The human body contains a broad diversity of microorganisms, collectively known as the microbiota, which form a dynamic and functional system that evolves alongside its host. Although the gut harbors the largest population of microorganisms, they are also present throughout the body, including the entire digestive tract, skin, mucous membranes, urogenital and respiratory tract. This wide distribution underscores the significance of the microbiota in shaping and impacting various aspects of human health and physiology (Turnbaugh et al., 2007).

The millions of microbial cells in the human body play important roles in physicochemical and physiological functions, including intestinal development, barrier integrity and function, metabolism, immunity, inflammation, and neurological signaling regulation (Marsland et al., 2015; Enaud et al., 2020). The gut microbiome is highly dynamic and can be modified or disturbed by many factors, such as genetics, age, circadian rhythm, dietary habits, use of antibiotics, and other environmental factors (Nicholson et al., 2012; Dickson et al., 2016b). Furthermore, these factors play a role in the susceptibility, pathogenesis, and development of both non-transmissible and infectious diseases (Dang and Marsland, 2019; Naidoo et al., 2019; Wypych et al., 2019). In particular, malnutrition, diabetes, obesity, alcoholism, smoking, and HIV are some of the conditions that result in gut microbiome dysbiosis and altered immune function, that are associated with increased susceptibility to disease (Zevin et al., 2016; Weiss and Hennet, 2017; Iddrisu et al., 2021; Bach et al., 2023).

The increased intestinal permeability derived from this altered immune response and chronic inflammation allows metabolites and microorganisms to leak into the bloodstream, where they can affect other anatomical parts of the body, including the respiratory system (Usuda et al., 2021). Likewise, clinical studies on chronic lung diseases suggest that pulmonary disorders may be implicated in intestinal diseases (Rutten et al., 2014; Gui et al., 2021). Interestingly, the respiratory and gastrointestinal epithelia have structural similarities (Budden et al., 2017) and, in fact, several pulmonary and intestinal diseases exhibit many overlapping components, including common risk factors like mucus reduction, increased permeability, and low expression of tight-junction proteins, that can exacerbate the progression of infections (Duarte et al., 2018).

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) that persists as one of the top 13 causes of death worldwide (World Health Organization [WHO], 2022a). TB mainly affects pulmonary parenchyma presenting sustained weight loss, night sweats, fever, chronic cough, wasting, and hemoptysis. Diagnosis relies on identifying the microorganism through an automated PCR test (Xpert MTB/RIF and Xpert Ultra) (World Health Organization [WHO], 2021b). However, the heterogeneity of the TB clinical spectrum delays diagnosis and, therefore, anti-TB treatment (Cadena et al., 2017). Furthermore, anti-TB treatment represents one of the longest-duration antibiotic regimens used globally. This treatment includes combinations of at least four specific and broad-range antibiotics in schedules that range from four to more than 20 months, depending on the strain of MTB infection (World Health Organization [WHO], 2022b,c). Regardless of the regime, anti-TB treatment is associated with alterations of the gut microbiota in patients and animal models; the effect of these alterations in the lung microbiome and the underlying immune system response is the focus of many studies (Langdon et al., 2016; Namasivayam et al., 2017; Naidoo et al., 2019; Wang et al., 2020). This review aims to present a picture of recent studies on anti-TB treatment alterations of the microbiota in the course of the disease and its effect on the gut-lung axis.

The microbiome is a dynamic community of microorganisms that is in constant interaction with the host and its environment. Under physiological conditions, the microbiome is resilient to changes, benefiting both host and microbial communities, and it is considered to be in eubiosis (Giulio, 2021). On the other hand, the reduction of the adaptive capacity of a microbiome to changes that cause unfavorable alterations for the host is referred to as dysbiosis (Barbosa-Amezcua et al., 2022). All the different microbiomes in the human body: gut, lung, mouth, skin, genitals, liver and other barrier sites, are unique communities with specific interactions with the immune system and other organs in the body (Belkaid and Naik, 2013).

In particular, the host-associated gut microbiota is involved in several critical physiological functions such as absorption of nutrients, fermentation of food, vitamin production, and importantly, stimulating and training the immune system (Shreiner et al., 2015; Hillman et al., 2017; Al Nabhani et al., 2019). The gut microbiota includes bacteria, archaea, fungi, protozoa and viruses. Its composition is dominated by six bacterial phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, and two fungi phyla: Ascomycota and Basidiomycota (Nash et al., 2017). Although the composition changes with geographic location, diet, and age, it reaches a stable composition in absence of antibiotic treatment (Ferrer et al., 2017).

The interaction among all the organ systems is essential for the proper functioning of the body. Traditionally, this communication has been studied in the context of the autonomic nervous system, immune responses, and the endocrine system. However, recent research highlights a novel dimension of bidirectional communication between the gut microbiome and other organs such as the brain, skin, and lungs. These interactions constitute what is now recognized as the gut-brain axis, gut-skin axis, and gut-lung axis of microbiome communication, with each axis playing a significant role in maintaining overall health (Enaud et al., 2020; De Pessemier et al., 2021; Giulio, 2021). Despite the physical separation of the gut and lungs, microorganisms and immune cells communicate with each other resulting in immune tolerance to innocuous stimuli, host defense against potentially harmful external agents and pathogens as well as prevention of commensals from over-exploitation of host resources (Lazar et al., 2018; Yoo et al., 2020; Zheng et al., 2020).

Although the precise mechanisms of communication between the gut and lungs are not yet fully understood, emerging evidence points to the involvement of various pathways, including neuroendocrine and immune systems, as well as the translocation of microorganisms (Table 1 and Figure 1). These pathways often involve the release of metabolites, including microbiome-derived, that can shape immune responses, and modulate intestinal homeostasis and hematopoietic precursors in the bone marrow (Dang and Marsland, 2019). The vagus nerve, which connects the brain to multiple organs, including the lungs and gastrointestinal tract, is an essential conduit for this communication (Yuan and Silberstein, 2016). Onyszkiewicz et al. (2019) reported that butyric acid, a short-chain fatty acid (SCFA) produced by gut microbiota, lowers arterial blood pressure via colon-vagus nerve signaling. Furthermore, recent evidence has shown that the gut microbiota influences the hypothalamic-pituitary-adrenal (HPA) axis and the body’s response to stress (Frankiensztajn et al., 2020). In particular the intake of Lactococcus lactis was shown to lower the basal activity of the HPA axis, improve sleep, mental health and immune response through the activation of MQs and NK cells (Jin et al., 2020; Matsuura et al., 2022).

The interaction between the gut microbiome and the respiratory system through the immune system is complex and dynamic; the microbiome exposes immune cells to a diverse range of antigens and microbial molecules, shaping its development and function, whereas the immune system maintains a permissive environment for the microbiota (Belkaid and Naik, 2013; Zheng et al., 2020). Both branches of the immune system participate in this communication. The innate immune system confers compartmentalization, preventing microbial translocation through a dense mucus layer, antimicrobial peptides (AMP), and tight junction proteins that preserve the epithelial barrier (Thaiss et al., 2016). Furthermore, the response of innate immune cells such as macrophages, dendritic cells, neutrophils, innate lymphoid cells, and epithelial cells respond to both commensal microbes signals and microbe-associated molecular patterns (MAMPs) (Chunxi et al., 2020). On the other hand, the gut commensal microbiome supports the production of secretory IgA by the adaptive immune system, which shapes microbial communities (Huus et al., 2021).

The integrity of the intestinal and lung epithelial barriers is crucial to prevent the translocation of microorganisms between the gut and respiratory tract and to maintain the internal physicochemical characteristics of both anatomical structures. However, the intestinal and lung epithelial barrier can be compromised under specific circumstances such as microaspirations, critical illness, sepsis, or chronic inflammation (Kang et al., 2023). As a result, microorganisms can translocate from the gut to the respiratory tract, potentially leading to the colonization of the respiratory tract by gut-derived microorganisms and contributing to the development or increase of severity of respiratory infections (Dickson et al., 2015; Wheatley et al., 2022). Similarly, respiratory system microorganisms, such as Streptococcus pneumoniae, have the potential to colonize the gastrointestinal tract (Floeystad et al., 2020). Furthermore, studies on a mice model, showed that the intratracheal inoculation of Lipopolysaccharides result in lung and gut microbiome perturbations with a parallel increase of bacterial load in the blood (Sze et al., 2014), underscoring the close interaction between these sites.

The dysbiosis and the resulting inflammation in one or both organs may contribute to the development of disease (Fabbrizzi et al., 2019). These interactions are influenced by immune cell migration and microbial metabolites in response to infection or inflammation (McGhee and Fujihashi, 2012; Zhao et al., 2022). Microbial metabolites produced by gut microbiota, such as SCFAs, tryptophan, secondary bile acids and their derivatives, modulate immune and epithelial cells (Agus et al., 2018; Ashique et al., 2022). SCFAs are a preferred energy source for colonocytes; they regulate the integrity of the intestinal barrier by inducing the secretion of IL-18 and antimicrobial peptides and the expression of the tight junctions. SCFAs inhibit macrophage production of proinflammatory cytokines and regulate T cell differentiation to Th1, Th17, and Tregs, thus are a central component of this interaction (Sun et al., 2017; Sencio et al., 2021).

Overall, the gut-lung axis is a complex and multifaceted system involving interactions between immune cells, microbiota, and signaling molecules from both systems. The response as a whole will depend on the health conditions and comorbidities of the individual and the different disease etiologies, which highlights the importance of understanding these interactions in different pathological conditions. An important factor to consider is the profound effect of antibiotics on the gut microbiome which have been found to have an increased risk for respiratory diseases in human studies as well as animal models (Ichinohe et al., 2011; Metsälä et al., 2015; Anand and Mande, 2018). The role of the gut-lung axis in tuberculosis has gained increasing recognition in recent years, highlighting its significance in the context of this infectious disease (Naidoo et al., 2019). Several studies have revealed that gut microbial dysbiosis can exacerbate lung inflammation and contribute to a dysregulated immune response to M. tuberculosis (Sekyere et al., 2020; Comberiati et al., 2021).

Tuberculosis is a disease that has co-evolved with humankind for millennia. Infection with MTB can result in a dynamic spectrum of clinical manifestations that range from elimination to asymptomatic latent TB to clinically active TB. Several factors influence these dynamic states, notably the immune response, microbiota, and the interaction between them. The main risk factors for tuberculosis include HIV infection [Relative Risk (RR) 18], alcohol use disorders (RR 3.3), undernourishment (RR 3.2), smoking (RR 1.6), and diabetes (RR 1.5) (World Health Organization [WHO], 2021a), all of which are associated with gut dysbiosis and proinflammatory susceptibility.

Of particular importance is the fact that MTB-infected individuals often have delayed diagnosis or undergo non-tuberculosis antibiotic treatment before a specific TB treatment is prescribed (Shi et al., 2021; Teo et al., 2021); in both instances, the resulting microbiome dysbiosis may increase the severity of the disease (Hogan et al., 2017). Broad-spectrum antibiotics, including cephalosporins and fluoroquinolones, are among the most frequently empirically prescribed antibiotics. Specifically, a decrease in the abundance of Roseburia, Kluyvera, and Citrobacter genera, and a near depletion of SCFA-producing bacteria, have been reported in these TB patients (Shi et al., 2021). Thus, gut microbiome dysbiosis, with a predisposition to inflammatory response, is expected in most patients secondary to the start of empirical antibiotic treatment, even before starting specific anti-TB treatment.

There has been a great deal of research on M. tuberculosis’s long and complex interaction with its host. Many of the factors that contribute to the susceptibility and development of the disease are associated directly or indirectly with immune maintenance, including HIV infection, malnutrition, diabetes, smoking, and substance abuse. All of these conditions result in gut microbiome dysbiosis. In turn, gut dysbiosis has been implicated in disease development locally or distal, including in the respiratory tract. Although we are just beginning to understand the crosstalk in the gut-lung axis that allows passage of microbial and host metabolites, it has become clear that these interactions affect the susceptibility and development of many respiratory diseases, including tuberculosis.

Gut microbiota is altered from the initial lung infection of MTB and increases substantially with the long anti-TB treatments. TB treatment is one of the world’s most widely administered antibiotic combinations. The long-term effect of antibiotic treatments is evident; from 6 months of DS TB, treatment that can last up to a year, to potentially irreversible changes after a 20-month DR-TB treatment (Wang et al., 2020). The loss of bacterial diversity as a result of antibiotic treatment can lead to an increased vulnerability to infections, as has been shown for C. difficile, E. coli, and S. enterica (Croswell et al., 2009; Wang et al., 2020), and may be part of the explanation for high relapse or reinfection rates on DR-TB patients. Additionally, even with treatment adherence, 14% of DS and nearly 40% of DR TB patients fail treatment, and 5% of all patients with successful treatment relapse (Getahun et al., 2011; World Health Organization [WHO], 2022a). This suggests that the cure and prevention of relapse in tuberculosis may not depend solely on anti-TB treatment. The respiratory and gut microbiota dysbiosis and its interplay with the immune response play an important part. There is numerous evidence that demonstrates changes in the taxonomic composition as well as the overall diversity of the gut and respiratory microbiome during anti-TB treatment. However, probably due to differences in study design and samples taken, or individual characteristics of each patient, there are inconsistent results in terms of changes of specific organisms. To fully understand the interplay between the microbiome and host defense mechanisms, longitudinal studies that follow patients’ respiratory and gut microbiome through their treatments, integrating the immune response, are needed. Furthermore, we need to go beyond the study of only bacteria and include all other microorganisms in the microbiota as well as metabolome and resistome.

Although we have pointed out some of the adverse effects of antibiotic therapies, it is clear that antibiotic therapy for TB and other infectious diseases is a central tool for their treatment. However, strategies that reduce dysbiosis and restore a healthy microbial balance are needed. In tuberculosis management, current efforts include shortened and narrow spectrum antibiotic therapies, together with host-directed-therapies that improve immune response. There are promising results in the use of pre- and probiotic adjunct therapies in TB treatment; however, more clinical studies are needed to establish their effectiveness in this specific context. Patients’ individual characteristics, choice of pre or probiotics, dosages, timing need careful consideration.

In sum, the treatment of tuberculosis has broad public health implications, with millions of people being treated with first-line anti-TB medicines for 6 months, resulting in microbiome dysbiosis lasting years after treatment completion (Wipperman et al., 2017). Future research should aim to develop strategies that optimize treatment outcomes by considering the dynamic interplay between the microbiome and host immune responses.

ES-H and NA-P: conceptualization. DG-C, IG-G, and NA-P: methodology. ES-H, DG-C, XM, IG-G, and NA-P: formal analysis, investigation, review and editing, and writing-original draft preparation. IG-G: visualization. ES-H: supervision and funding acquisition. All the authors contributed equally to writing and editing of the document, read, and agreed to the published version of the manuscript.