Tuberculosis (TB) is a deadly, airborne infectious disease caused by the acid-fast bacterium Mycobacterium tuberculosis (M. tb), and even after years of research, it still remains a major challenge to health globally. Nearly one-third of the world's population is infected with M. tb. However, most individuals do not develop active tuberculosis as some clear the infection and in others the bacteria can remain dormant in the host for a very long period of time; ~5–10% of the infected individuals develop active diseases (Emery et al., 2021; Global Tuberculosis Report, 2022). Immune deficiency and malnutrition are potential risk factors of host that enhance the rate of active disease development (Global Tuberculosis Report, 2022).

Individual's microbiota plays an important role in maintaining health and modulating treatment outcomes of various diseases. It is now well-established that gut microbiota (GM) has a complex and bidirectional relationship with its host. The GM regulates host's health by playing a significant role in various biological functions, such as immunity and inflammation, digestion and absorption of nutrients, bioavailability of vitamins and other micronutrients, hunger regulation, and metabolic homeostasis (Macpherson and Harris, 2004; Larsen et al., 2010). The intimate, symbiotic, and homeostatic coexistence of gut commensals with the humans entails an effective host immune system to uphold tolerance toward innocuous stimulants and restricting overuse of host resources (Macpherson et al., 2005; Dethlefsen et al., 2007; Chu and Mazmanian, 2013). Colonization happening during early stages of life is an important event of educating and maturing the host immune system (Gensollen et al., 2016). Up to ~2.5 years of age, the intra- and inter-individual microbiota variability is highest; then, it acquires a more stable adult-like composition (Russell et al., 2012; Yatsunenko et al., 2012; Backhed et al., 2015; Caballero-Flores et al., 2019; Zheng W. et al., 2020). Approximately 40% of the entire lymphocytes of the human body are situated in the gut, and changes in GM modulate gut inflammation, highlighting the importance of microbiota-immune system interactions (Grice and Segre, 2012). In addition, the altered composition and functions of microbiota are a key feature among individuals with different health conditions, such as obesity, type 2 diabetes, blood pressure, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD) (Hou et al., 2022; Vijay and Valdes, 2022). Studies support that M. tb infection causes the shift in gut microbiota (Hu et al., 2019a,b; Eribo et al., 2020; Wang et al., 2021). Moreover, the antibiotics used to treat infections and illnesses also affect the gut microbial composition and functions (Table 1) (Maji et al., 2017; Wang et al., 2020; Pant et al., 2022; Patangia et al., 2022; Dahiya and Nigam, 2023).

This review elucidates the structural and functional shift of GM upon M. tb infection and during the course of anti-TB treatment (ATT). This shift may result in differential metabolites and immune cells and the crucial mediators of gut–lung cross-talk via circulation. The functional capacity of GM also includes the genes required for synthesis or utilization of various macro/micronutrients which are further made available for host's utilization. Hence, dysbiosis of GM can have a major impact on host health by influencing the individual's response to ATT and treatment outcomes. Patient's compliance to treatment and complete cure from the disease are essential to curb M. tb dissemination and burden of antibiotic resistance. Therefore, gaining an understanding of the interplay between TB, ATT, and GM can help us discover the key players important for better treatment outcomes, new therapeutic strategies to treat TB, and reduce the treatment duration. Here, we have updated the current understanding of structural and functional composition of GM during TB infection and treatment and changes in nutrient profile and immune cell dynamics that are simultaneously happening in the patient's body. We also discuss the probable microbiome-based therapeutics to cure the TB disease along with drug resistance acquisition in M. tb.

In recent years, the NGS technology has made our understanding better in terms of gut microbial contribution in individual's nutrition, metabolism, and immune development. Dysbiosis leads to changes in the functional domain of GM and may contribute to the outcome of various diseases including TB (Qin et al., 2010, 2012; Karlsson et al., 2013). Recent studies suggest that various factors cause altered coding capacity of GM (Figure 1A). The HRZ-treated mice had reduced capacity for carbohydrate metabolism (Namasivayam et al., 2017). The HRZE therapy changed the microbial metabolic coding capacity which included protein secretion, sugar biosynthesis, and central metabolism. Enhanced vitamin biosynthesis and fatty acid oxidation and reduced conjugated bile acid biogenesis were also observed in HRZE-treated patients (Wipperman et al., 2017). Moreover, the indole propionate produced by gut bacteria is a potent inhibitor of M. tb both in vitro and in vivo (Negatu et al., 2019).

Structural and functional dysbiosis of GM has been linked with lung diseases through the gut–lung axis (Samuelson et al., 2015). The communication between respiratory mucosal surfaces and gut is through bidirectional movement of microbial products, cytokines, and metabolites (Figure 2). TB patient group at time-points, day 0, along with 1-week, and 1-month post-treatment initiation are significantly diverse from each other than are HCs in terms of functional repertoire of microbiota as shown by Hellinger distance calculated from KEGG Orthologs (KO) abundance. This suggested both phylogenetic and functional gut microbial dysbiosis in TB patients. In this study, many short chain fatty acid (SCFA) producers such as Pseudobutyrivibrio, Coprococcus, Faecalibacterium, and Phascolarctobacterium were significantly enhanced in the day 0 group. Interestingly, Prevotella, which is better equipped to consume plant-derived carbohydrates, was markedly depleted in TB patients, while the abundance of Bacteroides was increased (Maji et al., 2017). These two species were previously reported to show inverse correlation with the gut (Koropatkin et al., 2012; Ley, 2016; Maji et al., 2017).

In the gut of TB patients, altered relative abundance of certain genera was associated with marked changes in stool metabolites (Wang et al., 2021). The untargeted metabolic profile of TB patients identified 26 altered stool metabolites of which 17 were upregulated and 9 were downregulated. The pathways in which these metabolites were involved included ABC transporters, phosphatidylinositol signaling system, neuroactive ligand–receptor interaction, biosynthesis of primary bile acid, steroid, aminoacyl-tRNA, and amino acid, and metabolism of taurine and hypotaurine, phenylalanine, tyrosine, carbon, galactose, sulfur, inositol phosphate, ascorbate and aldarate, glycine, serine, threonine, cysteine, and methionine. M. tb infection reduced the SCFA production in feces which included significantly low levels of butyric acid, isobutyric acid, valeric acid, and 2-metylbutic acid. However, the levels of propionic acid and acetic acid were non-significantly reduced and elevated, respectively, in the TB group compared with HC. According to the Gini index, the models based on the combination of the top five metabolites, namely 3-hydroxypicolinic acid, 1-tetracosanol, pyrophosphate, behenic acid, and tromethamine, fairly discriminated for the TB group. These reports indicate that M. tb infection leads to significant changes in the metabolic profile with implications in the host metabolism.

TB patients had been found clinically to have low cholesterol level and BMI. Except for blood glucose (Glu) and albumin (Alb) levels, the serum levels of total cholesterol (Tch), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) were significantly lower in patients than in healthy controls (Deniz et al., 2007; Maji et al., 2017; Wang et al., 2021). Microbiota are well-appreciated to play an important role in the metabolic status of individuals. Four genera including Megasphaera, Blautia, Bilophila, and Rhodococcus enriched in healthy controls were positively associated with triglycerides (TG). Total cholesterol, LDL, and VLDL levels had a positive correlation with Romboutsia, Rhodococcus, Fusicatenibacter, and Gordonibacter and a negative correlation with Weissella, Cetobacterium, Campylobacter, and Dorea. HDL had a positive association with Elusimicrobium and Ezakiella, whereas Dorea and Blautia were negatively associated with glucose (Wang et al., 2021). In healthy controls, five metabolites enhanced, namely resorcinol, indoxyl sulfate, o-phosphoserine, orcinol, and inositol, had a positive association with the relative abundances of the following genera Fusicatenibacter, Barnesiella, unidentified Lachnospiraceae, Dorea, Tyzzerella, Raoultibacter, Butyricicoccus, Anaerotruncus, unidentified Ruminococcaceae, Collinsella, Roseburia, Bilophila, and Candidatus Soleaferrea. The TB group had 13 enhanced metabolites, namely ribonic acid, 5-aminolevulinic acid, 1,4-butanediol, taurine, 3-hydroxymethylglutaric acid, 2-keto-l-gluconate, 4-hydroxy-3-methoxyphenylglycol, 3-hydroxypicolinic acid, 4-hydroxycyclohexylcarboxylic acid, aconitic acid, hydrocinnamic acid, erythritol, and tromethamine, which were negatively associated with the following genera, Agathobacter, Blautia, Roseburia, Anaerotruncus, Candidatus Soleaferrea, Butyricicoccus, and Tyzzerella (Wang et al., 2021). Taken together, these studies indicate that M. tb infection and the anti-tuberculosis treatment lead to alteration of gut and systemic metabolic landscape (Figure 1A).

The respiratory tract is another important organ carrying a rich microbial consortium, although smaller than gut. Compared with gut, the lung microbiota is transient and more dynamic with low bacterial burden and influenced by influx and elimination of microbiota (Beck et al., 2012; Dickson et al., 2014; Bassis et al., 2015). The upper respiratory tract (URT) consists of nasal and oral cavities which comprise diverse microbiota (Wu and Segal, 2017). Furthermore, the microbiota associated with a healthy lower respiratory tract (LRT) has the predominant phyla, i.e., Bacillota, Bacteroidota, and Pseudomonadota, similar to that detected in the healthy intestine. However, the upper respiratory tract carries 100- to 10,000-fold more bacteria than the lower respiratory tract (He et al., 2017). In healthy individuals, the lung microbiota is more similar to that of the oropharynx than of the nasopharynx (Man and De Bogaert, 2017). It is evident from these studies that the lung microbiota is crucial for immunity and provides key signals for generating and proper functioning of the immune system. Our understanding of the compositional changes of the lung microbiota in the context of TB is on an early stage. A study reported that the sputum of TB patients had significantly higher bacterial diversity than of healthy controls. In addition, the clustering pattern of PTB patients was more scattered (564/614 total genera) compared with HCs (235/614 total genera). The PTB patient's sputum is found to carry many foreign/opportunistic bacteria, such as Mobilicoccus, Stenotrophomonas, Comamonas, Pseudomonas, Cupriavidus, Thermus, Methylobacterium, Sphingomonas, and Diaphorobacter (Cui et al., 2012; Wu et al., 2013; Krishna et al., 2016), and is associated with disease onset, recurrence, and TB treatment failure (Wu et al., 2013). Another study reported that PTB sputum was enriched with Bacillota and Actinomycetota, whereas sputum from HCs was significantly rich in Bacteroidota and Pseudomonadota (Krishna et al., 2016). Not only the bacteria but also the microbial metabolites also influence the TB infection outcomes. Higher active TB incidence was associated with increased SCFA production by anaerobic Prevotella in the lower respiratory tract of HIV-infected individuals (Lawani and Morris, 2016). Butyrate prevents M. tb antigen-specific IFN-γ and IL-17 responses and causes increased M. tb antigen-specific FOXP3+ Treg cells in the lungs, hence suggesting crucial role of microbial metabolites in immune responses (Lachmandas et al., 2016; Segal et al., 2017). Moreover, there is a continuous inter-communication between the gut and lungs, the so-called gut–lung axis, which is facilitated via the blood, lymph, or directly through aspiration by the movement of bacteria or their products and inflammatory markers. It will be interesting to study whether there is gut microbiome-induced modulation of immune response within the lungs of TB patients.

Malnutrition and deficiency of micronutrients are correlated with impaired immune responses, poor prognosis, and a huge risk factor for mortality in TB patients (Figure 3) (Lubart et al., 2007; Chang et al., 2013). Nearly two-thirds of TB patients show dramatic weight reduction and malnutrition. In various studies conducted in Indonesia, India, England, and Japan, nutritional status was significantly reduced in patients with active PTB patients (Karyadi et al., 2000; Gupta et al., 2009). It is difficult to determine whether TB disease occurs due to inappropriate nutritional status leading to compromised immune status or if this condition is displayed due to emergence of disease. Nutritional deficiency in patients may also be caused by anorexia and/or hyporexia and disorders associated with restricted food intake leading to body weight reduction (Portillo and Morera, 2012). Studies have shown that deficiency in single or multiple nutrients can enhance an individual's sensitivity to infections and disease emergence (Figure 3C) (Papathakis and Piwoz, 2013). Upon comparing and analyzing the nutritional level and macronutrient and micronutrient intake of TB patients and their household contacts, both the groups presented the problem of poor nutrition. Both the groups were deficient in energy, fiber, carbohydrate, and micronutrient (vitamins and minerals) intake, with a higher lipid and protein intake. Consistent with other results, the active patients presented lower BMI than HCs (Campos-Gongora et al., 2019). The groups also showed deficiencies in minerals such as copper, iron, magnesium, calcium, and zinc (Chan and Chan, 1994; Edem et al., 2015; Campos-Gongora et al., 2019). Another study estimated that the proportion of vitamin A deficiency in TB patients and controls was 56.4% and 39.0%, respectively, and all patients and 92.5% of controls were recognized with zinc deficiency (Ghulam et al., 2009; Keflie et al., 2018). The deficiencies in vitamins such as niacin, ascorbic acid, pyridoxine, and folic acid intake were also observed (Pakasi et al., 2009). The various micronutrient levels are also inter-twined, such as zinc deficiency is associated with vitamin A deficiency by two possible mechanisms as follows: (1) the oxidative conversion of retinol to retinal: involving zinc-dependent retinol dehydrogenase enzyme, (2) the hepatic synthesis of retinol-binding protein as retinol metabolism within the liver requiring suitable zinc concentration (Christian and West, 1998; Karyadi et al., 2002). These micronutrients are well-documented to protect against TB infection (Majeed et al., 1998; Stober et al., 2001; Pakasi et al., 2009; Ali et al., 2014). Supplementation of vitamin B6 and vitamin C improved TB patients' health by preventing ATT-associated side effects (Maggini et al., 2007; Pawar et al., 2011; Miric et al., 2013). In addition, the anti-TB drugs have shown to efficiently normalize the serum levels of selenium and zinc; however, the serum vitamin D, iron, and iodine levels were not normalized by these drugs (Feleke et al., 2019). Adequate nutrition prevents the progression of active TB; hence, it is recommended to have more research studies with larger human cohorts to understand long-term consequences of malnutrition on TB. In addition, strategies aimed to promote balanced diet with adequate nutrition among the household contacts of TB patients should be promoted.

Gut microbial capability to synthesize certain vitamins, particularly vitamin K and B group, is well recognized (Figure 3A) (Rowland et al., 2018; Yoshii et al., 2019; Lai et al., 2022). B. fragilis and P. copri (phylum Bacteroidota); C. difficile, L. plantarum, L. reuteri, L. delbrueckii ssp. bulgaricus, and S. thermophilus (phylum Bacillota), some species of Bifidobacterium spp (phylum Actinomycetota); F. varium (phylum Fusobacteriota); and S. enterica (phylum Pseudomonadota) possess a folate biosynthesis pathway suggesting that many species in all phyla produce folate. Bacteroides, Bifidobacterium, Streptococcus, and Lactococcus spp. can synthesize folate as a common food fermentation product of carbohydrates. Bifidobacterium and Lactobacillus spp. produce 7/8 B vitamins (Kleerebezem and Vaughan, 2009). GM produces thiamin that constitutes ~2.3% of the daily human requirement (Magnúsdóttir et al., 2015). The cobalamin biosynthetic pathway is presented in 42% (110/256) of the human GM genome and can be found in all Fusobacteriota; however, it is rare in Actinomycetota and Pseudomonadota, and half of the Bacteroidota genomes are missing this biosynthetic pathway. It also acts as an immunomodulator to promote cellular immunity (Degnan et al., 2014; Magnúsdóttir et al., 2015). Another human GM study showed that 83% of bacteria (260/313 species) encode cobalamin-dependent enzymes; however, most of these 260 species lack the genes required to synthesize cobalamin (Degnan et al., 2014; Uebanso et al., 2020). The changes in gut microbiota in TB patients could significantly affect the availability and/or utilization of nutrients and may contribute to the malnutrition.

Based on the role of microbiome in modulating the host immune response and metabolism, probiotics/microbiome-based therapeutics can be a potential therapeutic component against TB. Their effectiveness against a variety of infectious diseases has been well recognized (Jia et al., 2018; Pant and Das, 2022; Tegegne and Kebede, 2022). A study has suggested Lactobacillus crispatus PMC201, isolated from the vaginal microbiota of healthy Korean women, as a promising probiotic against TB. The bacterium inhibited the growth of M. tb H37Rv strain under co-culture conditions in broth and also lowered H37Rv and XDR M. tb in macrophages. This bacterium did not induce dysbiosis within a human gut microbial ecosystem simulator and was non-toxic to a guinea pig model. The inhibitory effect of PMC201 on M. tb was due to reduced pH triggered with organic acid production by this bacteria and lower level of pro-inflammatory molecule, nitric oxide (NO), which generally increased after M. tb infection. The study suggests PMC201 as a potential alternate drug candidate in improvising the current TB regime (Lee et al., 2021). Another study from the same group reported the anti-TB activity of another bacterial strain, Lacticaseibacillus rhamnosus PMC203, derived from vaginal microbiota of healthy women. This strain also suppressed M. tb growth under broth co-culture condition and displayed a promising intracellular killing against both antibiotic-sensitive and resistant M. tb-infected murine macrophage cell lines without exhibiting cytotoxicity. It induced expression of autophagy-related gene markers in dose-dependent manner, signifying a probable intracellular killing mechanism. In this study, they used probiotic lysate instead of live bacteria, which can be used as adjuvant with TB medication without worrying about the viability in the antibiotic environment. The study suggested that beclin 1 (core protein in autophagosome nucleation) and ATG (AuTophaGy-related gene) gene complex triggers PMC203-induced autophagy to lower the TB burden on macrophage cell lines, thereby suggesting its potential to use as an anti-TB drug candidate for treating both antibiotic-sensitive and resistant TB (Rahim et al., 2022). However, both these studies have used in vitro co-culturing and cell line experiments that display limitation in representing PTB within patient; therefore, further studies are required to evaluate the in vivo efficiency and confirm the mode of action of these strains. The probiotic Nyaditum resae^® (Nr), having heat-killed M. manresensis, abolished the development of TB in murine models and patients, by enhancing the specific effector and memory Treg cell function (Cardona, 2016; Montane et al., 2017). Oral administration of Bacteroides fragilis promoted anti-TB immunity by increasing long non-coding RNA, lncRNA-CGB expression via the gut bacteria-lncRNA-EZH2-H3K27Me3 axis (Yang et al., 2022). Lactobacillus plantarum MTCC 2621 supplementation reinstated the expression of macrophage-inducible C-type lectin (mincle) on lung dendritic cells (DCs) along with enhanced anti-M. tb response (Negi et al., 2019). Supplementation of L. casei to TB patients during intensive treatment phase resulted in significant reduction in inflammatory cytokines such as TNF-alpha, IL-6, IL-10, and IL-12, along with heightened metabolites, such as maresin 1, pyridoxamine, L-saccharopine, phosphatidylserine, and phosphatidylcholine (Jiang et al., 2022). The probiotic bacteria Lactobacillus plantarum, L. fermentum, and L. brevis exhibited antimycobacterial activity in an in vitro study (Gavrilova et al., 2014). Lactococcus lactis subsp. cremoris MG1363 produced an anti-microbial peptide, lacticin 3147, which demonstrated its potential as a therapeutic agent by strongly inhibiting the growth of M. tb strain H37Ra in vitro, with an MIC₉₀ value of 7.5 mg/L (Carroll et al., 2010). An anti-tubercular protein, NMANF2, with molecular mass of 7712.3 Da, produced by Staphylococcus hominis strain MANF2, has shown inhibition effect in a dose-dependent manner (Khusro et al., 2020).

Hence, to fight against the always evolving TB pathogen, identifying microbiome-based therapeutics and metabolic regulation of host could present opportunities to develop new strategies to combat drug resistance and poor treatment outcomes and reduce therapy duration.

Gut microbiota is a major modulator of immune function and systemic inflammation. Th17 cells, the potent immunomodulatory effector cells, found in bulk within lamina propria of the intestine, do not appear in germ-free (GF) mice but develop upon GM establishment (Ivanov et al., 2008). Hence, host–microbiota interactions have a substantial impact on innate and adaptive immune functions. Within the gut, various components of innate immunity, such as anti-microbial peptides (AMPs) and pattern recognition receptors (PRRs), constantly interact with the microbiota, thereby shaping their composition (Ehmann et al., 2019), and play a significant role in protecting host from pathogens and maintain tissue integrity (Brown, 2006; Dethlefsen et al., 2007; Mazmanian et al., 2008; Vijay-Kumar et al., 2010; Carvalho et al., 2012; Lee et al., 2018; Erturk-Hasdemir et al., 2019; Ramakrishna et al., 2019). The microbial metabolite sensor, such as Ffar2, is known to regulate the proliferation and function of a specific group of ILCs, i.e., group 3 ILCs (Chun et al., 2019). Moreover, the microbiota-derived metabolites such as secondary bile acids modulate intestinal RORγ+ Treg cell homeostasis (Song et al., 2020) and indole, encouraging the epithelial barrier fortification by upregulating the tight junctions and associated cytoskeletal proteins (Bansal et al., 2010; Zheng D. et al., 2020). T-cell-dependent and independent IgA secretion by the B cells in response to the commensals also play key role in gut homeostasis (Peterson et al., 2007; Sutherland et al., 2016).

GM dysbiosis, leading to immune dysregulation, is directly linked with chronic respiratory disease development such as asthma, cystic fibrosis, and COPD (Fujimura and Lynch, 2015; Hauptmann and Schaible, 2016; Wang et al., 2017). However, the role of microbiota-mediated immunity during M. tb infection remains less explored. Studies suggest the prominent role of GM in triggering and promoting the initiation and maintenance of immune responses during M. tb infection. Compared with H. pylori seronegative individuals, the seropositive individuals with LTBI show enhanced M. tb antigen-specific Th1 response and IFN-γ production and were less likely to progress to active TB (Perry et al., 2013). In infants, the abundance of Bifidobacterium spp. in GM was found to be linked with enhanced purified protein derivative (PPD)-specific T-cell responses after BCG vaccination (Ota et al., 2002). Fascinatingly, the GM disruption altered the adaptive immune response to TB, leading to enhanced Treg cells and lowering the TNF-α and IFN-γ secreting CD4+ T cells upon M. tb challenge (Khan et al., 2016). A gut commensal, B. fragilis, directly regulates lncRNA, termed lncRNA-CGB, which is downregulated due to GM dysbiosis induced by broad-spectrum antibiotics during TB infection in mice. Interaction of lncRNA-CGB with EZH2 negatively regulated H3K27 tri-methylation (H3K27Me3) epigenetic programming, resulting in heightened IFN-γ expression and enhanced anti-TB immunity (Yang et al., 2022). In another study, the mice exposed to broad-spectrum antibiotics to induce gut dysbiosis displayed reduced expression of mincle on lung DCs. These phenotypically and functionally impaired DCs, with reduced capacity to stimulate naive CD4 T cells, were not able to curb M. tb survival. This immune defect was significantly improved by in vivo trehalose-6,6-dibehenate (TDB: mincle ligand) administration, enhancing lung DC function and T-cell response along with expansion of Lactobacillus (Negi et al., 2019). These studies suggest that GM is important to establish either immunity or TB infection in the lungs and strongly support the scope of microbiota-based treatments as potential future therapeutics against TB.

Drug resistance (DR) in M. tb has limited the efforts to control and eradicate TB. In the next 35 years, it is predicted that ~75 million people would be killed due to DR-TB and put a cost of $16.7 trillion to the worldwide economy. Various factors for generation of DR-M. tb include strain's genetic background, its fitness, and capability to adapt to the niche, along with environmental and host-specific factors (Brites and Gagneux, 2015). Two factors responsible for development of DR in M. tb can be extrinsic and intrinsic. Extrinsic factors include the societal factors associated with TB and the quality of services provided in order to prevent and control TB. Intrinsic factors include acquiring genetic mutations (Gygli et al., 2017; Nguyen et al., 2018; Swain et al., 2020) in genes encoding for drug targets or enzymes for drug activation, which are introduced through single-nucleotide polymorphisms (SNPs) or insertion/deletions (indels). The role of horizontal gene transfer for DR acquisition is not very well informed in M. tb (Namouchi et al., 2012; Dookie et al., 2018). Drug concentration remains the important determining factor of mutation acquisition linked with resistance. The gut/lung microbiota carrying a huge enzymatic repertoire could play a significant role in inducing DR in M. tb as these antibiotics induced altered microbiota probably carrying an altered enzymatic and metabolic profile, thereby generating altered metabolites for gut–lung cross-talk. Hence, more studies should be carried out to explore and understand the microbiota-induced mechanisms in inducing drug resistance in M. tb, if any.

The understanding of the role of indigenous microbiota in infection, inflammation, and metabolic diseases and their homeostasis has substantially improved in the last two decades; however, several challenges and questions remain to be addressed (Box 1). Thorough investigations on the role of microbiota in contributing to differential inter-individual susceptibility to active TB and LTBI, reactivation from latency, and clearance with or without drugs are few, and more studies are urgently required. Another critical component is to find out whether ATT-induced GM dysbiosis could augment the susceptibility to TB reactivation after a successful cure and the emergence of drug resistance. Moreover, inter-individual variations in metabolizing dietary components are mainly due to the differential structural and functional composition of GM, which can have implications for the effects of some metabolites on health. Since, within this dynamic ecosystem, varying outcomes can result for the same substrate depending on the species existing and their proximity, therefore, apart from inspecting the microbiota in TB disease, a more in-depth understanding of GM cross-talk with airway epithelium, residing microbiota, and the innate or adaptive immune systems will be required. This understanding could transform the way TB is treated currently and may contribute to the development of novel therapeutic approaches.

AP conceived the idea, collected the literature, and drafted the review. BD and GA edited and finalized the review. All authors contributed to the article and approved the submitted version.