The role of the microbiome in inflammation during tuberculosis

The human gut microbiota, comprised of a diverse microbial ecosystem, consists of hundreds of groups of species that are relatively stable in healthy individuals, but its composition can change rapidly as a result of illness, age, diet, antibiotic use, host genetics, and inflammation. Recent reports have shown that the microbiome may be implicated in tuberculosis (TB) infection [[1]Mori G. Morrison M. Blumenthal A. Microbiome-immune interactions in tuberculosis.PLOS Pathog. 2021; 17e1009377https://doi.org/10.1371/journal.ppat.1009377Crossref PubMed Scopus (4) Google Scholar,[2]Namasivayam S. Maiga M. Yuan W. Thovarai V. Costa D.L. Mittereder L.R. et al.Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy.Microbiome. 2017; 5: 71https://doi.org/10.1186/s40168-017-0286-2Crossref PubMed Scopus (58) Google Scholar]. TB is one of the most fatal infectious disease that is caused by the Mycobacterium tuberculosis complex and remains a major cause of global morbidity and mortality [[3]Kone B. Somboro A.M. Holl J.L. Baya B. Togo A.A. Sarro Y.D.S. et al.Exploring the usefulness of molecular epidemiology of tuberculosis in Africa: a systematic review.Int J Mol Epidemiol Genet. 2020; 11: 1-15PubMed Google Scholar]. The microbiome and its associated metabolites are likely to play a role in susceptibility to TB infection and progression to and severity of disease. Changes in the structure of microbiome populations could impact immunity signaling. Gaining an in-depth understanding of the complex parameters of the relationship of the microbiome and TB infection could reveal key-elements that predict and modulate TB disease progression, severity, treatment outcomes and, possibly re-infection. The role of the gut microbiome in host immunity and inflammation is mostly described by the capacity of certain microbial species to produce specific enzymes that ferment nutrients into absorbable forms, such as carbohydrates in the form of short-chain fatty acids (SCFAs) that possess anti-inflammatory and immunomodulatory properties [[4]Eribo O.A. du Plessis N. Ozturk M. Guler R. Walzl G. Chegou N.N. The gut microbiome in tuberculosis susceptibility and treatment response: guilty or not guilty?.Cell Mol Life Sci. 2020; 77: 1497-1509Crossref PubMed Scopus (12) Google Scholar]. Moreover, metabolites and other components of microbes like cell capsule carbohydrates, lipopolysaccharides, and endotoxins, produced to maintain the integrity of the gut wall, intervene in the production of vitamins, regulation of intestinal endocrine hormones, energy activation, stimulation or inhibition of certain specific key immune system signaling molecules [[5]Venegas D.P. De La Fuente M.K. Landskron G. González M.J. Quera R. Dijkstra G. et al.Short chain fatty acids (SCFAs)mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases.Front Immunol. 2019; 10: 277https://doi.org/10.3389/fimmu.2019.00277Crossref PubMed Scopus (584) Google Scholar]. Therefore, interaction between the gut microbiome and the immune signaling system may affect the inflammation response, as this interaction can lead to either an anti-inflammatory path by stimulation of regulatory cells or to pro-inflammation. On the other hand, gut microbiota can affect drug metabolism and provide protection against pathogenic organisms through colonization and competition for resources. SCFAs, such as propionate, butyrate, acetate, and lactate are produced by the gut microbiome. They interact with G protein-coupled receptors to induce immune responses via signal transduction pathways. The mitogen-activated kinases (MAPK) pathway is involved in the pro-inflammatory response while the beta-arrestin-2 pathway is involved in the anti-inflammatory response. SCFAs bind to their receptors to stimulate IL-10 secretion from dendritic cells and macrophages in innate immunity. For an adaptive immune response, SCFAs can promote the expansion of regulatory T cells (Treg) and B cells in the gut-lung axis [[4]Eribo O.A. du Plessis N. Ozturk M. Guler R. Walzl G. Chegou N.N. The gut microbiome in tuberculosis susceptibility and treatment response: guilty or not guilty?.Cell Mol Life Sci. 2020; 77: 1497-1509Crossref PubMed Scopus (12) Google Scholar], all of which lead to the overall balance and modulation of the immune response. Initial findings suggested that TB is associated with gut microbiome alterations [6Hu Y. Feng Y. Wu J. Liu F. Zhang Z. Hao Y. et al.The gut microbiome signatures discriminate healthy from pulmonary tuberculosis patients.Front Cell Infect Microbiol. 2019; 9https://doi.org/10.3389/fcimb.2019.00090Crossref Scopus (41) Google Scholar, 7Li W. Zhu Y. Liao Q. Wang Z. Wan C. Characterization of gut microbiota in children with pulmonary tuberculosis.BMC Pediatr. 2019; https://doi.org/10.1186/s12887-019-1782-2Crossref Scopus (11) Google Scholar, 8Namasivayam S. Diarra B. Diabate S. Sarro Y.D.S. Kone A. Kone B. et al.Patients infected with Mycobacterium africanum versus Mycobacterium tuberculosis possess distinct intestinal microbiota.PLoS Negl Trop Dis. 2020; 14e0008230Crossref PubMed Scopus (4) Google Scholar]. They have found a significant decrease in microbial diversity in fecal samples of patients with TB compared to healthy controls. In this issue, Naidoo et al. described and compared different microbiome compartments, using oral wash, induced sputum, and stool samples in TB symptomatic cases, symptomatic no-TB controls, and no-TB household contacts of the previous two groups and performed a peripheral blood transcriptome comparative analysis. This represents the first TB microbiome study, to date, with the most comprehensive and thoughtful selection of control groups to reduce the maximum of bias. The study also linked the microbial changes to phenotype changes in inflammatory response during TB. The authors identified a distinct gut microbiome profile in TB infected cases as compared to their healthy close contacts, with Erysipelotrichaceae, Blautia, Anaerostipes in their stool, with precursor inferred pathways of short chain fatty acids that are known to modulate the immune response to TB [[9]Naidoo C.C. Nyawo G.R. Sulaiman I. Wu B.G. Turner C.T. Bu K. et al.Anaerobe-enriched gut microbiota predicts pro-inflammatory responses in pulmonary tuberculosis.EBioMedicine. 2021; 67103374https://doi.org/10.1016/j.ebiom.2021.103374Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. The enriched gut anaerobes predict the upregulation of pro-inflammatory pathways related to TB disease and its severity, while different gut microbiome-transcriptome network interactions were involved in the household contacts. Also, in TB infected cases, anaerobes, such as Paludibacter, Lautropia were enriched in oral washes and induced sputum. Overall this study convincingly shows that this microbiome-inflammation pattern is unique to the TB infected group, which clearly demonstrates the interaction of the microbiome and TB disease via the SCFAs pathway [[9]Naidoo C.C. Nyawo G.R. Sulaiman I. Wu B.G. Turner C.T. Bu K. et al.Anaerobe-enriched gut microbiota predicts pro-inflammatory responses in pulmonary tuberculosis.EBioMedicine. 2021; 67103374https://doi.org/10.1016/j.ebiom.2021.103374Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. The SCFAs microbial-related inflammation pathway has been described in other conditions, such as cancer, and certainly represents new avenues of research on TB biomarkers and on microbiome-targeted disease prevention or adjuvant treatments. In an earlier study, Namasivayam et al. found changes in the order Clostridiales of phylum Firmicutes and certain members of phylum Tenericutes with the mouse model [[2]Namasivayam S. Maiga M. Yuan W. Thovarai V. Costa D.L. Mittereder L.R. et al.Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy.Microbiome. 2017; 5: 71https://doi.org/10.1186/s40168-017-0286-2Crossref PubMed Scopus (58) Google Scholar], and similar observations were made by Hu et al. in pulmonary TB patients [[10]Hu Y. Yang Q. Liu B. Dong J. Sun L. Zhu Y. et al.Gut microbiota associated with pulmonary tuberculosis and dysbiosis caused by anti-tuberculosis drugs.J Infect. 2019; 78: 317-322Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. These commensals also produce metabolites that could modulate the immune signaling. This highlights some of the mechanistic differences between humans and mice, but outcome similarities, related to the TB and the microbiome. It is now evident that the gut microbiota community composition and associated inflammation metabolic pathways change considerably in TB infected cases compared to the healthy household controls [[9]Naidoo C.C. Nyawo G.R. Sulaiman I. Wu B.G. Turner C.T. Bu K. et al.Anaerobe-enriched gut microbiota predicts pro-inflammatory responses in pulmonary tuberculosis.EBioMedicine. 2021; 67103374https://doi.org/10.1016/j.ebiom.2021.103374Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar,[10]Hu Y. Yang Q. Liu B. Dong J. Sun L. Zhu Y. et al.Gut microbiota associated with pulmonary tuberculosis and dysbiosis caused by anti-tuberculosis drugs.J Infect. 2019; 78: 317-322Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. The differential abundance of gut microbiota may serve as microbiota biosignatures that discriminate active TB disease from healthy individuals and, could potentially be used as a therapeutic target of an immunomodulator adjuvant to TB treatment regimens or as a target for nutritional prevention of TB or severe disease [[6]Hu Y. Feng Y. Wu J. Liu F. Zhang Z. Hao Y. et al.The gut microbiome signatures discriminate healthy from pulmonary tuberculosis patients.Front Cell Infect Microbiol. 2019; 9https://doi.org/10.3389/fcimb.2019.00090Crossref Scopus (41) Google Scholar]. Probiotics, prebiotics, and gut microbiome transfer strategies are potential options for such interventions. All authors contributed to Conceptualization (AMS, DD, JLH and MM), data curation (AMS, DD and MM), formal analysis (AMS, DD and MM), funding aquisition (AMS and MM), investigation (AMS, DD, JLH and MM), methodology (AMS, DD, JLH and MM), Resources (MM), Supervision (MM), validation (AMS, DD, JLH and MM), visualization (AMS, DD, JLH and MM), Writing original draft (AMS, DD and MM), writing review and editing (AMS, DD, JLH and MM). There are no conflicts of interest. This work was supported by the National Institutes of Health ( R21AI148033 and D43TW010543 ). Anaerobe-enriched gut microbiota predicts pro-inflammatory responses in pulmonary tuberculosisTB-specific microbial relationships were identified in oral washes, induced sputum, and stool from cases before the confounding effects of antibiotics. Specific anaerobes in cases’ stool predict upregulation of pro-inflammatory immunological pathways, supporting the gut microbiota's role in TB. Full-Text PDF Open Access