Publications related to TB and the host microbiome were identified by searching PubMed, Google Scholar, and Web of Science using terms including but not limited to: (microbiota AND tuberculosis), (gut microbiome AND tuberculosis), (lung microbiome AND tuberculosis), (gut-lung axis AND microbiome AND tuberculosis), (tuberculosis treatment AND microbiome) and (recurrent tuberculosis AND microbiome). Further publications were identified from references cited in the relevant articles, reports, and conference proceedings. The search included all publications from inception until January 30, 2025, and was restricted to publications in or translated to English.

Recent studies have demonstrated that the composition and diversity of lung microbial communities significantly increase an individual’s susceptibility to MTB; however, this relationship is complex and multifaceted. Advances in next-generation sequencing have revealed intricate interactions between the lung microbiome, MTB, and the alveolar immune system, highlighting the critical role these interactions play in determining the outcome of MTB infection (Adami and Cervantes, 2015). These interactions directly affect the lung immune system, which in turn can influence the development of resistance or susceptibility to MTB infection (Balcells et al., 2019; Adami and Cervantes, 2015). One key factor influencing susceptibility is dysbiosis, or a reduction in diversity within the lung microbiome, which creates a more favorable environment for MTB proliferation. This was evident in a study using a mouse model, in which disruption of the microbiota led to increased early colonization of the lungs by MTB during the first week of infection (Dumas et al., 2018). Interestingly, this disruption was also correlated with changes in the gut microbiota, suggesting a link between the gut and lung microbiomes in modulating susceptibility to MTB. Furthermore, microbiota depletion led to a reduction in mucosal-associated invariant T (MAIT) cells and CD8+ natural killer T (iNKT) cells in the lungs 1 week after infection, which are essential for immune defense and whose development is dependent on the host microbiota (Jabeen and Hinks, 2023). This reduction in MAIT cells, IL-17A production, and iNKT cells, which are crucial for immune defense against MTB, could contribute to the increased susceptibility to MTB (Im et al., 2008; Mihi and Good, 2019).

It has been hypothesized that lung dysbiosis depletes beneficial bacterial species that are important for immune function, thereby weakening the host’s ability to resist MTB colonization and proliferation. Studies have shown that MTB infection alters the microbial landscape of the lungs, leading to dysbiosis, disruption of oral airway boundaries, and shifts in lung microbial diversity. A meta-analysis of microbiota studies identified distinct bacterial species signatures associated with healthy controls (Tumebacillus ginsengisoli, Propionibacterium acnes, and Haemophilus parahaemolyticus) and TB patients (Caulobacter henricii, Actinomyces graevenitzii, and Rothia mucilaginosa), suggesting that lung microbiome composition may be associated with MTB infection outcomes (Hong et al., 2018). Additionally, specific oral-associated bacterial taxa, such as SR1, Aggregatibacter, Leptotrichia, Prevotella, and Campylobacter, are more abundant in MTB-infected individuals (Cadena et al., 2018). In individuals infected with MTB, the lung microbiome is dominated by MTB, whereas in MTB-negative individuals, the microbiome is more diverse and enriched with species such as Streptococcus, Prevotella, Neisseria, Selenomonas, and Bifidobacterium (Hu et al., 2020). These changes, combined with the depletion of Helicobacter hepaticus, Firmicutes, Bacteroides, and Prevotella, can impair immune regulation and reduce the ability to control MTB infection (Osei Sekyere et al., 2020; Yu et al., 2023). As a result, the host experiences a reduction in the expression of pathogen recognition receptors (e.g., macrophage-inducible C-type lectin, MINCLE) and MTB-killing cytokines (e.g., IFN-γ, TNF-α, and IL-17), leading to a weakened immune response and compromised phagocytic activity (Osei Sekyere et al., 2020). Furthermore, dysbiosis impairs autophagy, which is a crucial immune mechanism for clearing MTB and controlling inflammation. The reduction in microbiota-derived short-chain fatty acids (SCFAs), which are important for modulating immune cell function and limiting MTB proliferation, further exacerbates weakened immune defenses (Osei Sekyere et al., 2020). Similarly, another study demonstrated that TB patients exhibit a reduced diversity of alveolar microbiota compared with healthy controls, characterized by a decrease in Streptococcus and Fusobacterium species and an increase in mycobacterial abundance, which are potentially influenced by the inflammatory milieu, wherein MTB may release virulence factors such as ESAT-6 and CFP-10 to compete for nutrients, thereby suppressing the macrophage response (Mihi and Good, 2019; Vázquez-Pérez et al., 2020; Zhuo et al., 2023). Interestingly, commensal species such as Lactobacillus plantarum and microbiota metabolites, including indole propionic acid, have been shown to help control the progression of TB (Osei Sekyere et al., 2020; Negatu et al., 2018; Negatu et al., 2019). However, prior colonization by other pathogens, such as Helicobacter hepaticus, can disrupt the microbiota balance and reduce the body’s ability to resist MTB infection (Osei Sekyere et al., 2020; Majlessi et al., 2017).

Taken together, these findings suggest that a healthy and diverse lung microbiome may offer some protection against MTB, whereas dysbiosis creates an environment that is conducive to MTB colonization and proliferation. The relationship between the lung microbiome and MTB is highly complex and multifaceted, involving immune regulation, microbial interactions, and host factors. Further research is essential to fully understand these complex relationships and their potential implications for TB prevention and treatment (Twigg 3rd et al., 2017; Balcells et al., 2019; Osei Sekyere et al., 2020).

The gut microbiome, a highly complex and diverse community of microorganisms residing within the gastrointestinal tract, has garnered significant attention as a crucial factor that influences various aspects of human health and disease. Emerging evidence from recent studies have indicated that the gut microbiome plays a pivotal role in modulating susceptibility to MTB infection, and may influence both the progression and outcome of TB (Negi et al., 2019; Khan et al., 2016). The gut microbiota affects MTB susceptibility through multiple mechanisms, including via the gut-lung axis. The gut-lung axis is a bidirectional communication pathway that enables the gut microbiota to modulate immune responses in the lungs, potentially altering the host’s ability to resist MTB infection (Namasivayam et al., 2018).

Recent research involving both animal models and human subjects has provided evidence that MTB infection is associated with changes in the composition and metabolic function of the gut microbiota. However, these changes are not universally observed across all studies and may vary depending on the host’s genetic background, environmental factors, and the specific stage of the disease (Namasivayam et al., 2018; Hu et al., 2019; Li et al., 2019). Furthermore, the temporal relationship between MTB infection and alterations of the gut microbiome in human are incompletely understood.

Yang et al. investigated the role of the gut microbiota in MTB-infected mice by administering antibiotics to deplete the intestinal microbiota and found that the gut microbiota modulates host susceptibility to TB and pulmonary inflammatory responses through commensal gut bacteria-regulated long non-coding RNA (lncRNA-CGB) (Yang et al., 2022). Using a murine MTB infection model, lncRNA-CGB was shown to be down-regulated by antibiotic-induced dysbiosis of gut microbiota during MTB infection. To confirm the functional significance of lncRNA-CGB, a lncRNA-CGB genomic knock-out mouse strain was developed, and ultimately, it was confirmed that knock-out mice had higher infection rates and more severe disease than controls. The basis for this observed protection in lncRNA-CGB-replete mice is posited to be due to reduced IFN-γ expression and impaired anti-TB immunity associated with the down-regulation or knock-out of lncRNA-CGB. The study also revealed that Bacteroides fragilis (B. fragilis) plays a crucial role in enhancing lncRNA-CGB expression, inducing IFN-γ expression, and promoting protective immunity against MTB. Mechanistically, lncRNA-CGB interacts with enhancer of zeste homolog 2 (EZH2) to negatively regulate trimethylation of histone H3 lysine 27 (H3K27Me3) epigenetic programming, ultimately enhancing IFN-γ expression. In a separate study, Yang et al. demonstrated that gut dysbiosis can remotely increase micro ribonucleic acid 21 (miRNA-21) expression in the lung, resulting in a significant decrease in IFN-γ in mice treated with exogenous miRNA-21. Furthermore, dysbiosis-mediated miRNA-21 expression was found to enhance MTB infection and progression (Yang et al., 2020). In a C3HeB/FeJ mouse model, a high-fat diet was associated with dysbiosis, a low Firmicutes/Bacteroides ratio, impaired immunological control of MTB following BCG vaccination, and enhanced MTB proliferation (Arias et al., 2019). Broad-spectrum antibiotic-treated mice were also shown to experience severe dysbiosis, enhanced MTB proliferation, and more frequent dissemination of MTB to the liver and spleen (Khan et al., 2016). Antibiotic-induced dysbiosis was associated with suppressed Th1 cell release of IFN-γ and TNF-α, and augmented regulatory T-cell frequency (Khan et al., 2016). Interestingly, fecal transplantation in the antibiotic-treated mice led to improved MTB control and restoration of Th1 cell frequency and activity (Khan et al., 2016). Helicobacter hepaticus colonization in mice has been shown to lead to shifts in the gut microbiota, characterized by a predominance of Bacteroides and a decrease in Firmicutes, resulting in impaired immune control (innate immunity and accumulation of activated T cells) of MTB and greater lung tissue damage (Majlessi et al., 2017; Arnold et al., 2015). Furthermore, research in macaques has suggested that Helicobacter pylori infection reduces the risk of progression to active TB following exposure to MTB by increasing IFN-γ and Th1-like responses, implying a potential protective immunological effect.

Several studies have reported changes in the gut microbiota composition during MTB infection in mice, macaques, and humans, noting alterations in genera such as Ruminococcaceae, Enterobacteriaceae, Erysipelotrichaceae, and Bifidobacterium (Cadena et al., 2018; Winglee et al., 2014; Khaliq et al., 2021; Valdez-Palomares et al., 2021; Ding et al., 2022; Huang et al., 2023). MTB infection in mice has also been show to result in a reduction in the relative abundance of bacterial families, including Clostridiales (specifically Lachnospiraceae and Ruminococcaceae) and the Bacteroidales order, within 6 days of infection, with this shift persisting even in the absence of antibiotic treatment or detectable MTB DNA in fecal samples (Winglee et al., 2014).

While human data on the role of microbiota in the initial resistance to MTB infection remain limited, evidence suggests that commensal bacteria and their antimicrobial products may modulate resistance to various pathogens, including Clostridium difficile, Salmonella enterica, and vancomycin-resistant Enterococcus (Namasivayam et al., 2018). Notably, Helicobacter pylori, which infects millions of people globally, appears to have a protective effect against MTB infection. In keeping with this observation, individuals with LTBI who do not progress to active TB are more likely to be infected with H. pylori, supporting its potential role in conferring protection against TB (Perry et al., 2010). In pediatric populations, children with TB exhibit reduced gut microbiota diversity compared to healthy controls, with an upregulation of pro-inflammatory bacteria such as Prevotella and Enterococcus and downregulation of beneficial bacteria such as the Bifidobacteriaceae family (phylum Actinobacteria), Ruminococcaceae family, particularly SCFA-producing species Faecalibacterium ruminococcaceae and Faecalibacterium prausnitzii (order Clostridiales; phylum Firmicutes), and Bacteroidaceae family (phylum Bacteroidetes) (Li et al., 2019). Similarly, a study involving adult human subjects with active and latent tuberculosis infection (LTBI) revealed a slight decrease in the alpha diversity of the gut microbiota compared with healthy controls, particularly in the genus Bacteroides (phylum Bacteroidetes) (Hu et al., 2019). A clinical trial focused on gut microbiota diversity in patients with TB revealed a significantly lower diversity index in individuals with new or recurrent TB than in healthy controls. In these patients, the abundance of Bacteroides was reduced, whereas Proteobacteria, which includes many pathogenic species, was enriched. Interestingly, the genera Prevotella and Lachnospira were negatively correlated with peripheral CD4+ cell counts in the recurrent TB group, suggesting that specific gut microbes may influence the immune status and outcome of TB infection (Luo et al., 2017). These findings suggest that changes in the Bacteroides population may be a common feature of TB infection. As gut commensals, Bacteroides species contribute to host immunity by providing nutrients to other microbes and maintaining gut homeostasis through the release of outer membrane vesicles (OMVs).

Additionally, Bacteroides can modulate immune responses by secreting antimicrobial toxins and competing with pathogens (Hu et al., 2019; Zafar and Saier, 2021). Contrasting results were observed in a study conducted in Xinjiang, a multi-ethnic region, where the abundance of Bacteroides was found to be higher in people with TB than in individuals with LTBI or healthy controls (Wang et al., 2022). This discrepancy may reflect geographical differences, population genetics, or other environmental factors that influence microbial populations. Wang et al. reported alterations in fecal metabolites and microbial composition in TB patients, with genera such as Bacteroides, Parabacteroides, Fusobacterium, and Lachnoclostridium being enriched in people with TB, while Blautia, Roseburia, Bifidobacterium, and unidentified Ruminococcaceae were enriched in healthy individuals. Notably, this dysbiosis is associated with a reduction in SCFA production, particularly acetic, propionic, and butyric acids, which are known for their anti-inflammatory properties and role in regulating immune function (Qin et al., 2015; Wang et al., 2022).

In summary, these findings suggest that specific gut microbes may be closely associated with the host immune status, which in turn can influence the susceptibility, progression, and severity of TB. Shifts in the gut microbiota, such as changes in the abundance of specific microbial genera, including Bacteroides, Prevotella, and Ruminococcaceae, can modulate immune responses and potentially enhance or impair the host’s ability to control MTB infection. Futhermore, MTB infection may deleteriously alter the gut microbiome, promoting disease progression and dissemination. The influence of the gut microbiome on immune function highlights its potential role in determining whether TB remains latent or progresses to active disease, underscoring the importance of the microbiome in shaping TB outcomes.

People living with human immunodeficiency virus/acquired immunodeficiency syndrome (PLWHA) are 26–31 times more likely to develop active TB than HIV-negative individuals, primarily due to the immunosuppressive effects of HIV on the host immune system (World Health Organization, 2012). Co-infection with HIV and MTB exacerbates the disease burden through immunological deterioration and HIV-induced dysbiosis, which increases the susceptibility to TB infection and accelerates disease progression. HIV-induced dysbiosis predominantly affects the gut microbiome, which plays a crucial role in immune regulation, with 70–80% of the immune cells residing in the gut-associated lymphoid tissue (Wiertsema et al., 2021). HIV disrupts the intestinal immune barrier, enabling microbial translocation and chronic systemic inflammation, both of which contribute to disease progression (Vujkovic-Cvijin et al., 2013). This disruption leads to gut dysbiosis, characterized by a reduction in microbial gene counts and an overabundance of gram-negative bacteria, acetogenic bacteria, and Proteobacteria, which can metabolize reactive oxygen and nitrogen species and potentially influence immune responses (Guillén et al., 2019). Disruptions in this axis may exacerbate TB progression and impair lung immunity, further contributing to the heightened susceptibility to TB observed in HIV-infected individuals.

In HIV-positive individuals with active TB, alterations in the lung microbiome may contribute to disease pathogenesis. Ueckermann et al. (2022) demonstrated that significant dysbiosis in a cohort of patients with HIV-associated TB, characterized by an increased abundance of Burkholderia and Stenotrophomonas in the lung microbiome of HIV-positive patients with active TB (Ueckermann et al., 2022). Burkholderia and Stenotrophomonas are commonly associated with underlying damage of the distal airways, especially in individuals with severe immunosuppression (Chawla et al., 2014; Huang et al., 2011; Regan and Bhatt, 2019). Similarly, in HIV-positive patients with pneumonia, a Prevotellaceae-dominated lower airway microbiome was found to independently predict mortality, with a distinct bacterial metabolome enriched in amino acid metabolites, monoacylglycerols, and inosine, along with elevated levels of pro-inflammatory cytokines such as IL-17A (Ueckermann et al., 2022). Further research into the impact of the microbiome on lung immunity revealed that, in PLWHA receiving antiretroviral therapy in a high-TB risk environment, the increased abundance of oral anaerobes, particularly Prevotella, in the lower airways correlated with higher serum levels of SCFAs (Segal et al., 2017). These elevated SCFA levels are associated with the induction of FoxP3-expressing Tregs in bronchoalveolar lavage lymphocytes following stimulation with a purified protein derivative (Segal et al., 2017; Zevin et al., 2016). These findings underscore the dual roles of gut and lung microbiomes in modulating immune responses to TB in HIV-infected individuals. The gut microbiome influences systemic immunity and the gut-lung axis, whereas alterations in the lung microbiome directly impact pulmonary immunity and host defense against TB. Targeting microbial dysbiosis in both the gut and lungs may represent a promising therapeutic strategy to improve immune responses and mitigate TB susceptibility in HIV-infected individuals. However, further research is required to elucidate the precise mechanisms by which gut and lung microbiome alterations contribute to TB pathogenesis and to identify effective interventions to address these microbial imbalances.

The co-occurrence of TB and diabetes mellitus (DM) poses a significant global health challenge owing to the high disease burden of both conditions. One potential explanation for the heightened co-prevalence of these diseases is the alteration of immune and microbial responses to MTB infection driven by hyperglycemia in diabetic individuals. Studies have shown that TB patients with DM exhibit distinct changes in their lung microbial communities compared with non-diabetic patients (Hong et al., 2018; Hong et al., 2016). The combination of TB and DM is characterized by dysbiosis of the airway microbiota, which may play a role in the pathophysiological processes associated with TB disease (Hong et al., 2016). Interestingly, poor glycemic control in patients with diabetes and TB is associated with more severe TB symptoms and higher bacterial loads. Patients with HbA1C > 9% were significantly more likely to be smear-positive than non-diabetic patients, indicating a potential link between glycemic control and TB severity (Chiang et al., 2015). Hyperglycemia can lead to changes in lung microbiota and disrupt immune function by causing fluctuations in cytokine levels. This weakens the host’s ability to control MTB infection, increases susceptibility, and worsens the disease severity. Key cytokines associated with both hyperglycemia and lung dysbiosis, such as IFN-γ, IL-17, and TNF-α, play crucial roles in inflammatory pathways that influence the progression of TB (Mori et al., 2021). Thus, hyperglycemia may contribute to TB development by altering lung microbiota and impairing immune responses through cytokine imbalances. In patients with both DM and TB, elevated IL-6 levels are commonly observed, which may result from changes in the lung microbiome. The reduced presence of Corynebacterium in the lung microbiota is associated with higher IL-6 levels, highlighting its role in modulating lung immune responses (Liu et al., 2017). As IL-6 is a pro-inflammatory cytokine central to immune regulation (Uciechowski and Dempke, 2020), fluctuations in its levels are important for understanding the link between hyperglycemia and TB pathogenesis. In newly diagnosed DM-TB patients, IFN-γ, IL-2, IL-17, and TNF-α levels are lower, but tend to increase in patients with a history of DM-TB, likely due to the control of hyperglycemia following diabetes treatment (Li et al., 2020). Chronic hyperglycemia, rather than acute spikes, has a significant influence on lung inflammation through cytokines, such as IL-2, IL-17, and TNF-α (Ngo et al., 2021). IL-17 aids immune defense against MTB by recruiting neutrophils and promoting inflammation. In contrast, TNF-α and IL-2, which are essential for macrophage activation and adaptive immunity, are dysregulated by hyperglycemia in established DM-TB cases, potentially impairing immune tolerance, enhancing inflammatory responses, and compromising immune function, thereby exacerbating TB pathogenesis.

Emerging evidence has established a link between DM-related gut microbiota dysbiosis and altered host immune responses to MTB infection. However, the precise interactions between the gut microbiota composition and immune responses in the development of TB in patients with DM remain poorly understood. The relationship between DM and gut microbiota appears to be bidirectional; while diabetes can induce changes in gut microbiota composition, shifts in the microbiota may also affect glucose metabolism and energy homeostasis, potentially contributing to the pathogenesis of diabetes (Lv et al., 2018; Craciun et al., 2022). This interplay involves multiple mechanisms, including the production of metabolites such as SCFAs, branched-chain amino acids (BCAAs), and lipopolysaccharides (LPS) (Zhang et al., 2021; Hamamah et al., 2024). Comparative studies indicate that relative to healthy individuals, patients with DM exhibit a reduced abundance of genera such as Bacteroides, Alistipes, and Blautia (Zhu et al., 2020; Que et al., 2021; Liu et al., 2022), along with an increased presence of Actinomyces and Prevotella (Leite et al., 2017). Moreover, DM patients with LTBI demonstrate elevated levels of Bacteroides, Alistipes, and Blautia in contrast to those without LTBI, suggesting that LTBI status may be associated with microbiota dysbiosis in individuals with pre-existing DM. These microbiota alterations are implicated in modifications of metabolic, inflammatory, and immune functions, all of which play critical roles in the onset and progression of diabetes (Zhang et al., 2021). Taken together, these findings highlight the critical role of hyperglycemia in modulating immune responses in TB patients with DM, emphasizing the need for further research into the mechanisms by which metabolic conditions influence immune function to inform targeted therapeutic strategies.