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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2023.1149679</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>The gut microbiome: A line of defense against tuberculosis development</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Yu</surname>
<given-names>Ziqi</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1618737"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Shen</surname>
<given-names>Xiang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/575901"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Aiyao</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hu</surname>
<given-names>Chong</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Chen</surname>
<given-names>Jianyong</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Munich Medical Research School, Ludwig Maximilian University of Munich (LMU)</institution>, <addr-line>Munich</addr-line>, <country>Germany</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Nanchang Medical College, Jiangxi Provincial People&#x2019;s Hospital</institution>, <addr-line>Nanchang, Jiangxi</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Susanta Pahari, Texas Biomedical Research Institute, United States</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Andreas Kupz, James Cook University, Australia; Shikha Negi, Cincinnati Children&#x2019;s Hospital Medical Center, United States</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Jianyong Chen, <email xlink:href="mailto:cjyacy69@163.com">cjyacy69@163.com</email>
</p>
</fn>
<fn fn-type="equal" id="fn003">
<p>&#x2020;These authors have contributed equally to this work</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Intestinal Microbiome, a section of the journal Frontiers in Cellular and Infection Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>18</day>
<month>04</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>13</volume>
<elocation-id>1149679</elocation-id>
<history>
<date date-type="received">
<day>22</day>
<month>01</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>29</day>
<month>03</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2023 Yu, Shen, Wang, Hu and Chen</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Yu, Shen, Wang, Hu and Chen</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums 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.</p>
</license>
</permissions>
<abstract>
<p>The tuberculosis (TB) burden remains a significant global public health concern, especially in less developed countries. While pulmonary tuberculosis (PTB) is the most common form of the disease, extrapulmonary tuberculosis, particularly intestinal TB (ITB), which is mostly secondary to PTB, is also a significant issue. With the development of sequencing technologies, recent studies have investigated the potential role of the gut microbiome in TB development. In this review, we summarized studies investigating the gut microbiome in both PTB and ITB patients (secondary to PTB) compared with healthy controls. Both PTB and ITB patients show reduced gut microbiome diversity characterized by reduced <italic>Firmicutes</italic> and elevated opportunistic pathogens colonization; <italic>Bacteroides</italic> and <italic>Prevotella</italic> were reported with opposite alteration in PTB and ITB patients. The alteration reported in TB patients may lead to a disequilibrium in metabolites such as short-chain fatty acid (SCFA) production, which may recast the lung microbiome and immunity <italic>via</italic> the &#x201c;gut-lung axis&#x201d;. These findings may also shed light on the colonization of <italic>Mycobacterium tuberculosis</italic> in the gastrointestinal tract and the development of ITB in PTB patients. The findings highlight the crucial role of the gut microbiome in TB, particularly in ITB development, and suggest that probiotics and postbiotics might be useful supplements in shaping a balanced gut microbiome during TB treatment.</p>
</abstract>
<kwd-group>
<kwd>gut microbiome</kwd>
<kwd>
<italic>Mycobacterium tuberculosis</italic>
</kwd>
<kwd>
<italic>Firmicutes</italic>
</kwd>
<kwd>
<italic>Bacteroidetes</italic>
</kwd>
<kwd>short-chain fatty acids</kwd>
<kwd>tuberculosis</kwd>
</kwd-group>
<contract-num rid="cn001">81960111</contract-num>
<contract-num rid="cn002">20202BABL206013</contract-num>
<contract-num rid="cn003">202008360174, 201909110092</contract-num>
<contract-sponsor id="cn001">National Natural Science Foundation of China<named-content content-type="fundref-id">10.13039/501100001809</named-content>
</contract-sponsor>
<contract-sponsor id="cn002">Natural Science Foundation of Jiangxi Province<named-content content-type="fundref-id">10.13039/501100004479</named-content>
</contract-sponsor>
<contract-sponsor id="cn003">China Scholarship Council<named-content content-type="fundref-id">10.13039/501100004543</named-content>
</contract-sponsor>
<counts>
<fig-count count="2"/>
<table-count count="1"/>
<equation-count count="0"/>
<ref-count count="110"/>
<page-count count="11"/>
<word-count count="5018"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>Tuberculosis (TB) caused by <italic>Mycobacterium tuberculosis</italic> is one of the leading infectious disease killers worldwide (<xref ref-type="bibr" rid="B6">Avoi and Liaw, 2021</xref>). According to the latest WHO report, it is estimated that a quarter of the global population is infected with <italic>M. tuberculosis</italic>. Even though only about 5-10% of infected people develop active TB, in 2020 alone, the incidence of TB was about 127 cases per 100,000 people, and approximately 1.3 million HIV-negative people died of TB (<xref ref-type="bibr" rid="B99">WHO, 2021</xref>). Furthermore, most TB cases were reported in less developed regions, especially in South-East Asia, Africa, and the Western Pacific regions (<xref ref-type="bibr" rid="B99">WHO, 2021</xref>). However, the incidence might be underestimated as in some areas, especially in sub-Saharan Africa, the diagnosis of TB is still a challenge, and it is estimated that approximately 50% of TB cases remain undiagnosed (<xref ref-type="bibr" rid="B57">Mnyambwa et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B36">Jayasooriya et&#xa0;al., 2022</xref>). In the year 2015, all WHO members adopted the WHO&#x2019;s End TB strategy which aims to reduce the absolute number of TB deaths by 95% and the incidence rate by 90% by 2035 compared to the 2015 baseline. Six years have passed, and the incidence of TB has only dropped by 10%. With only 13 years left, the situation is still challenging.</p>
<p>TB is transmitted by cough-generated aerosols from patients, and it primarily affects the lungs, causing pulmonary tuberculosis (PTB) (<xref ref-type="bibr" rid="B91">Tan et&#xa0;al., 2020</xref>). However, it can also involve other parts of the body. TB that affects areas outside the lungs is called extrapulmonary tuberculosis. Approximately 1-3% of total TB cases (<xref ref-type="bibr" rid="B83">Sheer and Coyle, 2003</xref>; <xref ref-type="bibr" rid="B16">Cho et&#xa0;al., 2018</xref>) and 10% of all extrapulmonary tuberculosis cases involve the gastrointestinal tract, causing intestinal tuberculosis (ITB) (<xref ref-type="bibr" rid="B1">Abu-Zidan and Sheek-Hussein, 2019</xref>; <xref ref-type="bibr" rid="B54">Maulahela et&#xa0;al., 2022</xref>). Swallowing of sputum in PTB patients has a certain chance of causing ITB (<xref ref-type="bibr" rid="B27">Gan et&#xa0;al., 2016</xref>). This is because <italic>M. tuberculosis</italic> is more resistant to the gastric acid barrier due to its special cell wall structure (<xref ref-type="bibr" rid="B94">Vandal et&#xa0;al., 2009</xref>). However, not all PTB patients develop ITB, as they might benefit from the protective effect of the intestinal barrier.</p>
<p>The intestinal barrier is a highly complex system, including the outer mucus layer, the epithelial layer, the underlying lamina propria, and components such as commensal microbiota, antimicrobial peptides, secretory immunoglobulin A, and immune cells (<xref ref-type="bibr" rid="B41">K&#xf6;nig et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B93">Vancamelbeke and Vermeire, 2017</xref>). Intestinal microbiota with a complex and dynamic microbial community is of vital importance to human health (<xref ref-type="bibr" rid="B15">Chen et&#xa0;al., 2021</xref>). It can not only regulate host physiological processes such as digestion, nutrient absorption, and metabolism, but also modulate host immunity in protection against pathogens and toxins (<xref ref-type="bibr" rid="B98">Wang et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B17">Comberiati et&#xa0;al., 2021</xref>). It is of great importance in gut homeostasis and colonization resistance to exogenous pathogens (<xref ref-type="bibr" rid="B21">Ducarmon et&#xa0;al., 2019</xref>), and dysbiosis in microbiome composition can result in susceptibility to infections and disease development (<xref ref-type="bibr" rid="B9">Budden et&#xa0;al., 2017</xref>). It is reported that altered microbiota composition can cause increased epithelial permeability and disruption in the mucus layer, resulting in susceptibility to <italic>Clostridioides difficile</italic> (<xref ref-type="bibr" rid="B8">Bien et&#xa0;al., 2013</xref>) and <italic>Citrobacter rodentium</italic> infection (<xref ref-type="bibr" rid="B102">Wlodarska et&#xa0;al., 2011</xref>). A recent study in patients with COVID-19 observed significant gut dysbiosis with enrichment of opportunistic pathogens (<xref ref-type="bibr" rid="B110">Zuo et&#xa0;al., 2020</xref>). Therefore, the gut microbiome of the host might also be crucial in preventing TB infection or decelerating the disease progression (<xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>).</p>
<p>With the universal application of Next-Generation Sequencing and bioinformatic analysis, there are increasing studies investigating the association between <italic>M. tuberculosis</italic> infection and alteration of gut microbiota. Here, we reviewed all the previous reports on the intestinal microbiome in active TB patients (including PTB and ITB) without any treatment, summarized their main findings, and tried to deduce the reasons for ITB development in PTB patients.</p>
</sec>
<sec id="s2">
<label>2</label>
<title>Alteration of gut microbiome in active TB patients</title>
<p>
<italic>M. tuberculosis</italic> infection is known to cause dysregulation of the immune system, resulting in dysregulation of the gut microbiome (<xref ref-type="bibr" rid="B67">Osei Sekyere et&#xa0;al., 2020</xref>). In this review, we included studies referring to the alterations in the gut microbiome of TB patients (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B34">Huang et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>; <xref ref-type="bibr" rid="B44">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B10">Cao et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B60">Naidoo et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B104">Yang et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>). All patients included in the study were without antibiotic treatment, as the antibiotics can result in dysbiosis and mask the results caused by <italic>M. tuberculosis</italic> infection (<xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>). The main findings are summarized in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref> and <xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>. The study design and sequencing techniques used in these studies are also included.</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Studies investigating the alteration of gut microbiome in pulmonary tuberculosis patients or intestinal tuberculosis patients without antibiotics comparing with the healthy controls.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" colspan="2" align="center">Study design</th>
<th valign="top" rowspan="2" align="center">Change in diversity</th>
<th valign="top" rowspan="2" align="center">Change in microbiota composition</th>
<th valign="top" rowspan="2" align="center">Sequencing technology</th>
<th valign="top" rowspan="2" align="center">Literature</th>
</tr>
<tr>
<th valign="top" align="center">Patients</th>
<th valign="top" align="center">Controls</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from active PTB patients (n=29)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=22)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bifidobacterium</italic> and <italic>Prevotella</italic> decreased in patients</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B10">Cao et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Bacteroidetes</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from PTB patients (n=10)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=20)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bacteroidetes</italic>, <italic>Clostridales</italic>, <italic>Ruminococcaceae</italic>, <italic>Lachnospiraceae</italic>, <italic>Prevotella</italic>, <italic>Romboutsia</italic>, <italic>Dialister</italic>, <italic>Gemmiger</italic>, <italic>Collinsella</italic> and <italic>Roseburia</italic> decreased in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Proteobacteria</italic>, <italic>Actinobacteria</italic>, <italic>Bifidobacteriales</italic>, <italic>Coriobacteriales</italic>, <italic>Rhizobiales</italic>, <italic>Bifidobacteriaceae</italic>, <italic>Coriobacteriaceae</italic>, <italic>Caulobacteraceae</italic>, <italic>Phyllobacteriaceae</italic>, <italic>Burkholderiaceae</italic>, <italic>Granulicatella</italic>, <italic>Solobacterium</italic>, <italic>Erysipelotrichaceae unclassified</italic> and <italic>Actinomyces</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Colon biopsy samples from ITB patients (n=6)</td>
<td valign="top" rowspan="2" align="center">Colon biopsy samples from healthy controls (n=4)</td>
<td valign="top" rowspan="2" align="center">no significant difference</td>
<td valign="top" align="center">
<italic>Firmicutes</italic>, <italic>Lachnospiraceae</italic>, <italic>Ruminococcaceae</italic>, <italic>Bacteroidaceae</italic>, <italic>Bacteroides</italic>, <italic>Faecalibacterium</italic>, <italic>Roseburia</italic>, <italic>Collinsella</italic>, <italic>Dorea</italic>, <italic>Oscillibacter</italic>, <italic>Ruminococcus</italic> decreased in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Proteobacteria</italic>, <italic>Enterobacteriaceae</italic>, <italic>Lactobacillus</italic>, <italic>Pseudomonas</italic>, <italic>Klebsiella</italic>, <italic>Mycobacterium</italic> increased <italic>in patients</italic>
</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from PTB patients (n=30)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=52)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Roseburia hominis</italic>, <italic>Roseburia inulinivorans</italic>, <italic>Roseburia intestinalis</italic>, <italic>Eubacterium rectale</italic>, <italic>Coprococcus comes</italic>, <italic>Bifidobacterium adolescentis</italic>, <italic>Bifidobacterium longum</italic>, <italic>Ruminococcus obeum</italic>, <italic>Akkermansia muciniphila</italic>, <italic>Haemophilus parainfluenzae</italic> decreased in patients;</td>
<td valign="top" rowspan="2" align="center">Shotgun metagenomic Illumina sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">unclassified <italic>Coprobacillus bacterium</italic>, <italic>Clostridium bolteae</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" align="left">Stool samples from active PTB patients (n=28), latent PTB (n=10)</td>
<td valign="top" align="center">Stool samples from healthy controls (n=13)</td>
<td valign="top" align="center">minor decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bacteroides</italic> slightly increased in patients</td>
<td valign="top" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from active PTB patients (n=25), latent PTB (n=32)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=23)</td>
<td valign="top" rowspan="2" align="center">not reported</td>
<td valign="top" align="center">
<italic>Firmicutes</italic>/<italic>Bacteroidetes</italic> ratio decreased in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B34">Huang et&#xa0;al., 2019</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Bacteroidetes</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from PTB patients (n=18)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=18)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bifidobacteriaceae</italic>, <italic>Ruminococcaceae</italic>, <italic>Bacteroidaceae</italic>, <italic>Faecalibacterium</italic>, <italic>Faecalibacterium prausnitzii</italic> decreased in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (454) pyrosequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B44">Li et&#xa0;al., 2019</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Prevotellaceae</italic>, <italic>Enterococcus</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="left">Stool samples from new PTB patients (n=19), recurrent PTB (n=18)</td>
<td valign="top" rowspan="3" align="center">Stool samples from healthy controls (n=20) but with younger age structure and more female</td>
<td valign="top" rowspan="3" align="center">increased alpha-diversity</td>
<td valign="top" align="center">
<italic>Bacteroidetes</italic> and <italic>Coprococcus</italic> depletion in RTB and NTB;</td>
<td valign="top" rowspan="3" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="3" align="center">(<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Firmicutes</italic> decreased in RTB, <italic>Roseburia</italic> decreased in NTB, <italic>Lachnospira</italic> and <italic>Prevotella</italic> decreased in both NTB and RTB patients;</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Actinobacteria</italic>, <italic>Proteobacteria</italic>, <italic>Streptococcus</italic> increased in both NTB and RTB patients, <italic>Escherchia</italic> and <italic>Collinsella</italic> increased in RTB</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from PTB patients (n=6)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy blood relatives of each patient (n=6)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bifidobacterium</italic> decreased and <italic>Prevotella</italic> depletion in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing; faecal whole genome shotgun sequencing (Illumina)</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Faecalibacterium</italic>, <italic>Coprococcus</italic>, <italic>Phascolarctobacterium</italic>, <italic>Pseudobutyrivibrio</italic>, <italic>Bacteroides</italic>, <italic>Eubacterium rectale</italic>, <italic>Phascolarctobacterium succinatutens</italic>, <italic>Roseburia inulinivorans</italic>, <italic>Faecalibacterium prausnitzii</italic>, <italic>Shigella sonnei</italic>, <italic>Escherichia Coli</italic>, <italic>Streptococcus pneumoniae</italic>, <italic>Streptococcus vestibularis</italic> were increased in patients</td>
</tr>
<tr>
<td valign="top" align="left">Stool samples from PTB patients (n=58) and symptomatic controls (n=47)</td>
<td valign="top" align="center">Stool samples from close contacts PTB cases (n=73) and close contacts of symptomatic controls (n=82)</td>
<td valign="top" align="center">inconclusive</td>
<td valign="top" align="center">
<italic>Erysipelotrichaceae</italic>, <italic>Anaerostipes</italic> and <italic>Blautia</italic> increased in patients</td>
<td valign="top" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B60">Naidoo et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">Stool samples from new <italic>M. tuberculosis</italic> PTB patients (n=21)</td>
<td valign="top" align="center">Stool samples from healthy controls (n=10)</td>
<td valign="top" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bacteroidetes</italic>, <italic>Actinobacteria</italic>, <italic>Veillonellaceae</italic>, <italic>Succinivibrionaceae</italic> and <italic>Crocinitomicaceae</italic> decreased in patients </td>
<td valign="top" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from PTB patients with antibiotics (n=39) and PTB patients without antibiotics (n=55)</td>
<td valign="top" rowspan="2" align="center">Stool samples from TB negative controls (n=62)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Lachnospiraceae</italic>, <italic>Lachnoclostridium</italic>, <italic>Anaeroglobus</italic> decreased in PTB patients without antibiotics;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (454) pyrosequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Enterococcus</italic>, <italic>Clostridiales</italic> and <italic>Rothia</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from new PTB patients (n=83)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=31)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Firmicutes</italic>, <italic>Actinobacteria</italic>, <italic>Clostridales</italic>, <italic>Bifidobacteriales</italic>, <italic>Bifidobacteriaceae</italic>, <italic>Lachnospiraceae</italic>, <italic>Ruminococcaceae</italic>, <italic>Marinifilaceae</italic>, <italic>Eggerhellaceae</italic>, <italic>Barnesiellaceae</italic>, <italic>Blautia</italic>, <italic>Roseburia, Bifidobacterium</italic>, undifined <italic>Ruminococcaceae</italic>, <italic>Fusicatenibacter</italic>, <italic>Romboutsia</italic> decreased in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (454) pyrosequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Bacteroidetes</italic>, <italic>Bacteroidales</italic>, <italic>Bacteroidaceae</italic>, <italic>Tannerellaceae</italic>, <italic>Fusobacteriaceae</italic>, <italic>Erysipelotrichaceae</italic>, <italic>Prevotellaceae</italic>, <italic>Bacteroides</italic>, <italic>Parabacteroides</italic>, <italic>Fusobacterium</italic>, <italic>Lachnoclostridium</italic>, <italic>Bacteroides vulgatus</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from new PTB patients (n=56) and latent PTB (n=36)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=50)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Firmicutes</italic>, <italic>Tenericutes</italic>, <italic>Roseburia</italic> decreased in patients;</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Actinobacteria</italic>, <italic>Bifidobacterium</italic> increased in patients</td>
</tr>
<tr>
<td valign="top" align="left">Stool samples from new PTB patients (n=55)</td>
<td valign="top" align="center">Stool samples from healthy controls (n=50) with slightly younger median age</td>
<td valign="top" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bacteroidetes</italic> and <italic>Bacteroides fragilis</italic> decreased in patients</td>
<td valign="top" align="center">RT-qPCR for targeting certain phylum, family or species</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B104">Yang et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from PTB patients (n=69)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=10)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Bacteroidetes, Proteobacteria, Fusobacteria, Bacteroidaceae, Tannerllaceae, Bacteroides, Veillonella</italic> increased in patients</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (515, 806) pyrosequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Firmicutes, Actinobacteria, Bifidobacteriaceae, Butyricioccaceae, Ruminococcaceae, Faecalibacterium, Bifidobacterium, Agathobacter</italic> decreased in patients</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="left">Stool samples from ITB patients (n=11)</td>
<td valign="top" rowspan="2" align="center">Stool samples from healthy controls (n=63)</td>
<td valign="top" rowspan="2" align="center">decreased alpha-deversity</td>
<td valign="top" align="center">
<italic>Proteobacteria</italic>, <italic>Megasphaera</italic>, <italic>Veillonellales</italic> decreased in patients</td>
<td valign="top" rowspan="2" align="center">16S rRNA gene amplicon (Illumina) sequencing</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<italic>Verrucomicrobia</italic>, <italic>Rhizobiales</italic>, <italic>Blautia</italic> increased in patients</td>
</tr>
</tbody>
</table>
</table-wrap>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>The main findings in alteration of gut microbiomes in TB patients compared to healthy controls at the phylum, order, family, and genus level. Red: elevation; blue: reduction; grey: not reported; white: no reported genus within the family.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1149679-g001.tif"/>
</fig>
<p>Most of the studies found a decreased alpha-diversity in TB patients (<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>; <xref ref-type="bibr" rid="B44">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B10">Cao et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B104">Yang et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>), with only one exception reporting increased diversity in both newly diagnosed PTB and recurrent PTB patients (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>). However, it should be noted that the study by Luo et&#xa0;al. reported a significant difference in the age structure between the healthy control group and the two TB patient groups (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>), which might have contributed to the observed enhancement in gut microbiome diversity. In a mouse model challenged with <italic>M. tuberculosis</italic>, dysbiosis resembling that observed in TB patients was observed in TB patients was reported (<xref ref-type="bibr" rid="B100">Winglee et&#xa0;al., 2014</xref>). The authors found a rapid initial post-infection reduction in alpha-diversity of the gut microbiome followed by slight recovery of diversity until death (<xref ref-type="bibr" rid="B100">Winglee et&#xa0;al., 2014</xref>). They proposed that the change in gut microbiome was due to the crosstalk between microbiota and immune system activation, while the recovery of diversity indicated the attainment of balance.</p>
<p>The dysbiosis observed in the gut microbiome of TB patients at the taxonomic level was mainly in the following aspects.</p>
<sec id="s2_1">
<label>2.1</label>
<title>Firmicutes
</title>
<p>
<italic>Firmicutes</italic>, which play a role in nutrition and metabolism (<xref ref-type="bibr" rid="B88">Stojanov et&#xa0;al., 2020</xref>), are the most abundant microbiome in the healthy human colon, comprising 64% of the gut microbiome (<xref ref-type="bibr" rid="B70">Piccioni et&#xa0;al., 2022</xref>). The imbalance in the ratio of <italic>Firmicutes/Bacteroides</italic> was also reported to indicate disrupted intestinal homeostasis, pathogen invasion, or unhealthy conditions (<xref ref-type="bibr" rid="B88">Stojanov et&#xa0;al., 2020</xref>). The significant reduction in the phylum <italic>Firmicutes</italic> in TB patients was observed by several independent groups (<xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>). The relationship between reduced <italic>Firmicutes</italic> and <italic>M. tuberculosis</italic> infection might be regarded as reciprocal causation. On one hand, the imbalanced microbiome composition caused by <italic>Firmicutes</italic> reduction might cause susceptibility to <italic>M. tuberculosis</italic> infection or the activation of TB in latent TB infection. On the other hand, the reduction of <italic>Firmicutes</italic> might also be triggered by the dysregulated immune system caused by <italic>M. tuberculosis</italic> infection.</p>
<p>Precisely, within <italic>Firmicutes</italic>, <italic>Clostridiales</italic> and <italic>Veillonellales</italic> were found to be decreased by some studies (<xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>). Meanwhile, many observations support the reduction of families <italic>Lachnospiraceae</italic>, <italic>Ruminococcaceae</italic>, and <italic>Clostridiaceae</italic> within <italic>Clostridiales</italic> (<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B44">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>) and the reduction of <italic>Veillonellaceae</italic> within <italic>Veillonellales</italic> (<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>). More interesting findings were observed at the genus level. Some of the most common genera in <italic>Firmicutes</italic> such as <italic>Faecalibacterium</italic>, <italic>Ruminococcus</italic>, <italic>Blautia</italic>, <italic>Roseburia</italic>, <italic>Lachnospira</italic>, <italic>Eubacterium</italic>, <italic>Coprococcus</italic>, and <italic>Dorea</italic> were all observed to be decreased (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>; <xref ref-type="bibr" rid="B44">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B104">Yang et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>), whereas <italic>Granulicatella</italic>, <italic>Lactobacillus</italic>, <italic>Enterococcus</italic>, and <italic>Streptococcus</italic> were observed to be increased in patients (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B44">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>).</p>
<p>As mentioned earlier, the reduced genera primarily belong to the two most abundant families in <italic>Firmicutes</italic>, <italic>Lachnospiraceae</italic> and <italic>Ruminococcacea</italic>e. They are obligate anaerobic and butyrate-producing bacteria (<xref ref-type="bibr" rid="B86">Sorbara et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B47">Liu et&#xa0;al., 2021</xref>). Butyrate is a short-chain fatty acid (SCFA) that is an essential regulator for the maintenance of intestinal homeostasis (<xref ref-type="bibr" rid="B68">Parada Venegas et&#xa0;al., 2019</xref>). Butyrate can interact with G-coupled receptors such as GPR43, GPR41, and GPR109a (<xref ref-type="bibr" rid="B30">Hodgkinson et&#xa0;al., 2023</xref>), leading to increased regulatory T cells (Tregs) and dendritic cell precursors, improved epithelial barrier function, as well as the increased expression of anti-inflammatory cytokines such as IL-10 (<xref ref-type="bibr" rid="B46">Liu et&#xa0;al., 2018</xref>). Additionally, butyrate can also inhibit HDAC activity to decompact chromatin and upregulate gene expression, inducing Tregs and the antimicrobial activity in intestinal macrophages (<xref ref-type="bibr" rid="B80">Schulthess et&#xa0;al., 2019</xref>). In addition, Phenylbutyrate (PBA), a derivative of butyrate, has been found to induce the expression of antimicrobial peptides in lung epithelial cells (<xref ref-type="bibr" rid="B87">Steinmann et&#xa0;al., 2009</xref>) and directly restrict the growth of <italic>M. tuberculosis in vitro</italic> or even within macrophages (<xref ref-type="bibr" rid="B18">Coussens et&#xa0;al., 2015</xref>). In clinical trials for TB patients, PBA in combination with vitamin D has also been shown to increase the clearance of <italic>M. tuberculosis</italic> by inducing the antimicrobial peptide LL-37 (<xref ref-type="bibr" rid="B55">Mily et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B56">Mily et&#xa0;al., 2015</xref>), while also ameliorating inflammation and improving symptom relief (<xref ref-type="bibr" rid="B7">Bekele et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B74">Rekha et&#xa0;al., 2018</xref>). LL-37 was reported to disrupt the cell wall of intra- and extracellular <italic>M. tuberculosis</italic> (<xref ref-type="bibr" rid="B19">Deshpande et&#xa0;al., 2020</xref>) and also activate the autophagy of macrophages (<xref ref-type="bibr" rid="B75">Rekha et&#xa0;al., 2015</xref>). Therefore, a decreased butyrate level would result in elevated pro-inflammatory responses, reduced antimicrobial activity, and impaired epithelial barrier function (<xref ref-type="bibr" rid="B14">Chen et&#xa0;al., 2019b</xref>).</p>
<p>Conversely, the increased genera in patients all belong to the order <italic>Lactobacillales</italic>, a group of lactic acid-producing bacteria. Lactic acid bacteria are generally regarded as beneficial microorganisms that support the host&#x2019;s gut homeostasis and enhance the epithelial barrier (<xref ref-type="bibr" rid="B76">Ren et&#xa0;al., 2020</xref>). However, it is also reported that lactic acid bacteria can induce Th1 and suppress Th2 responses during <italic>M. tuberculosis</italic> infection (<xref ref-type="bibr" rid="B28">Ghadimi et&#xa0;al., 2010</xref>). Meanwhile, it is also worth noting that some of the bacteria in <italic>Enterococcus</italic>, <italic>Streptococcus</italic>, and <italic>Granulicatella</italic> are opportunistic pathogens. The disrupted epithelial barrier caused by reduced butyrate can facilitate the colonization of these opportunistic pathogens.</p>
</sec>
<sec id="s2_2">
<label>2.2</label>
<title>Bacteroidetes
</title>
<p>
<italic>Bacteroidetes</italic> are the second most abundant microbiota in the healthy human colon, comprising 23% of the gut microbiota (<xref ref-type="bibr" rid="B79">S&#xe1;nchez-Tapia et&#xa0;al., 2019</xref>). Similar to <italic>Firmicutes</italic>, alterations in <italic>Bacteroidetes</italic> are also important in metabolism and energy balance (<xref ref-type="bibr" rid="B12">Chen et&#xa0;al., 2019a</xref>). However, unlike <italic>Firmicutes</italic>, <italic>Bacteroidetes</italic> are the main producer of the other two members of SCFAs, namely acetate and propionate (<xref ref-type="bibr" rid="B25">Feng et&#xa0;al., 2018</xref>).</p>
<p>Despite the contradictory findings in the alteration of <italic>Bacteroidetes</italic>, the most predominant findings were related to the three most abundant genera in <italic>Bacteroidetes</italic>, namely <italic>Bacteroides</italic>, <italic>Prevotella</italic>, and <italic>Parabacteroides</italic> (<xref ref-type="bibr" rid="B77">Rinninella et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B107">Zafar and Saier, 2021</xref>). In most studies, <italic>Bacteroides</italic> and <italic>Parabacteroides</italic> were reported to be increased in TB patients while <italic>Prevotella</italic> was reported to be decreased (<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B32">Hu et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B105">Ye et&#xa0;al., 2022</xref>).</p>
<p>Both <italic>Bacteroides</italic> and <italic>Parabacteroides</italic> are acetate-producing bacteria. Like butyrate, acetate can enhance antimicrobial peptides such as defensins, and also increase the epithelial barrier repairment by inducing the production of IL-22 (<xref ref-type="bibr" rid="B24">Fachi et&#xa0;al., 2020</xref>). Defensin, such as defensin-1, was found to inhibit the intracellular growth of mycobacterium inside granulomas (<xref ref-type="bibr" rid="B82">Sharma et&#xa0;al., 2017</xref>). Moreover, acetate was also reported to increase phagocytosis and bacterial killing by macrophages and neutrophils (<xref ref-type="bibr" rid="B26">Galv&#xe3;o et&#xa0;al., 2018</xref>). In addition, <italic>Bacteroides</italic> was also one of the major sources of propionate in the gut microbiota (<xref ref-type="bibr" rid="B48">Louis and Flint, 2017</xref>). Propionate was also shown to have antimicrobial activity. Propionate produced by <italic>Bacteroides</italic> was reported to limit the colonization of many bacteria such as <italic>Salmonella</italic> (<xref ref-type="bibr" rid="B35">Jacobson et&#xa0;al., 2018</xref>) and <italic>E.coli</italic> (<xref ref-type="bibr" rid="B66">Ormsby et&#xa0;al., 2020</xref>) by regulating intracellular pH. However, it should not be neglected that acetate may also suppress CD4+ T cell activation and Th1 and Th17 response while propionate may suppress antigen-specific CD8+ T cell activation by alleviating the IL-12 production by dendritic cells (<xref ref-type="bibr" rid="B63">Nastasi et&#xa0;al., 2017</xref>). These effects may also increase the susceptibility of the host to infections (<xref ref-type="bibr" rid="B2">Ahn et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B69">Piccinni et&#xa0;al., 2019</xref>).</p>
<p>In contrast, studies have shown that <italic>Prevotella</italic> can augment Th17-mediated mucosal inflammation (<xref ref-type="bibr" rid="B39">Kempski et&#xa0;al., 2017</xref>) and increase epithelial permeability to bacterial products (<xref ref-type="bibr" rid="B43">Larsen, 2017</xref>). This might be because <italic>Prevotella</italic> can activate TLR2-signaling and induce the secretion of IL-6, IL-8, and CCL20 by epithelial cells (<xref ref-type="bibr" rid="B90">Tamanai-Shacoori et&#xa0;al., 2022</xref>), as well as the secretion of IL-1&#x3b2;, IL-6, and IL-23 by dendritic cells (<xref ref-type="bibr" rid="B42">Kwok et&#xa0;al., 2012</xref>). These cytokines can induce Th17 immune response and neutrophil recruitment, increasing infection severity and tissue damage (<xref ref-type="bibr" rid="B43">Larsen, 2017</xref>; <xref ref-type="bibr" rid="B84">Shen and Chen, 2018</xref>). Therefore, reduced <italic>Prevotella</italic> as well as increased <italic>Bacteroides</italic> and <italic>Parabacteroides</italic> might simultaneously exert an anti-inflammatory effect.</p>
<p>Intriguingly, in the context of ITB, there seems to be minor differences compared with PTB patients. The most significant observation would be the opposite trends with decreased <italic>Bacteroides</italic> and increased <italic>Prevotella</italic> in ITB patients (<xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>). As the major sources of both acetate and propionate, decreased <italic>Bacteroides</italic> together with downregulated <italic>Firmicutes</italic> in ITB patients would result in a dramatic depletion of SCFA production. Based on the critical role that SCFAs play in epithelial barrier function, antimicrobial protein production, and immunomodulation, this depletion would cause excessive immune responses, increased inflammatory lesions, and antimicrobial peptide production. It might also increase the invasion and colonization of <italic>M. tuberculosis</italic> and other opportunistic pathogens in the gut.</p>
<p>Moreover, the increased <italic>Prevotella</italic> would also increase the Th17 response inducing neutrophil accumulation and granuloma formation after <italic>M. tuberculosis</italic> infection (<xref ref-type="bibr" rid="B81">Seiler et&#xa0;al., 2003</xref>). However, when exposed to excessive IL-17 produced by Th17 cells, longer survival of neutrophils can cause increased neutrophil infiltration and the formation of pathological lesions (<xref ref-type="bibr" rid="B92">Torrado and Cooper, 2010</xref>). This is also in line with the observation of elevated IL-17 expression in ITB patients (<xref ref-type="bibr" rid="B71">Pugazhendhi et&#xa0;al., 2013</xref>).</p>
</sec>
<sec id="s2_3">
<label>2.3</label>
<title>
<italic>Proteobacteria</italic> and <italic>Actinobacteria</italic>
</title>
<p>At the phylum level, <italic>Proteobacteria</italic> were observed to be increased in TB patients (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>), while conflicting trends were reported for <italic>Actinobacteria</italic> (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B61">Namasivayam et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B96">Wang Y. et&#xa0;al., 2022</xref>). However, at the genus level, <italic>Pseudomonas (</italic>
<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B29">He et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>
<italic>)</italic>, <italic>Shigella</italic> (<xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>)and <italic>Escherichia</italic> from <italic>Proteobacteria</italic> (<xref ref-type="bibr" rid="B50">Luo et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>)and <italic>Actinomyces</italic> from <italic>Actinobacteria</italic> (<xref ref-type="bibr" rid="B52">Maji et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B85">Shi et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B20">Ding et&#xa0;al., 2022</xref>)were all reported to be increased in patients. These bacteria are all common opportunistic pathogens and are always associated with the disruption of mucosal barriers (<xref ref-type="bibr" rid="B72">Pujic et&#xa0;al., 2015</xref>). An imbalanced SCFA constitution alters the gut environment resulting in dysregulated immune response and breakdown of the epithelial barrier, causing the colonization of opportunistic pathogens.</p>
</sec>
</sec>
<sec id="s3">
<label>3</label>
<title>Microbiome-immune crosstalk during <italic>M. tuberculosis</italic> infection</title>
<p>The gut microbiome and lung microbiome are not separate groups within an organism. They are tightly related by the so-called &#x201c;gut-lung axis&#x201d;, which means that the metabolites produced by the gut microbiome can reach the systemic circulation and shape the lung microbiome and the immune response in the lung, and vice versa (<xref ref-type="bibr" rid="B22">Enaud et&#xa0;al., 2020</xref>). Among the metabolites of the microbiome, SCFAs are the most extensively studied. SCFAs including acetate, propionate, and butyrate have been shown to have a modulatory role in the immune system and epithelial function.</p>
<p>In PTB patients, compared with healthy controls (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>), the main findings are the loss of <italic>Firmicutes</italic> such as <italic>Lachnospiraceae</italic> and <italic>Ruminococcaceae</italic>, and the enrichment of <italic>Bacteroidetes</italic> (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2B</bold>
</xref>). In the murine model challenged with <italic>M. tuberculosis</italic>, the authors also observed a post-infection reduction of butyrate-producing <italic>Lachnospiraceae</italic> and <italic>Ruminococcaceae</italic> and enrichment of acetate/propionate-producing <italic>Bacteroides</italic>, similar to the observations in humans (<xref ref-type="bibr" rid="B100">Winglee et&#xa0;al., 2014</xref>). Furthermore, two studies on the relationship between <italic>Helicobacter hepaticus</italic> and <italic>M. tuberculosis infection</italic> found that infection by <italic>Helicobacter hepaticus</italic> resulting in similar dysbiosis with increased <italic>Bacteroidaceae</italic> and decreased <italic>Clostridiales</italic>, <italic>Ruminococcaceae</italic>, <italic>Lachnospiraceae</italic>, and <italic>Prevotellaceae</italic> could cause hyperactivated immune response, overexpressed pro-inflammatory cytokines, and increased susceptibility to <italic>M. tuberculosis</italic>, resulting in severe lung damage (<xref ref-type="bibr" rid="B4">Arnold et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B53">Majlessi et&#xa0;al., 2017</xref>). These observations in patients and murine models may lead to the potential altered SCFA composition with decreased butyrate but increased acetate and propionate. A fecal metabolomic study also revealed slightly increased acetate and a significant decrease in butyrate in PTB patients (<xref ref-type="bibr" rid="B97">Wang S. et&#xa0;al., 2022</xref>).</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>The main findings in gut microbiome composition in PTB and ITB patients. Compared with the healthy conditions <bold>(A)</bold>, in PTB patients <bold>(B)</bold>, reduced <italic>Firmicutes</italic> and <italic>Prevotella</italic> and increased <italic>Bacteroides</italic> altered the proportion of each SCFA, causing immune cell recruitment and mildly increased immune response. However, when <italic>Bacteroides</italic> decreased and <italic>Prevotella</italic> increased <bold>(C)</bold>, decreased SCFAs production resulted in drastic activation of immune response and disruption of epithelial barrier, facilitating the colonization of <italic>M. tuberculosis</italic> in the intestine and the development of ITB.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1149679-g002.tif"/>
</fig>
<p>Acetate, butyrate, and propionate are all SCFAs that can exert anti-inflammatory effects by binding to GPR41 and GPR43. However, butyrate is the only SCFA known to bind to GPR109A (<xref ref-type="bibr" rid="B46">Liu et&#xa0;al., 2018</xref>). <italic>In vivo</italic> experiments using <italic>Gpr109a</italic>
<sup>-/-</sup> mice failed to ameliorate the inflammatory response and epithelial barrier dysfunction after sodium butyrate administration (<xref ref-type="bibr" rid="B13">Chen et&#xa0;al., 2018</xref>), indicating the importance of GPR109A in anti-inflammatory response and epithelial barrier construction. Another experiment using <italic>Gpr109a</italic>
<sup>-/-</sup> mice observed dysregulated immune responses and increased M1 macrophage polarization (<xref ref-type="bibr" rid="B108">Zhang Z. et&#xa0;al., 2022</xref>). Increased acetate and propionate may remedy the loss of butyrate in GPR41 and GPR43 activation but may not rescue the loss of GPR109A activation. The loss of butyrate in the gut microbiome and further in the circulation by the &#x201c;gut-lung axis&#x201d; results in dysbiosis in the lung microbiome (<xref ref-type="bibr" rid="B31">Hu et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B95">V&#xe1;zquez-P&#xe9;rez et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B103">Xiao et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B109">Zhang M. et&#xa0;al., 2022</xref>), as well as the disruption of the lung epithelial barrier and upregulation of pro-inflammatory cytokines in the systemic circulation such as IFN-&#x3b3;, TNF, and IL-17A (<xref ref-type="bibr" rid="B51">Machado et&#xa0;al., 2021</xref>). These pro-inflammatory cytokines and the opening up of tight junctions in the lung epithelial barrier can facilitate the migration of immune cells such as neutrophils and macrophages (<xref ref-type="bibr" rid="B3">Akdis, 2021</xref>). Macrophages and neutrophils are the first-line innate immune defense against <italic>M. tuberculosis</italic> by phagocytosis (<xref ref-type="bibr" rid="B78">Roca et&#xa0;al., 2019</xref>). Moreover, immune cells such as macrophages and dendritic cells can present antigens to T and B cells and augment adaptive immune responses. After infection, CD4+ T cells can not only further strengthen the innate immunity but also promote the function and survival of CD8+ T cells (<xref ref-type="bibr" rid="B49">Lu et&#xa0;al., 2021</xref>), whilst CD8+ T cells can directly kill <italic>M. tuberculosis</italic> by their cytolytic function (<xref ref-type="bibr" rid="B45">Lin and Flynn, 2015</xref>). Antibody opsonization was also shown to promote the phagocytosis of macrophages (<xref ref-type="bibr" rid="B11">Chandra et&#xa0;al., 2022</xref>).</p>
<p>However, when the SCFA level in circulation is sustainably reduced due to an imbalanced microbiome in TB, as observed in ITB patients with decreased Bacteroides (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2C</bold>
</xref>), the resulting depletion of IL-10 production and anti-inflammatory response can provoke the persistence of an overactivated pro-inflammatory response. Meanwhile, excessive TNF production was found to induce necroptosis of granuloma macrophages by activating the RIP1-RIP3 necroptosome (<xref ref-type="bibr" rid="B89">Stutz et&#xa0;al., 2018</xref>), which can facilitate bacterial replication and activation (<xref ref-type="bibr" rid="B78">Roca et&#xa0;al., 2019</xref>). Moreover, the increased <italic>Prevotella</italic> in ITB patients&#x2019; gut microbiota could further induce Th17 responses and aggravate neutrophil infiltration and pathological lesions in both lung and gut. The upregulated pro-inflammatory cytokine production may contribute to the overactivation of neutrophils and lead to impairment of mycobacterial controls within granulomas and thus exacerbate disease (<xref ref-type="bibr" rid="B59">Moreira-Teixeira et&#xa0;al., 2020</xref>). The observation of higher levels of neutrophils in the circulation of active TB patients also indicates the detrimental role of an overactivated immune response (<xref ref-type="bibr" rid="B58">Moideen et&#xa0;al., 2018</xref>). The uncontrolled replication and invasion of <italic>M. tuberculosis</italic> might facilitate its colonization in the gut and cause intestinal TB.</p>
</sec>
<sec id="s4">
<label>4</label>
<title>Perspectives and conclusions</title>
<p>The treatment of TB requires long-term multidrug treatment with a mixture of broad-spectrum and mycobacterial-specific antibiotics, especially for multidrug-resistant TB. However, it has also been reported that anti-TB medications can result in further dysbiosis of the intestinal microbiome in TB patients (<xref ref-type="bibr" rid="B62">Namasivayam et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B101">Wipperman et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B33">Hu et&#xa0;al., 2019b</xref>; <xref ref-type="bibr" rid="B106">Yoon et&#xa0;al., 2022</xref>). Intestinal microbiome disruption can also, in turn, limit the efficiency of treatment (<xref ref-type="bibr" rid="B65">Negi et&#xa0;al., 2020</xref>). A study of <italic>M. tuberculosis</italic> infection in mice pre-treated with isoniazid and pyrazinamide for 8 weeks also showed a higher lung bacterial burden. Besides, alleviated TNF and IL-1&#x3b2; production, decreased MHCII expression, and defective <italic>M. tuberculosis</italic> control were found in the alveolar macrophages of the mice. This phenotype can be partially reversed by fecal transplantation (<xref ref-type="bibr" rid="B40">Khan et&#xa0;al., 2019</xref>). Moreover, in our review, the current findings in TB patients also indicate a correlation between severely imbalanced gut microbiome with the development of ITB in PTB patients. Therefore, a balanced gut microbiome is crucial during <italic>M. tuberculosis</italic> infection. To achieve this goal, probiotics and postbiotics as potential routine supplements during TB treatment could be a one-stone-two-birds strategy.</p>
<p>Probiotics, such as <italic>Bacteroides fragilis</italic> and <italic>Lactobacillus plantarum</italic>, have already been considered novel probiotics in TB treatment (<xref ref-type="bibr" rid="B47">Liu et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B23">Eribo et&#xa0;al., 2022</xref>). <italic>B. fragilis</italic> has been reported to exert anti-inflammatory function by decreasing excessive IFN-&#x3b3; and inducing IL-10 secretion in mice through its metabolite PSA (polysaccharide) (<xref ref-type="bibr" rid="B37">Johnson et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B38">Johnson et&#xa0;al., 2018</xref>). The study by Negi et&#xa0;al., also reported increased MHCII expression on lung dendritic cells and a lower <italic>M. tuberculosis</italic> burden in the lung of mice after treatment with <italic>Lactobacillus plantarum</italic>. Another <italic>in vitro</italic> study using <italic>Lacticaseibacillus rhamnosus</italic> PMC203 found a direct restriction in <italic>M. tuberculosis</italic> growth and increased killing ability in infected RAW 264.7 cells (<xref ref-type="bibr" rid="B73">Rahim et&#xa0;al., 2022</xref>).</p>
<p>Postbiotics, such as indole propionic acid, can inhibit <italic>M. tuberculosis</italic> by targeting tryptophan synthesis (<xref ref-type="bibr" rid="B64">Negatu et&#xa0;al., 2019</xref>). PBA as a derivative of probiotics (butyrate) has also been tested in clinical trials and observed to provide significant relief of symptoms (<xref ref-type="bibr" rid="B7">Bekele et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B74">Rekha et&#xa0;al., 2018</xref>). However, the usage and concentration of probiotics and postbiotics must be individualized in the context of the patients. For example, different concentrations of SCFAs might have distinct functions (<xref ref-type="bibr" rid="B5">Ashique et&#xa0;al., 2022</xref>). Another example is the usage of SCFAs, which might be helpful in normal TB patients, but detrimental in people with HIV co-infection (<xref ref-type="bibr" rid="B51">Machado et&#xa0;al., 2021</xref>)</p>
<p>As mentioned above, studies have shown that the gut microbiome alteration in general TB patients (PTB) is characterized by dysbiosis, which is defined as reduced butyrate-producing <italic>Firmicutes</italic> and <italic>Prevotella</italic> (<italic>Bacteroidetes</italic>), and increased lactic acid-producing <italic>Firmicutes</italic>, <italic>Bacteroides</italic>, <italic>Parabacteroides</italic>, and opportunistic pathogens in <italic>Proteobacteria</italic> and <italic>Actinobacteria</italic>. The most significant consequence of this alteration, given the abundance of Firmicutes and Bacteroidetes in the human gut microbiome, is the change in the composition of SCFAs, with reduced butyrate and increased acetate and propionate metabolite production. When acetate and propionate production is further decreased by the reduction of <italic>Bacteroides</italic>, there might be an increased susceptibility to <italic>M. tuberculosis</italic> infection in the gut, causing ITB. Therefore, the gut microbiome may act as the defense line in preventing ITB development. Probiotics and postbiotics could become potential supplements in TB treatment and ITB prevention.</p>
</sec>
<sec id="s5" sec-type="author-contributions">
<title>Author contributions</title>
<p>ZY and JC designed the study. ZY and XS wrote the manuscript. AW and CH made contributions to the revision. All authors contributed to the article and approved the submitted version.</p>
</sec>
</body>
<back>
<sec id="s6" sec-type="funding-information">
<title>Funding</title>
<p>This study is supported by The National Natural Science Foundation of China (81960111) and Natural Science Foundation of Jiangxi Province (20202BABL206013). ZY has been supported by the China Scholarship Council (202008360174), XS has been supported by the China Scholarship Council (201909110092).</p>
</sec>
<ack>
<title>Acknowledgments</title>
<p>The authors would like to thank the reviewers of the manuscript, whose thoughtful and insightful comments helped to improve this review, and also thank the funding sources and all colleagues for useful discussion.</p>
</ack>
<sec id="s7" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>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.</p>
</sec>
<sec id="s8" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>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.</p>
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