World Journal of Medical Microbiology
Essay | Open Access | 10.31586/wjmm.2022.479

Probiotics and Intestinal Microbiome: A Review of Literature

Hadeer Abdel-Aleem Hassan Mohamed Tawfik1, Mohamed Nazmy Farris2, Rasha Samir2,3, Mohamed Nabil Badawy Al Ashram2, Mina Mikhail Nessim2 and Mohamed Farouk Allam1,*
1
Department of Family Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2
Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3
Department of Internal Medicine, Armed Forces College of Medicine, Cairo, Egypt

Abstract

Probiotics, prebiotics, and synbiotics modify various aspects of local and systemic immune function in multiple experimental models. However, their impact and mechanisms of action are not known across all products or noticed in every population studied, and impacts on in vitro, ex vivo, or other measures of immune function do not necessarily result in an impact on infection and illness in vivo. Studies have discussed that intestinal microbiota has an essential role in enhancing the immune system against viruses. The regulatory impact of the intestinal microbiota on viral infection is connected with local and systemic immune responses and plays a part in congenital and adaptive immune responses. The microbiota composition critically modulates the production of virus-specific CD4 and CD8 T cells and antibody responses following influenza virus infection. The intestinal microbiota has an important role in the stabilizing of immune homeostasis by augmenting the integrity of the barrier functions of the gut mucosa, which is a crucial aspect of systemic immunity. In conclusion, the intestinal microbiota can influence organismal immunity locally and systemically, proximally, and distally. Studying the possible mechanism by which the intestinal microbiota maintains host immunity can provide a clearer understanding of the occurrence and development of diseases.

Review

Historically, the approaches that were popular for targeting and modifying the gut microbiota have involved introducing new bacteria into the community and supporting substrate to feed good community members [1]. The previous approach relies on probiotics, known as “live microorganisms that, when taken in appropriate amounts, reflect a health benefit on the host” [2]. On the contrary, the latter approach depends on prebiotics, defined as “substrates [e.g., nutrients] that are selectively used by host microorganisms [e.g., gut microbes] offering a health benefit” [3]. Though there are few ready prebiotics at present, several oligosaccharides, polysaccharides, and other compounds are considered “candidate prebiotics” [3], because their usage by gut microbes is considered to provide a health benefit. Synbiotics are a mixture of probiotics and prebiotics. Probiotics, prebiotics, and synbiotics modify various aspects of local and systemic immune function in multiple experimental models [4, 5]. However, their impact and mechanisms of action are not known across all products [i.e., bacterial strains, or prebiotic type] or noticed in every population studied, and impacts on in vitro, ex vivo, or other measures of immune function do not necessarily result in an impact on infection and illness in vivo. As such, proof for synthesis and recommendations for utility require attention to the form of the intervention itself, needed outcomes, and target population [6].

Studies have discussed that intestinal microbiota has an essential role in enhancing the immune system against viruses [7, 8]. The regulatory impact of the intestinal microbiota on viral infection is connected with local and systemic immune responses and plays a part in congenital and adaptive immune responses [9, 10]. The intestinal microbiome may prevent or upgrade viral infections, essentially through bacterial components, and metabolites, and control the immune response of the host [11, 12].

Recently, the most popular experimented probiotics include Lactobacillus, Bifidobacteria, Escherichia coli, Enterococcus, etc. Although probiotics' mechanism greatly focuses on the GIT, the action of probiotics is not restricted to the primary infection site. Probiotics can affect the whole body through immune regulation. Probiotics and their metabolites are phagocytosed by small cells to form endosomes in gut-associated lymphoid tissues. These antigens are suddenly produced and held by Dendritic cells (DCs), which can transfer them to local lymph nodes which results in the activation of naive T and B cells to differentiate into various effector subpopulations. This promotes the increase of the relevant cytokines and different immune responses [12].

Pleiotropism of probiotics form enhancement of biological barriers in the GIT and regulating the balance of intestinal microbiota. Probiotics have antimicrobial action, maintain intestinal epithelial cell function, prevent adhesion and growth of pathogens through a space-occupying effect, boost competitive antagonism, secrete antimicrobial substances as bacteriocins, augment the activity of digestive enzymes, and synthesize organic acids [12, 13]. Probiotics enhance the expression and production of mucous glycoproteins through intensified tight junction proteins synthesis between epithelial cells, thereby enhancing epithelial integrity and mechanical barrier function, and inhibiting the displacement of the intestinal microbes and endotoxins. Besides, Probiotics can repair the damaged barrier function through reconstruction of the tight junction complex via increased expression and redistribution of zonula occludens (ZO-2) proteins of the tight junction and protein kinase C (PKC) [13, 14]. The administration of probiotics inhibits cytokine-induced epithelial destruction, which is also assigned to mucosal barrier enhancement. Moreover, probiotics reinforce mucous secretion and provide better barrier function and pathogen exclusion. Probiotics also prevent pathogen adherence by promoting qualitative alterations in intestinal mucins [14, 15]. Excitedly, the bacterial component also degenerates into an AMP, which gives anti-pathogenic characteristics to the host. This provides an example of the great beneficial pleiotropic effect of large surface proteins. Besides, probiotics also activate the production of defensins from epithelia, the small peptides act against bacteria, fungi, and viruses. Additionally, these peptides maintain the barrier function of the gut. Probiotics prevent the binding of the pathogen through steric hindrance at pathogen receptors of the enterocyte. Certain metabolites of probiotics regulate signaling and metabolic pathways in various cells. Different components of the probiotic metabolome (e.g., hydrogen peroxide, amines, organic acids, and bacteriocins) interact with many targets in host metabolic pathways that adjust inflammation, angiogenesis, metastasis, cellular proliferation, differentiation, and apoptosis [15].

Short-chain fatty acids (SCFAs) are the most essential metabolites of the intestinal microbiota, involving acetic acid, propionic acid, and butyric acid. SCFAs decrease the growth and binding of pathogenic microorganisms, enhance the integrity of the epithelium, and further improve systemic host immunity by decreasing the intestinal pH, resulting in increasing the production of mucin [13, 14]. SCFAs induce G protein-coupled receptors (GPCRs) and prevent histone deacetylase (HDAC) to provide their biological functions [15]. Per a study by Trompette et al. [12], SCFAs also modulate the hematopoietic function of Ly6c(-) patrolling monocytes, prompt the function of CD8 T cells, and induce GPR41 to supply protection against influenza virus infection [16]. Besides SCFAs, there are multiple other metabolites of the intestinal microbiota that are recorded to be related to host immunity. Pyruvate and lactate, which are released by the intestinal microbiota, help to improve immune responses by activating the growth of GPR31-mediated CX3CR1+ dendrites in the gut [17]. Research by Steed et al. [17] discussed that desaminotyrosine (DAT), a metabolite of the intestinal microbiota, prevents influenza infection by increasing type I IFN signaling in macrophages [18].

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs). In innate immunity, TLRs identify pathogen-associated molecular patterns (PAMPs). TLRs can place bacterial flagellin and single-stranded viral RNA to regulate antiviral and antibacterial immune responses [19, 20]. Influenza virus infection markedly raises the mRNA expression of TLR7 in lung immune cells. Antibiotic-induced dysregulation decreases the expression of genes included in the TLR7 signaling pathway, while probiotic administration maintains the initial expression upregulation of genes, such as TLR7 [21]. Moreover, the microbiota composition critically modulates the production of virus-specific CD4 and CD8 T cells and antibody responses following influenza virus infection [22]. The intestinal microbiota has an important role in the stabilizing of immune homeostasis by augmenting the integrity of the barrier functions of the gut mucosa, which is a crucial aspect of systemic immunity [23, 24]. Furthermore, the beneficial intestinal microbiota plays an essential role in modulating TLR 7 signal transduction, which was found to alleviate common mucosal immune system (MIS) destruction caused by antibiotic treatment in mice [21]. However, if microbiota is disrupted for any reason, a reduction in the non-pathogenic dominant microbiota members declines the extent of colonization resistance, resulting in colonization and overgrowth of the opportunistic pathogens in the vacant nooks. A well-known example of this issue is the infection with Clostridium difficile which can cause pseudo-membranous colitis, sepsis, and death in severe cases [24].

Furthermore, a lot of researchers are studying how the gut microbiome affects immunity in different parts of the body, such as the lungs, brain, and liver. For example, disturbance in the microbial community in the lungs, involving the airways, can change the composition of the intestinal microbiota. In addition, some gastrointestinal diseases are also combined with changes in the respiratory tract [25]. The transfer of immunomodulatory signals and the transduction of metabolites between the lungs and gut form the gut-lung axis [26]. The intestinal and respiratory mucous membranes supply physical barriers to microbial penetration, and the colonization of the normal microbiome is resistant to pathogens. Bacterial travel from the gastrointestinal tract to the lungs has been noticed in sepsis and acute respiratory distress syndrome, in which barrier integrity is damaged [27, 28]. The gut-brain axis is related to the two-way information network between the intestinal microbiota and the brain. In the intestine, segmented filamentous bacteria can maintain the functions of B and T lymphocytes [29]. T lymphocyte receptors (TLRs) are also widely spread on neurons [30]. Therefore, gut epithelial cells transfer viral and bacterial metabolites to the inner environment, neurons respond to microbial components, and the nervous system interacts with these bacterial and viral components. The equilibrium of the intestinal Microbiota may change the modulation of the inflammatory response and may participate in regulating emotion and behavior [31, 32]. Though the liver is exposed to gut-derived microbial metabolites and components, intestinal dysbiosis is included in liver disease, inflammation, and fibrosis [33]. The gut-liver axis is also connected with autoimmune liver diseases, like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) [34].

In conclusion, the intestinal microbiota can influence organismal immunity locally and systemically, proximally, and distally. Studying the possible mechanism by which the intestinal microbiota maintains host immunity can provide a clearer understanding of the occurrence and development of diseases [35].

References

  1. Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat Rev Gastroenterol Hepatol 2019; 16: 605-16.[CrossRef] [PubMed]
  2. Hill C, Guarner F, Reid G, et al. 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: 506-14.[CrossRef] [PubMed]
  3. Gibson GR, Hutkins R, Sanders ME, et al.: Expert consensus document. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 2017; 14: 491-502.[CrossRef] [PubMed]
  4. Roberfroid M, Gibson GR, Hoyles L, et al. Prebiotic effects: metabolic and health benefits. Br J Nutr 2010; 104(Suppl 2): S1-63.[CrossRef] [PubMed]
  5. Peters VBM, van de Steeg E, van Bilsen J, Meijerink M: Mechanisms and immunomodulatory properties of pre-and probiotics. Benef Microbes 2019; 10: 225-36.[CrossRef] [PubMed]
  6. Karl JP. Gut microbiota-targeted interventions for reducing the incidence, duration, and severity of respiratory tract infections in healthy non-elderly adults. Military Medicine 2021; 186(3-4): e310-8.[CrossRef] [PubMed]
  7. Graversen KB, Bahl MI, Larsen JM, Ballegaard AR, Licht TR, Bogh KL. Short-Term Amoxicillin-Induced Perturbation of the Gut Microbiota Promotes Acute Intestinal Immune Regulation in Brown Norway Rats. Front Microbiol 2020; 11: 496.[CrossRef] [PubMed]
  8. Yaron JR, Ambadapadi S, Zhang L, Chavan RN, Tibbetts SA, Keinan S, et al. Immune Protection is Dependent on the Gut Microbiome in a Lethal Mouse Gammaherpesviral Infection. Sci Rep 2020; 10(1): 2371.[CrossRef] [PubMed]
  9. Hoeppli RE, Wu D, Cook L, Levings MK. The Environment of Regulatory T Cell Biology: Cytokines, Metabolites, and the Microbiome. Front Immunol 2015; 6: 61.[CrossRef] [PubMed]
  10. Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, et al. . Neutrophil Ageing is regulated by the Microbiome. Nature 2015; 525(7570): 528-32.[CrossRef] [PubMed]
  11. Lu W, Feng Y, Jing F, Han Y, Lyu N, Liu F, et al. Association Between Gut Microbiota and CD4 Recovery in HIV-1 Infected Patients. Front Microbiol 2018; 9: 1451.[CrossRef] [PubMed]
  12. Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, et al. Dietary Fiber Confers Protection Against Flu by Shaping Ly6c(-) Patrolling Monocyte Hematopoiesis and CD8(+) T Cell Metabolism. Immunity 2018; 48(5): 992-1005.[CrossRef] [PubMed]
  13. Jung TH, Park JH, Jeon WM, Han KS. Butyrate Modulates Bacterial Adherence on LS174T Human Colorectal Cells by Stimulating Mucin Secretion and MAPK Signaling Pathway. Nutr Res Pract 2015; 9(4): 343-9.[CrossRef] [PubMed]
  14. Schilderink R, Verseijden C, Seppen J, Muncan V, van den Brink GR, Lambers TT, et al. The SCFA Butyrate Stimulates the Epithelial Production of Retinoic Acid Via Inhibition of Epithelial HDAC. Am J Physiol Gastrointest Liver Physiol 2016; 310(11): G1138-46.[CrossRef] [PubMed]
  15. Li M, van Esch B, Wagenaar GTM, Garssen J, Folkerts G, Henricks PAJ. Pro- and Anti-Inflammatory Effects of Short Chain Fatty Acids on Immune and Endothelial Cells. Eur J Pharmacol 2018; 831: 52-9.[CrossRef] [PubMed]
  16. Morita N, Umemoto E, Fujita S, Hayashi A, Kikuta J, Kimura I, et al. . GPR31-Dependent Dendrite Protrusion of Intestinal CX3CR1(+) Cells by Bacterial Metabolites. Nature 2019; 566(7742): 110-4.[CrossRef] [PubMed]
  17. Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, et al. . The Microbial Metabolite Desaminotyrosine Protects From Influenza Through Type I Interferon. Sci (New York NY) 2017; 357(6350): 498-502.[CrossRef] [PubMed]
  18. Kamdar K, Nguyen V, DePaolo RW. Toll-Like Receptor Signaling and Regulation of Intestinal Immunity. Virulence 2013; 4(3): 207-12.[CrossRef] [PubMed]
  19. Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell 2010; 140(6): 805-20.[CrossRef] [PubMed]
  20. Wu S, Jiang ZY, Sun YF, Yu B, Chen J, Dai CQ, et al. . Microbiota Regulates the TLR7 Signaling Pathway Against Respiratory Tract Influenza A Virus Infection. Curr Microbiol 2013; 67(4): 414-22.[CrossRef] [PubMed]
  21. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, et al. Microbiota Regulates Immune Defense Against Respiratory Tract Influenza A Virus Infection. Proc Natl Acad Sci USA 2011; 108(13): 5354-9.[CrossRef] [PubMed]
  22. Honda K, Littman DR. The Microbiota in Adaptive Immune Homeostasis and Disease. Nature 2016; 535(7610): 75-84.[CrossRef] [PubMed]
  23. Thaiss CA, Zmora N, Levy M, Elinav E. The Microbiome and Innate Immunity. Nature 2016; 535(7610): 65-74.[CrossRef] [PubMed]
  24. Ahlawat S, Asha, Sharma KK. Immunological Co-Ordination between Gut and Lungs in SARS-CoV-2 Infection. Virus Res 2020; 286: 198103.[CrossRef] [PubMed]
  25. Trivedi R, Barve K. Gut Microbiome a Promising Target for Management of Respiratory Diseases. Biochem J 2020; 477(14): 2679-96.[CrossRef] [PubMed]
  26. Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, et al. Enrichment of the Lung Microbiome With Gut Bacteria in Sepsis and the Acute Respiratory Distress Syndrome. Nat Microbiol 2016; 1(10): 16113.[CrossRef] [PubMed]
  27. Budden KF, Gellatly SL, Wood DL, Cooper MA, Morrison M, Hugenholtz P, et al. Emerging Pathogenic Links Between Microbiota and the Gut-Lung Axis. Nat Rev Microbiol 2017; 15(1): 55–63.[CrossRef] [PubMed]
  28. Wang HX, Wang YP. Gut Microbiota-Brain Axis. Chin Med J 2016; 129(19): 2373-80.[CrossRef] [PubMed]
  29. McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG. Enhanced Peripheral Toll-Like Receptor Responses in Psychosis: Further Evidence of a Pro-Inflammatory Phenotype. Trans Psychiatry 2011; 1(8): e36.[CrossRef] [PubMed]
  30. Foster JA, McVey Neufeld KA. Gut-Brain Axis: How the Microbiome Influences Anxiety and Depression. Trends Neurosci 2013; 36(5): 305–12.[CrossRef] [PubMed]
  31. Bruce-Keller AJ, Salbaum JM, Berthoud HR. Harnessing Gut Microbes for Mental Health: Getting From Here to There. Biol Psychiatry 2018; 83(3): 214-23.[CrossRef] [PubMed]
  32. Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the Gut-Liver Axis in Liver Disease. J Hepatol 2017; 67(5): 1084-103.[CrossRef] [PubMed]
  33. Li B, Selmi C, Tang R, Gershwin ME, Ma X. The Microbiome and Autoimmunity: A Paradigm from the Gut-Liver Axis. Cell Mol Immunol 2018; 15(6): 595-609.[CrossRef] [PubMed]
  34. Yang M, Yang Y, He Q, Zhu P, Liu M, Xu J, Zhao M. Intestinal Microbiota—A Promising Target for Antiviral Therapy?. Frontiers in immunology 2021; 12: 1771.[CrossRef] [PubMed]
  35. Zeng W, Shen J, Bo T. Cutting edge. Probiotics and fecal microbiota transplantation in immunomodulation. J Immunol Res 2019; 2019.[CrossRef] [PubMed]
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Tawfik, H. A.-A. H. M., Farris, M. N., Samir, R., Ashram, M. N. B. A., Nessim, M. M., & Allam, M. F. (2022). Probiotics and Intestinal Microbiome: A Review of Literature. World Journal of Medical Microbiology, 1(1), 25–29. Retrieved from https://www.scipublications.com/journal/index.php/wjmm/article/view/479

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Copyright © 2023 by authors and Science Publications. This is an open access article and the related PDF distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  1. Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat Rev Gastroenterol Hepatol 2019; 16: 605-16.[CrossRef] [PubMed]
  2. Hill C, Guarner F, Reid G, et al. 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: 506-14.[CrossRef] [PubMed]
  3. Gibson GR, Hutkins R, Sanders ME, et al.: Expert consensus document. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 2017; 14: 491-502.[CrossRef] [PubMed]
  4. Roberfroid M, Gibson GR, Hoyles L, et al. Prebiotic effects: metabolic and health benefits. Br J Nutr 2010; 104(Suppl 2): S1-63.[CrossRef] [PubMed]
  5. Peters VBM, van de Steeg E, van Bilsen J, Meijerink M: Mechanisms and immunomodulatory properties of pre-and probiotics. Benef Microbes 2019; 10: 225-36.[CrossRef] [PubMed]
  6. Karl JP. Gut microbiota-targeted interventions for reducing the incidence, duration, and severity of respiratory tract infections in healthy non-elderly adults. Military Medicine 2021; 186(3-4): e310-8.[CrossRef] [PubMed]
  7. Graversen KB, Bahl MI, Larsen JM, Ballegaard AR, Licht TR, Bogh KL. Short-Term Amoxicillin-Induced Perturbation of the Gut Microbiota Promotes Acute Intestinal Immune Regulation in Brown Norway Rats. Front Microbiol 2020; 11: 496.[CrossRef] [PubMed]
  8. Yaron JR, Ambadapadi S, Zhang L, Chavan RN, Tibbetts SA, Keinan S, et al. Immune Protection is Dependent on the Gut Microbiome in a Lethal Mouse Gammaherpesviral Infection. Sci Rep 2020; 10(1): 2371.[CrossRef] [PubMed]
  9. Hoeppli RE, Wu D, Cook L, Levings MK. The Environment of Regulatory T Cell Biology: Cytokines, Metabolites, and the Microbiome. Front Immunol 2015; 6: 61.[CrossRef] [PubMed]
  10. Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, et al. . Neutrophil Ageing is regulated by the Microbiome. Nature 2015; 525(7570): 528-32.[CrossRef] [PubMed]
  11. Lu W, Feng Y, Jing F, Han Y, Lyu N, Liu F, et al. Association Between Gut Microbiota and CD4 Recovery in HIV-1 Infected Patients. Front Microbiol 2018; 9: 1451.[CrossRef] [PubMed]
  12. Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, et al. Dietary Fiber Confers Protection Against Flu by Shaping Ly6c(-) Patrolling Monocyte Hematopoiesis and CD8(+) T Cell Metabolism. Immunity 2018; 48(5): 992-1005.[CrossRef] [PubMed]
  13. Jung TH, Park JH, Jeon WM, Han KS. Butyrate Modulates Bacterial Adherence on LS174T Human Colorectal Cells by Stimulating Mucin Secretion and MAPK Signaling Pathway. Nutr Res Pract 2015; 9(4): 343-9.[CrossRef] [PubMed]
  14. Schilderink R, Verseijden C, Seppen J, Muncan V, van den Brink GR, Lambers TT, et al. The SCFA Butyrate Stimulates the Epithelial Production of Retinoic Acid Via Inhibition of Epithelial HDAC. Am J Physiol Gastrointest Liver Physiol 2016; 310(11): G1138-46.[CrossRef] [PubMed]
  15. Li M, van Esch B, Wagenaar GTM, Garssen J, Folkerts G, Henricks PAJ. Pro- and Anti-Inflammatory Effects of Short Chain Fatty Acids on Immune and Endothelial Cells. Eur J Pharmacol 2018; 831: 52-9.[CrossRef] [PubMed]
  16. Morita N, Umemoto E, Fujita S, Hayashi A, Kikuta J, Kimura I, et al. . GPR31-Dependent Dendrite Protrusion of Intestinal CX3CR1(+) Cells by Bacterial Metabolites. Nature 2019; 566(7742): 110-4.[CrossRef] [PubMed]
  17. Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, et al. . The Microbial Metabolite Desaminotyrosine Protects From Influenza Through Type I Interferon. Sci (New York NY) 2017; 357(6350): 498-502.[CrossRef] [PubMed]
  18. Kamdar K, Nguyen V, DePaolo RW. Toll-Like Receptor Signaling and Regulation of Intestinal Immunity. Virulence 2013; 4(3): 207-12.[CrossRef] [PubMed]
  19. Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell 2010; 140(6): 805-20.[CrossRef] [PubMed]
  20. Wu S, Jiang ZY, Sun YF, Yu B, Chen J, Dai CQ, et al. . Microbiota Regulates the TLR7 Signaling Pathway Against Respiratory Tract Influenza A Virus Infection. Curr Microbiol 2013; 67(4): 414-22.[CrossRef] [PubMed]
  21. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, et al. Microbiota Regulates Immune Defense Against Respiratory Tract Influenza A Virus Infection. Proc Natl Acad Sci USA 2011; 108(13): 5354-9.[CrossRef] [PubMed]
  22. Honda K, Littman DR. The Microbiota in Adaptive Immune Homeostasis and Disease. Nature 2016; 535(7610): 75-84.[CrossRef] [PubMed]
  23. Thaiss CA, Zmora N, Levy M, Elinav E. The Microbiome and Innate Immunity. Nature 2016; 535(7610): 65-74.[CrossRef] [PubMed]
  24. Ahlawat S, Asha, Sharma KK. Immunological Co-Ordination between Gut and Lungs in SARS-CoV-2 Infection. Virus Res 2020; 286: 198103.[CrossRef] [PubMed]
  25. Trivedi R, Barve K. Gut Microbiome a Promising Target for Management of Respiratory Diseases. Biochem J 2020; 477(14): 2679-96.[CrossRef] [PubMed]
  26. Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, et al. Enrichment of the Lung Microbiome With Gut Bacteria in Sepsis and the Acute Respiratory Distress Syndrome. Nat Microbiol 2016; 1(10): 16113.[CrossRef] [PubMed]
  27. Budden KF, Gellatly SL, Wood DL, Cooper MA, Morrison M, Hugenholtz P, et al. Emerging Pathogenic Links Between Microbiota and the Gut-Lung Axis. Nat Rev Microbiol 2017; 15(1): 55–63.[CrossRef] [PubMed]
  28. Wang HX, Wang YP. Gut Microbiota-Brain Axis. Chin Med J 2016; 129(19): 2373-80.[CrossRef] [PubMed]
  29. McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG. Enhanced Peripheral Toll-Like Receptor Responses in Psychosis: Further Evidence of a Pro-Inflammatory Phenotype. Trans Psychiatry 2011; 1(8): e36.[CrossRef] [PubMed]
  30. Foster JA, McVey Neufeld KA. Gut-Brain Axis: How the Microbiome Influences Anxiety and Depression. Trends Neurosci 2013; 36(5): 305–12.[CrossRef] [PubMed]
  31. Bruce-Keller AJ, Salbaum JM, Berthoud HR. Harnessing Gut Microbes for Mental Health: Getting From Here to There. Biol Psychiatry 2018; 83(3): 214-23.[CrossRef] [PubMed]
  32. Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the Gut-Liver Axis in Liver Disease. J Hepatol 2017; 67(5): 1084-103.[CrossRef] [PubMed]
  33. Li B, Selmi C, Tang R, Gershwin ME, Ma X. The Microbiome and Autoimmunity: A Paradigm from the Gut-Liver Axis. Cell Mol Immunol 2018; 15(6): 595-609.[CrossRef] [PubMed]
  34. Yang M, Yang Y, He Q, Zhu P, Liu M, Xu J, Zhao M. Intestinal Microbiota—A Promising Target for Antiviral Therapy?. Frontiers in immunology 2021; 12: 1771.[CrossRef] [PubMed]
  35. Zeng W, Shen J, Bo T. Cutting edge. Probiotics and fecal microbiota transplantation in immunomodulation. J Immunol Res 2019; 2019.[CrossRef] [PubMed]