernandes IG, Sato MN, Alberca RW. What Is COVID-19? Front Young Minds. 2020;8:74.  [PubMed]  [DOI]
4.  WHO  WHO Coronavirus Disease (COVID-19) Dashboard. [cited July 30, 2020]. Available from: https://covid19.who.int/.  [PubMed]  [DOI]
5.  Alberca RW, Andrade MM de S, Castelo Branco ACC, Pietrobon AJ, Pereira NZ, Fernandes IG, Oliveira LDM, Teixeira FME, Beserra DR, Araujo E, Gozzi-Silva SC, Ramos YÁL, De Brito CA, Arnone M, Orfali RL, Aoki V, Duarte AJDS, Sato MN. Frequencies of CD33+ CD11b+ HLA-DR- CD14- CD66b+ and CD33+ CD11b+ HLA-DR- CD14+ CD66b- cells in peripheral blood as severity immune biomarkers in COVID-19. Front Med (Lausanne) . 2020;7:654.  [PubMed]  [DOI]
6.  Alberca RW, Lima JC, de Oliveira EA, Gozzi-Silva SC, Leuzzi YÁ, Mary De Souza Andrade M, Beserra DR, Oliveira LDM, Castelo Branco ACC, Pietrobon AJ, Pereira NZ, Teixeira FME, Fernandes IG, Benard G, Sato MN. COVID-19 disease course in formers smokers, smokers and COPD patients. Front Physiol. 2020;11:1860.  [PubMed]  [DOI]
7.  Alberca RW, Oliveira LM, Branco ACCC, Pereira NZ, Sato MN. Obesity as a risk factor for COVID-19: an overview. Crit Rev Food Sci Nutr. 2020;1-15.  [PubMed]  [DOI]
8.  Alberca RW, Pereira NZ, Oliveira LMDS, Gozzi-Silva SC, Sato MN. Pregnancy, Viral Infection, and COVID-19. Front Immunol. 2020;11:1672.  [PubMed]  [DOI]
9.  Alberca RW, Yendo TM, Leuzzi Ramos YÁ, Fernandes IG, Oliveira LM, Teixeira FME, Beserra DR, de Oliveira EA, Gozzi-Silva SC, Andrade MMS, Branco ACCC, Pietrobon AJ, Pereira NZ, de Brito CA, Orfali RL, Aoki V, Duarte AJDS, Benard G, Sato MN. Case Report: COVID-19 and Chagas Disease in Two Coinfected Patients. Am J Trop Med Hyg. 2020;103:2353-2356.  [PubMed]  [DOI]
10.  Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Götze O, Verrey F. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015;47:693-705.  [PubMed]  [DOI]
11.  Zhang H, Li HB, Lyu JR, Lei XM, Li W, Wu G, Lyu J, Dai ZM. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection. Int J Infect Dis. 2020;96:19-24.  [PubMed]  [DOI]
12.  Wang J, Zhao S, Liu M, Zhao Z, Xu Y, Wang P, Lin M, Huang B, Zuo X, Chen Z, Bai F, Cui J, Lew A, Zhao J, Zhang Y, Luo H. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism. medRxiv. .  [PubMed]  [DOI]
13.  Dong M, Zhang J, Ma X, Tan J, Chen L, Liu S, Xin Y, Zhuang L. ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. Biomed Pharmacother. 2020;131:110678.  [PubMed]  [DOI]
14.  Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, Braun F, Lu S, Pfefferle S, Schröder AS, Edler C, Gross O, Glatzel M, Wichmann D, Wiech T, Kluge S, Pueschel K, Aepfelbacher M, Huber TB. Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med. 2020;383:590-592.  [PubMed]  [DOI]
15.  Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, Ravelli RBG, Paul van Schayck J, Mykytyn AZ, Duimel HQ, van Donselaar E, Riesebosch S, Kuijpers HJH, Schipper D, van de Wetering WJ, de Graaf M, Koopmans M, Cuppen E, Peters PJ, Haagmans BL, Clevers H. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020;369:50-54.  [PubMed]  [DOI]
16.  Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology 2020; 158: 1831-1833. e3.  [PubMed]  [DOI]
17.  Cheng VC, Hung IF, Tang BS, Chu CM, Wong MM, Chan KH, Wu AK, Tse DM, Chan KS, Zheng BJ, Peiris JS, Sung JJ, Yuen KY. Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome. Clin Infect Dis. 2004;38:467-475.  [PubMed]  [DOI]
18.  Gupta S, Parker J, Smits S, Underwood J, Dolwani S. Persistent viral shedding of SARS-CoV-2 in faeces - a rapid review. Colorectal Dis. 2020;22:611-620.  [PubMed]  [DOI]
19.  Amaral LTW, Brito VM, Beraldo GL, Fonseca EKUN, Yokoo P, Talans A, Oranges Filho M, Chate RC, Baroni RH, Szarf G. Abdominal symptoms as initial manifestation of COVID-19: a case series. Einstein (Sao Paulo). 2020;18:eRC5831.  [PubMed]  [DOI]
20.  Nelson AM, Walk ST, Taube S, Taniuchi M, Houpt ER, Wobus CE, Young VB. Disruption of the human gut microbiota following Norovirus infection. PLoS One. 2012;7:e48224.  [PubMed]  [DOI]
21.  Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, Wan Y, Chung ACK, Cheung CP, Chen N, Lai CKC, Chen Z, Tso EYK, Fung KSC, Chan V, Ling L, Joynt G, Hui DSC, Chan FKL, Chan PKS, Ng SC. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology 2020; 159: 944-955. e8.  [PubMed]  [DOI]
22.  Zhang T, Cui X, Zhao X, Wang J, Zheng J, Zheng G, Guo W, Cai C, He S, Xu Y. Detectable SARS-CoV-2 viral RNA in feces of three children during recovery period of COVID-19 pneumonia. J Med Virol. 2020;92:909-914.  [PubMed]  [DOI]
23.  Wei XS, Wang X, Niu YR, Ye LL, Peng WB, Wang ZH, Yang WB, Yang BH, Zhang JC, Ma WL, Wang XR, Zhou Q. Diarrhea Is Associated With Prolonged Symptoms and Viral Carriage in Corona Virus Disease 2019. Clin Gastroenterol Hepatol 2020; 18: 1753-1759. e2.  [PubMed]  [DOI]
24.  Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, Yin H, Xiao Q, Tang Y, Qu X, Kuang L, Fang X, Mishra N, Lu J, Shan H, Jiang G, Huang X. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5:434-435.  [PubMed]  [DOI]
25.  Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect. 2020;26:1622-1629.  [PubMed]  [DOI]
26.  Miranda C, Silva V, Capita R, Alonso-Calleja C, Igrejas G, Poeta P. Implications of antibiotics use during the COVID-19 pandemic: present and future. J Antimicrob Chemother. 2020;75:3413-3416.  [PubMed]  [DOI]
27.  Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome. Front Microbiol. 2014;5:494.  [PubMed]  [DOI]
28.  Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107-133.  [PubMed]  [DOI]
29.  Lee SM, Kim N, Park JH, Nam RH, Yoon K, Lee DH. Comparative Analysis of Ileal and Cecal Microbiota in Aged Rats. J Cancer Prev. 2018;23:70-76.  [PubMed]  [DOI]
30.  Fiocchi C, Souza HSPD. Microbiota intestinal: sua importância e função. J Bras Med . 2012;100:30-38.  [PubMed]  [DOI]
31.  Torrazza RM, Neu J. The developing intestinal microbiome and its relationship to health and disease in the neonate. J Perinatol. 2011;31:S29-S34.  [PubMed]  [DOI]
32.  Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell . 2006;124:837-848.  [PubMed]  [DOI]
33.  Ma N, Guo P, Zhang J, He T, Kim SW, Zhang G, Ma X. Nutrients Mediate Intestinal Bacteria-Mucosal Immune Crosstalk. Front Immunol. 2018;9:5.  [PubMed]  [DOI]
34.  Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: An update. Clin Exp Immunol . 2010;160:1-9.  [PubMed]  [DOI]
35.  Scudellari M. News Feature: Cleaning up the hygiene hypothesis. Proc Natl Acad Sci USA . 2017;114:1433-1436.  [PubMed]  [DOI]
36.  Ling Z, Li Z, Liu X, Cheng Y, Luo Y, Tong X, Yuan L, Wang Y, Sun J, Li L, Xiang C. Altered fecal microbiota composition associated with food allergy in infants. Appl Environ Microbiol. 2014;80:2546-2554.  [PubMed]  [DOI]
37.  Bisgaard H, Li N, Bonnelykke K, Chawes BLK, Skov T, Paludan-Müller G, Stokholm J, Smith B, Krogfelt KA. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J Allergy Clin Immunol 2011; 128: 646-652. e1-5.  [PubMed]  [DOI]
38.  Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, Gill N, Blanchet MR, Mohn WW, McNagny KM, Finlay BB. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012;13:440-447.  [PubMed]  [DOI]
39.  Saltzman ET, Palacios T, Thomsen M, Vitetta L. Intestinal Microbiome Shifts, Dysbiosis, Inflammation, and Non-alcoholic Fatty Liver Disease. Front Microbiol. 2018;9:61.  [PubMed]  [DOI]
40.  Alberca GGF, Sato MN, Alberca RW. Human microbiota and allergy. Gen Intern Med Clin Innov. 2019;4:1-5.  [PubMed]  [DOI]
41.  Anand S, Mande SS. Diet, Microbiota and Gut-Lung Connection. Front Microbiol. 2018;9:2147.  [PubMed]  [DOI]
42.  Zuo T, Liu Q, Zhang F, Lui GC, Tso EY, Yeoh YK, Chen Z, Boon SS, Chan FK, Chan PK, Ng SC. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut. 2021;70:276-284.  [PubMed]  [DOI]
43.  Boulangé CL, Neves AL, Chilloux J, Nicholson JK, Dumas ME. Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med. 2016;8:42.  [PubMed]  [DOI]
44.  Ding RX, Goh WR, Wu RN, Yue XQ, Luo X, Khine WWT, Wu JR, Lee YK. Revisit gut microbiota and its impact on human health and disease. J Food Drug Anal. 2019;27:623-631.  [PubMed]  [DOI]
45.  Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 2009;21:317-337.  [PubMed]  [DOI]
46.  Yiu JH, Dorweiler B, Woo CW. Interaction between gut microbiota and toll-like receptor: from immunity to metabolism. J Mol Med (Berl). 2017;95:13-20.  [PubMed]  [DOI]
47.  Zuo T, Ng SC. The Gut Microbiota in the Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Front Microbiol. 2018;9:2247.  [PubMed]  [DOI]
48.  Fonseca DM Da, Hand TW, Han SJ, Gerner MY, Zaretsky AG, Byrd AL, Harrison OJ, Ortiz AM, Quinones M, Trinchieri G, Brenchley JM, Brodsky IE, Germain RN, Randolph GJ, Belkaid Y. Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity. Cell. 2015;163:354-366.  [PubMed]  [DOI]
49.  Cieza RJ, Cao AT, Cong Y, Torres AG. Immunomodulation for gastrointestinal infections. Expert Rev Anti Infect Ther. 2012;10:391-400.  [PubMed]  [DOI]
50.  Akasov RA, Khaydukov EV. Mucosal-Associated Invariant T Cells as a Possible Target to Suppress Secondary Infections at COVID-19. Front Immunol. 2020;11:1896.  [PubMed]  [DOI]
51.  Mrityunjaya M, Pavithra V, Neelam R, Janhavi P, Halami PM, Ravindra PV. Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19. Front Immunol. 2020;11:570122.  [PubMed]  [DOI]
52.  Alberca RW, Teixeira FME, Beserra DR, de Oliveira EA, Andrade MMS, Pietrobon AJ, Sato MN. Perspective: The Potential Effects of Naringenin in COVID-19. Front Immunol. 2020;11:570919.  [PubMed]  [DOI]
53.  Taylor EW, Radding W. Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the Viral Mpro Protease Target Host Selenoproteins and Glutathione Synthesis? Front Nutr. 2020;7:143.  [PubMed]  [DOI]
54.  Sahin E, Orhan C, Uckun FM, Sahin K. Clinical Impact Potential of Supplemental Nutrients as Adjuncts of Therapy in High-Risk COVID-19 for Obese Patients. Front Nutr. 2020;7:580504.  [PubMed]  [DOI]
55.  Mertens E, Peñalvo JL. The Burden of Malnutrition and Fatal COVID-19: A Global Burden of Disease Analysis. Front Nutr. 2020;7:619850.  [PubMed]  [DOI]
56.  Olumi AF. Commentary on "identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Urol Oncol. 2014;32:211.  [PubMed]  [DOI]
57.  Name JJ, Souza ACR, Vasconcelos AR, Prado PS, Pereira CPM. Zinc, Vitamin D and Vitamin C: Perspectives for COVID-19 With a Focus on Physical Tissue Barrier Integrity. Front Nutr. 2020;7:606398.  [PubMed]  [DOI]
58.  Leonel AJ, Alvarez-Leite JI. Butyrate: implications for intestinal function. Curr Opin Clin Nutr Metab Care. 2012;15:474-479.  [PubMed]  [DOI]
59.  Wang S, Xiao Y, Tian F, Zhao J, Zhang H, Zhai Q, Chen W. Rational use of prebiotics for gut microbiota alterations: Specific bacterial phylotypes and related mechanisms. J Funct Foods . 2020;66:103838.  [PubMed]  [DOI]
60.  Davani-Davari D, Negahdaripour M, Karimzadeh I, Seifan M, Mohkam M, Masoumi SJ, Berenjian A, Ghasemi Y. Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods. 2019;8.  [PubMed]  [DOI]
61.  Viljanen M, Kuitunen M, Haahtela T, Juntunen-Backman K, Korpela R, Savilahti E. Probiotic effects on faecal inflammatory markers and on faecal IgA in food allergic atopic eczema/dermatitis syndrome infants. Pediatr Allergy Immunol. 2005;16:65-71.  [PubMed]  [DOI]
62.  Pohjavuori E, Viljanen M, Korpela R, Kuitunen M, Tiittanen M, Vaarala O, Savilahti E. Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy. J Allergy Clin Immunol. 2004;114:131-136.  [PubMed]  [DOI]
63.  Marschan E, Kuitunen M, Kukkonen K, Poussa T, Sarnesto A, Haahtela T, Korpela R, Savilahti E, Vaarala O. Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation. Clin Exp Allergy. 2008;38:611-618.  [PubMed]  [DOI]
64.  Belenguer A, Duncan SH, Calder AG, Holtrop G, Louis P, Lobley GE, Flint HJ. Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut. Appl Environ Microbiol. 2006;72:3593-3599.  [PubMed]  [DOI]
65.  Falony G, Vlachou A, Verbrugghe K, De Vuyst L. Cross-feeding between Bifidobacterium longum BB536 and acetate-converting, butyrate-producing colon bacteria during growth on oligofructose. Appl Environ Microbiol. 2006;72:7835-7841.  [PubMed]  [DOI]
66.  Ze X, Duncan SH, Louis P, Flint HJ. Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. ISME J. 2012;6:1535-1543.  [PubMed]  [DOI]
67.  Walker AW, Duncan SH, McWilliam Leitch EC, Child MW, Flint HJ. pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon. Appl Environ Microbiol. 2005;71:3692-3700.  [PubMed]  [DOI]
68.  Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, Yang X, Zhu F, Liu J, Wang S, Monsma F, Vassileva G, Maguire M, Gustafson E, Bayne M, Chou CC, Lundell D, Jenh CH. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol. 2009;15:5549-5557.  [PubMed]  [DOI]
69.  Xu M, Jiang Z, Wang C, Li N, Bo L, Zha Y, Bian J, Zhang Y, Deng X. Acetate attenuates inflammasome activation through GPR43-mediated Ca2+-dependent NLRP3 ubiquitination. Exp Mol Med. 2019;51:83.  [PubMed]  [DOI]
70.  Wang J, Wei Z, Zhang X, Wang Y, Yang Z, Fu Y. Propionate Protects against Lipopolysaccharide-Induced Mastitis in Mice by Restoring Blood-Milk Barrier Disruption and Suppressing Inflammatory Response. Front Immunol. 2017;8:1108.  [PubMed]  [DOI]
71.  Thio CL, Chi PY, Lai AC, Chang YJ. Regulation of type 2 innate lymphoid cell–dependent airway hyperreactivity by butyrate. J Allergy Clin Immunol 2018; 142: 1867-1883. e12.  [PubMed]  [DOI]
72.  Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40:128-139.  [PubMed]  [DOI]
73.  Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019;16:461-478.  [PubMed]  [DOI]
74.  Fang W, Xue H, Chen X, Chen K, Ling W. Supplementation with Sodium Butyrate Modulates the Composition of the Gut Microbiota and Ameliorates High-Fat Diet-Induced Obesity in Mice. J Nutr. 2019;149:747-754.  [PubMed]  [DOI]
75.  Sun M, Wu W, Chen L, Yang W, Huang X, Ma C, Chen F, Xiao Y, Zhao Y, Yao S, Carpio VH, Dann SM, Zhao Q, Liu Z, Cong Y. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun. 2018;9:3555.  [PubMed]  [DOI]
76.  Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.  [PubMed]  [DOI]
77.  Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy-Review of a new approach. Pharmacol Rev . 2003;55:241-269.  [PubMed]  [DOI]
78.  Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science . 2017;356:513-519.  [PubMed]  [DOI]
79.  Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11:506-514.  [PubMed]  [DOI]
80.  Derrien M, van Hylckama Vlieg JE. Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends Microbiol. 2015;23:354-366.  [PubMed]  [DOI]
81.  O'Toole PW, Cooney JC. Probiotic bacteria influence the composition and function of the intestinal microbiota. Interdiscip Perspect Infect Dis. 2008;2008:175285.  [PubMed]  [DOI]
82.  Ki Cha B, Mun Jung S, Hwan Choi C, Song ID, Woong Lee H, Joon Kim H, Hyuk J, Kyung Chang S, Kim K, Chung WS, Seo JG. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012;46:220-227.  [PubMed]  [DOI]
83.  Cox MJ, Huang YJ, Fujimura KE, Liu JT, McKean M, Boushey HA, Segal MR, Brodie EL, Cabana MD, Lynch SV. Lactobacillus casei abundance is associated with profound shifts in the infant gut microbiome. PLoS One. 2010;5:e8745.  [PubMed]  [DOI]
84.  McNulty NP, Yatsunenko T, Hsiao A, Faith JJ, Muegge BD, Goodman AL, Henrissat B, Oozeer R, Cools-Portier S, Gobert G, Chervaux C, Knights D, Lozupone CA, Knight R, Duncan AE, Bain JR, Muehlbauer MJ, Newgard CB, Heath AC, Gordon JI. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med. 2011;3:106ra106.  [PubMed]  [DOI]
85.  Lilly DM, Stillwell RH. Probiotics: growth-promoting factors produced by microorganisms. Science. 1965;147:747-748.  [PubMed]  [DOI]
86.  Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;12:CD006095.  [PubMed]  [DOI]
87.  Wu S, Yoon S, Zhang YG, Lu R, Xia Y, Wan J, Petrof EO, Claud EC, Chen D, Sun J. Vitamin D receptor pathway is required for probiotic protection in colitis. Am J Physiol Gastrointest Liver Physiol. 2015;309:G341-G349.  [PubMed]  [DOI]
88.  Tomosada Y, Chiba E, Zelaya H, Takahashi T, Tsukida K, Kitazawa H, Alvarez S, Villena J. Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. BMC Immunol. 2013;14:40.  [PubMed]  [DOI]
89.  Kobayashi N, Saito T, Uematsu T, Kishi K, Toba M, Kohda N, Suzuki T. Oral administration of heat-killed Lactobacillus pentosus strain b240 augments protection against influenza virus infection in mice. Int Immunopharmacol. 2011;11:199-203.  [PubMed]  [DOI]
90.  Oh NS, Joung JY, Lee JY, Kim Y. Probiotic and anti-inflammatory potential of Lactobacillus rhamnosus 4B15 and Lactobacillus gasseri 4M13 isolated from infant feces. PLoS One. 2018;13:e0192021.  [PubMed]  [DOI]
91.  Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: "When You Come Out of the Storm, You Won't Be the Same Person Who Walked in". Front Immunol. 2020;11:2132.  [PubMed]  [DOI]
92.  Plaza-Díaz J, Ruiz-Ojeda FJ, Vilchez-Padial LM, Gil A. Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases. Nutrients. 2017;9.  [PubMed]  [DOI]
93.  Lehtoranta L, Pitkäranta A, Korpela R. Probiotics in respiratory virus infections. Eur J Clin Microbiol Infect Dis. 2014;33:1289-1302.  [PubMed]  [DOI]
94.  Xu K, Cai H, Shen Y, Ni Q, Chen Y, Hu S, Li J, Wang H, Yu L, Huang H, Qiu Y, Wei G, Fang Q, Zhou J, Sheng J, Liang T, Li L. [Management of corona virus disease-19 (COVID-19): the Zhejiang experience]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49:147-157.  [PubMed]  [DOI]
95.  Yeoh YK, Zuo T, Lui GC-Y, Zhang F, Liu Q, Li AY, Chung AC, Cheung CP, Tso EY, Fung KS, Chan V, Ling L, Joynt G, Hui DS-C, Chow KM, Ng SSS, Li TC-M, Ng RW, Yip TC, Wong GL-H, Chan FK, Wong CK, Chan PK, Ng SC. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut . 2021;Online ahead of print.  [PubMed]  [DOI]
96.  Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA, Donus C, Hardt PD. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring). 2010;18:190-195.  [PubMed]  [DOI]
97.  Namekawa J, Takagi Y, Wakabayashi K, Nakamura Y, Watanabe A, Nagakubo D, Shirai M, Asai F. Effects of high-fat diet and fructose-rich diet on obesity, dyslipidemia and hyperglycemia in the WBN/Kob-Leprfa rat, a new model of type 2 diabetes mellitus. J Vet Med Sci. 2017;79:988-991.  [PubMed]  [DOI]
98.  Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, Anastasovska J, Ghourab S, Hankir M, Zhang S, Carling D, Swann JR, Gibson G, Viardot A, Morrison D, Louise Thomas E, Bell JD. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5:3611.  [PubMed]  [DOI]
99.  Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58:1509-1517.  [PubMed]  [DOI]
100.  Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022-1023.  [PubMed]  [DOI]
101.  Smits SA, Leach J, Sonnenburg ED, Gonzalez CG, Lichtman JS, Reid G, Knight R, Manjurano A, Changalucha J, Elias JE, Dominguez-Bello MG, Sonnenburg JL. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science. 2017;357:802-806.  [PubMed]  [DOI]
102.  Mardinoglu A, Wu H, Bjornson E, Zhang C, Hakkarainen A, Räsänen SM, Lee S, Mancina RM, Bergentall M, Pietiläinen KH, Söderlund S, Matikainen N, Ståhlman M, Bergh PO, Adiels M, Piening BD, Granér M, Lundbom N, Williams KJ, Romeo S, Nielsen J, Snyder M, Uhlén M, Bergström G, Perkins R, Marschall HU, Bäckhed F, Taskinen MR, Borén J. An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans. Cell Metab 2018; 27: 559-571. e5.  [PubMed]  [DOI]
103.  Deehan EC, Duar RM, Armet AM, Perez-Muñoz ME, Jin M, Walter J. Modulation of the Gastrointestinal Microbiome with Nondigestible Fermentable Carbohydrates To Improve Human Health. Microbiol Spectr. 2017;5.  [PubMed]  [DOI]
104.  Negi S, Pahari S, Bashir H, Agrewala JN. Gut Microbiota Regulates Mincle Mediated Activation of Lung Dendritic Cells to Protect Against Mycobacterium tuberculosis. Front Immunol. 2019;10:1142.  [PubMed]  [DOI]
105.  Frati F, Salvatori C, Incorvaia C, Bellucci A, Di Cara G, Marcucci F, Esposito S. The role of the microbiome in asthma: The gut–lung axis. Int J Mol Sci . 2018;20.  [PubMed]  [DOI]
106.  Vieira RS, Castoldi A, Basso PJ, Hiyane MI, Câmara NOS, Almeida RR. Butyrate Attenuates Lung Inflammation by Negatively Modulating Th9 Cells. Front Immunol. 2019;10:67.  [PubMed]  [DOI]
107.  Hemarajata P, Versalovic J. Effects of probiotics on gut microbiota: Mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol . 2013;6:39-51.  [PubMed]  [DOI]
108.  Zeng J, Wang CT, Zhang FS, Qi F, Wang SF, Ma S, Wu TJ, Tian H, Tian ZT, Zhang SL, Qu Y, Liu LY, Li YZ, Cui S, Zhao HL, Du QS, Ma Z, Li CH, Li Y, Si M, Chu YF, Meng M, Ren HS, Zhang JC, Jiang JJ, Ding M, Wang YP. Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial. Intensive Care Med. 2016;42:1018-1028.  [PubMed]  [DOI]
109.  Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am J Respir Crit Care Med. 2010;182:1058-1064.  [PubMed]  [DOI]
110.  Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J Exp Med. 2014;211:2397-2410.  [PubMed]  [DOI]
111.  Wiche Salinas TR, Zheng B, Routy JP, Ancuta P. Targeting the interleukin-17 pathway to prevent acute respiratory distress syndrome associated with SARS-CoV-2 infection. Respirology. 2020;25:797-799.  [PubMed]  [DOI]
112.  Gurczynski SJ, Moore BB. IL-17 in the lung: the good, the bad, and the ugly. Am J Physiol Lung Cell Mol Physiol. 2018;314:L6-L16.  [PubMed]  [DOI]
113.  Song J, Zeng M, Wang H, Qin C, Hou HY, Sun ZY, Xu SP, Wang GP, Guo CL, Deng YK, Wang ZC, Ma J, Pan L, Liao B, Du ZH, Feng QM, Liu Y, Xie JG, Liu Z. Distinct effects of asthma and COPD comorbidity on disease expression and outcome in patients with COVID-19. Allergy. 2021;76:483-496.  [PubMed]  [DOI]
114.  Markou P, Apidianakis Y. Pathogenesis of intestinal Pseudomonas aeruginosa infection in patients with cancer. Front Cell Infect Microbiol. 2014;3:115.  [PubMed]  [DOI]
115.  Li J, Casanova JL, Puel A. Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation. Mucosal Immunol. 2018;11:581-589.  [PubMed]  [DOI]
116.  Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, Ubags N, Fajas L, Nicod LP, Marsland BJ. Dietary Fiber Confers Protection against Flu by Shaping Ly6c- Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism. Immunity 2018; 48: 992-1005. e8.  [PubMed]  [DOI]
117.  Jakobsdottir G, Jädert C, Holm L, Nyman ME. Propionic and butyric acids, formed in the caecum of rats fed highly fermentable dietary fibre, are reflected in portal and aortic serum. Br J Nutr. 2013;110:1565-1572.  [PubMed]  [DOI]
118.  Miyoshi M, Sakaki H, Usami M, Iizuka N, Shuno K, Aoyama M, Usami Y. Oral administration of tributyrin increases concentration of butyrate in the portal vein and prevents lipopolysaccharide-induced liver injury in rats. Clin Nutr. 2011;30:252-258.  [PubMed]  [DOI]
119.  Beauvieux MC, Roumes H, Robert N, Gin H, Rigalleau V, Gallis JL. Butyrate ingestion improves hepatic glycogen storage in the re-fed rat. BMC Physiol. 2008;8:19.  [PubMed]  [DOI]
120.  Shukla G, Bhatia R, Sharma A. Prebiotic inulin supplementation modulates the immune response and restores gut morphology in Giardia duodenalis-infected malnourished mice. Parasitol Res. 2016;115:4189-4198.  [PubMed]  [DOI]
121.  Waller AP, Geor RJ, Spriet LL, Heigenhauser GJ, Lindinger MI. Oral acetate supplementation after prolonged moderate intensity exercise enhances early muscle glycogen resynthesis in horses. Exp Physiol. 2009;94:888-898.  [PubMed]  [DOI]
122.  Jiehao C, Jin X, Daojiong L, Zhi Y, Lei X, Zhenghai Q, Yuehua Z, Hua Z, Ran J, Pengcheng L, Xiangshi W, Yanling G, Aimei X, He T, Hailing C, Chuning W, Jingjing L, Jianshe W, Mei Z. A Case Series of Children With 2019 Novel Coronavirus Infection: Clinical and Epidemiological Features. Clin Infect Dis. 2020;71:1547-1551.  [PubMed]  [DOI]
123.  Lo IL, Lio CF, Cheong HH, Lei CI, Cheong TH, Zhong X, Tian Y, Sin NN. Evaluation of SARS-CoV-2 RNA shedding in clinical specimens and clinical characteristics of 10 patients with COVID-19 in Macau. Int J Biol Sci. 2020;16:1698-1707.  [PubMed]  [DOI]
124.  Peng L, Liu J, Xu W, Luo Q, Chen D, Lei Z, Huang Z, Li X, Deng K, Lin B, Gao Z. SARS-CoV-2 can be detected in urine, blood, anal swabs, and oropharyngeal swabs specimens. J Med Virol. 2020;92:1676-1680.  [PubMed]  [DOI]
125.  Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, Guo Q, Sun X, Zhao D, Shen J, Zhang H, Liu H, Xia H, Tang J, Zhang K, Gong S. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020;26:502-505.  [PubMed]  [DOI]
126.  Chen W, Lan Y, Yuan X, Deng X, Li Y, Cai X, Li L, He R, Tan Y, Gao M, Tang G, Zhao L, Wang J, Fan Q, Wen C, Tong Y, Tang Y, Hu F, Li F, Tang X. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity. Emerg Microbes Infect. 2020;9:469-473.  [PubMed]  [DOI]
127.  Han C, Duan C, Zhang S, Spiegel B, Shi H, Wang W, Zhang L, Lin R, Liu J, Ding Z, Hou X. Digestive Symptoms in COVID-19 Patients With Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes. Am J Gastroenterol. 2020;115:916-923.  [PubMed]  [DOI]
128.  Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020;323:1843-1844.  [PubMed]  [DOI]
129.  Zhang N, Gong Y, Meng F, Shi Y, Wang J, Mao P, Chuai X, Bi Y, Yang P, Wang F. Comparative study on virus shedding patterns in nasopharyngeal and fecal specimens of COVID-19 patients. Sci China Life Sci. 2020;.  [PubMed]  [DOI]
130.  Zhang W, Du RH, Li B, Zheng XS, Yang XL, Hu B, Wang YY, Xiao GF, Yan B, Shi ZL, Zhou P. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020;9:386-389.  [PubMed]  [DOI]