Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb), with approximately 10 million people being infected each year and 1.6 million deaths in 2021 (Furin et al., 2019; Bagcchi, 2023). The epidemic of TB has brought heavy economic and social burdens to countries around the world. According to the World Health Organization (WHO) Global TB Report 2022, the global spending on essential TB services for TB diagnosis, treatment, and prevention has exceeded $6.4 billion (Global tuberculosis report 2023, 2023). Besides, drug-resistant forms of Mtb are currently on course to be the world’s deadliest pathogens, responsible for a quarter of deaths due to antimicrobial resistance (Furin et al., 2019). The prevalence of drug-resistant Mtb is also a major threat to the control of TB. Hence, it has been an urgent task for researchers to develop more effective measures for the prevention and treatment of TB.

Recent advances in gut microbiota explorations have led to improved knowledge of the ‘gut–lung axis’. Some studies have shown that intestinal microbiota dysbiosis may affect the occurrence and development of respiratory diseases including asthma, chronic obstructive pulmonary disease, respiratory pathogens infection, etc. by the ‘gut–lung axis’ (Keely et al., 2012; Barcik et al., 2020; Wang et al., 2023). The documents about the relationship between gut microbiota and TB have increased in recent years, and increasing evidence supports the presence of intestinal microbiota dysbiosis in TB patients. A case–control study of pulmonary TB in pediatric patients showed that the abundance of Prevotellaceae and Enterococcaceae was increased, and the abundance of Oscillospiraceae and Bifidobacteriaceae was decreased in TB patients compared with healthy control subjects (Li et al., 2019). Maji et al. have found that the levels of Provetalla decreased and Bacteroides increased in TB patients (Maji et al., 2018). Recently, our teams’ study in active TB patients showed the abundance of Bacteroidetes significantly altered compared with health subjects (Han et al., 2024). Another study also showed the phylum of Bacteroidetes altered in the feces samples of patients with recurrent TB (Luo et al., 2017). All these researches indicated that Mtb infection can lead to the alteration of intestinal microbiota composition.

However, the causal relations between Mtb infection and intestinal microbiota dysbiosis have not been fully elucidated. Some factors including alcohol, smoking, HIV infection, and diabetes have been proven to cause gut microbiota dysbiosis, and these also are important risk factors for TB (Naidoo et al., 2019). A recent study has shown that the mice fed with a high-fat diet-induced gut microbiota dysbiosis increased the risk of developing active TB in mice (Arias et al., 2019). Another study found Firmicutes/Bacteroidetes ratio increased in a murine model of type 2 diabetes induced by an energy-dense diet, and increased the susceptibility to Mtb infection (Sathkumara et al., 2021). These findings support a viewpoint that the changes in the gut microbiome are a contributing factor in Mtb infection pathogenesis and its clinical presentation. Many documents supposed that gut microbiota dysbiosis could modulate immunity and inflammation reaction at distal sites such as the lungs, reduce colonization resistance by external pathogens, and promote TB susceptibility (Naidoo et al., 2019; Osei Sekyere et al., 2020). Hence, modulation of the gut microbiota and balance of the gut–lung axis was a potential avenue for TB prevention and management.

Based on our previous studies and other reports, we found the effect of Mtb infection on the gut Bacteroidetes was most significant. Hence, in the present study, clindamycin (CL), an antibiotic that selectively disorders anaerobic Bacteroidetes (You et al., 2019), was used to establish a mouse model of intestinal microbiota dysbiosis. We uncovered the important role of gut microbiome dysbiosis affecting Mycobacteria colonization in the mouse lungs using the technology of fecal microbiota transplantation (FMT). Furthermore, based on the ‘gut–lung axis’ theory, we performed a transcriptomic analysis of the mice lungs after Mycobacteria infection. We aim to explore the potential role and mechanism of gut microbiome dysbiosis enhancing Mycobacteria colonization in the lungs of mice.

TB remains a major health challenge globally. How to effectively limit or reduce Mtb colonization in the host is a potential strategy to prevent this disease transmission and development. Recent studies have shown that the gut microbiome can affect distant organs via the ‘gut–lung axis’, and gut microbiota dysbiosis is a potential factor inducing respiratory diseases including TB (Waldman and Balskus, 2018; Ma et al., 2022). Previous studies have shown that the gut microbiota was significantly different in TB patients compared with healthy humans and revealed gut microbiota dysbiosis, especially Bacteroidota, and Firmicutes, is strongly associated with the development of TB (Maji et al., 2018; Luo et al., 2017). However, how the gut microbiota affects TB development by the ‘gut–lung axis’ remains unclear. In the present study, we established a mouse model of gut microbiota dysbiosis and an FMT model using clindamycin treatment and revealed the potential mechanisms of intestinal microbiota dysbiosis promoting MS pulmonary colonization in the mouse by upregulating Nos2 gene-associated pathways.

Antibiotics can induce intestinal microbiota dysbiosis, which in turn affects host immunity and leads to increased susceptibility and deterioration of a variety of diseases (Fishbein et al., 2023). Previous research has verified that gut Bacteroidota dysbiosis is strongly associated with the development of TB (Du et al., 2022; Huang et al., 2019; Yunusbaeva et al., 2024). Hence, we select clindamycin, an antibiotic that selectively disrupts anaerobic Bacteroidota (You et al., 2019), to treat the mice in this study. Our results show that the abundance of Bacteroidota was significantly reduced and the abundance of Firmicutes was increased in the CL group compared with the CON group. This result is consistent with the previous study which reported that CL is effective in clearing Bacteroidota (You et al., 2019). Bacteroidota is a consortium of many commensal bacterial species responsible for major fermentation processes, glycolipid production, and promoting systemic Th1 immune responses (Mazmanian et al., 2005).

The fungi are also important components of the gut microbiome. The gut fungi mycobiota dysbiosis is related to many diseases (Azzam et al., 2020). In the present study, we found that the gut fungi mycobiota balance of mice was disrupted by CL, especially, Aspergillus and Cladosporium significant increase in the CL vs the CON groups. Aspergillus and Cladosporium are opportunistic pathogens that usually cause lung infections in immunocompromised patients (Wheeler et al., 2017; Sandoval-Denis et al., 2015). Bacteria and fungi harbor together in the gastrointestinal tract and occupy the same ecological niche. They interact with each other and develop complex ecological networks through these interactions. Homeostasis of microbial ecological networks limits pathogen invasion and infection (Lozupone et al., 2012). The ratio of ITS2/16S rRNA can reflect the diversity and composition structural alterations of the fungi–bacterial microbiota (Lemoinne et al., 2020). In general, antibiotics are directed against bacteria and do not affect fungi. However, our data revealed that CL treatment significantly altered the diversity and composition structure of the fungi–bacterial microbiota, and reduced the trans-kingdom network complexity and interaction between bacteria and fungi. These suggested that the alterations of gut bacteria can affect the composition and diversity of fungi. Previous documents had also reported that any changes in gut bacteria would inadvertently cause alterations in the gut fungal community, and targeted fungal interventions would also cause changes in the gut bacterial community (Haak et al., 2021; Sovran et al., 2018; Charlet et al., 2018; van Tilburg Bernardes et al., 2020). Hence, gut microbiota should be taken as a whole rather than a single genus to explain the relationship between gut microbiota and associated diseases.

Since most of the microbes in the gut are non-culturable, the FMT is considered to be an ideal model to study the function of gut microbiota. The success or not of FMT is influenced by many factors, such as host intestinal microbiota, immunity, and genetic factors (Porcari et al., 2023). During the FMT, not all microbiota in the donor feces have the same colonization ability in the receptors. Some research has revealed that the colonization success rate of Bacteroidetes is higher than that of Firmicutes (Hintze et al., 2014). In the present study, we found that the ratio of Firmicutes/Bacteroidetes in the CL treatment group increased compared to the control group (Figure 3b). However, after FMT, the ratio of Firmicutes/Bacteroidetes decreased in the CL-FMT group vs the CON-FMT group (Figure 4d). We speculated that the possible reason for this difference was that the colonization of Firmicutes decreased in the CL-FMT receptor group after transplantation. In contrast, the colonization of Bacteroides increased, resulting in a decrease in the proportion of Firmicutes/Bacteroides in the CL-FMT group. However, we considered the gut microbiota as a whole in the analysis of the experimental results. After FMT, we found that 85.11% of bacterial genera and 52.38% of fungi genera present in the CL inocula were successfully transferred to the CL-recipient mice, and 91.45% of bacteria genera and 56.36% of fungi genera in the CON inocula were also successfully transferred to the CON-recipient mice, respectively (Figure 4g). The trans-kingdom network analyses between bacteria and fungi showed that the trends of the gut microbiome in recipient mice were consistent with those in the donor mice. Therefore, the inconsistent results between Figures 3b and 4d will not affect this study’s findings, and the FMT model established in this study is successful.

The FMT results revealed that gut commensal bacteria dysbiosis can promote MS colonization in the lungs of mice, but the underlying mechanisms remain not fully understood. Recent studies have suggested that changes in the ‘gut–lung axis’ are a contributing factor in the pathogenesis and clinical manifestations of Mtb infection (Yang et al., 2022; Alvarado-Peña et al., 2023.) What is the substance mediating the interaction between the lung and the gut? There have been a variety of results in the different studies. Yang et al. have found that the gut microbiota via modulation of lncRNA-mediated protective immunity against Mtb, and they found Bacteroides fragilis directly upregulated expression of lncRNA and promoted anti-TB immunity (Yang et al., 2022). However, another clinical study on TB found that the expression level of iNOS in the plasma of new-onset pulmonary TB patients was significantly higher than that of healthy humans (Chinta et al., 2016). In the present study, we found that Nos2 expression significantly rises in the CL and CL-FMT groups. Hence, we speculated that the gut microbiota may increase MS colonization in mouse lungs by upregulation of Nos2 gene expression and associated pathways. Lung epithelial cells, as first responders during Mtb infection, have been shown to play an important role in TB pathogenesis (Scordo et al., 2016; Ryndak and Laal, 2019). Our results also confirmed that overexpression of Nos2 in A549 cells (a human alveolar epithelial cell) can enhance MS colonization in these cells.

Nos2, also termed iNOS, is a homodimeric enzyme that is induced by immune stimulation in an independent of intracellular Ca²⁺ manner and plays an important role in infection, inflammation, immune regulation, and the control of intracellular bacterial pathogen infection (Chakravortty and Hensel, 2003). Compared with Nos1 and Nos3, Nos2 has the highest efficiency for production NO (Fischer et al., 2002). NO has direct antibacterial effects and immune-modulating function to intracellular pathogens and was considered a key molecule in controlling pathogens infections (Chakravortty and Hensel, 2003). It has been verified that reactive nitrogen intermediates produced by murine cells could inhibit Mtb infection (Scanga et al., 2001). The use of Nos2 knock-out mice and NO synthase inhibitors is impaired in the control of Mtb growth (MacMicking et al., 1997; Chan et al., 1995). However, our data found that the high concentration of NO increased the colonization of MS in A549 cells. This result seems to contradict that NO has antibacterial activity. Some studies have also shown that NO can promote bacterial growth. Gusarov et al. reported that NO increases the resistance of bacteria to a broad spectrum of antibiotics, enabling the bacteria to survive and share habitats with antibiotic-producing microorganisms (Gusarov et al., 2009). Cole et al. showed that host cell-derived NO promoted the escape of listerolysin-dependent bacteria from phagocytic vacuoles into the cytoplasm by inhibiting the proton-pumping activity of V-ATPase and delaying phagolysosome fusion (Cole et al., 2012; Bogdan, 2012). Another study has shown that the maximal level of NO produced by human macrophages was not bactericidal or bacteriostatic to Mtb, and the number of viable mycobacteria was increased in macrophages that produced NO, and this is correlated with the expression of nitrate reductase (Jung et al., 2013). Therefore, we speculate that intracellular NO synthesized by Nos2 has dual roles, including bactericidal at high concentrations and promoting bacterial growth at low concentrations.

ROS are commonly present in various habitats occupied by living organisms and the production of ROS appears as a very ancient host strategy for coping with pathogens (Rhen, 2019; Roy et al., 2017). ROS has shown potent antimicrobial activity against many pathogens including bacteria, fungi, and viruses. The accumulation of ROS is required for killing or inhibiting bacteria (Hong et al., 2019). NO interferes with antimicrobial killing by suppressing ROS accumulation (Gusarov et al., 2009). Hence, we assess the level of ROS in the overexpression of Nos2 plasmids A549 cells. The results show that the ROS concentration in A549 cells transfected with Nos2-pcDNA3.1 was significantly lower than that in the control A549 and A549 cells transfected with pcDNA3.1 empty vector. This suggested that the promotion of bacterial proliferation by Nos2 is dependent on lower ROS levels. The crosstalk between Nos2 and ROS has been investigated in other research. Zheng et al. reported that the lower ROS level induced by Nos2a significantly inhibited E. piscicida proliferation and infection in zebrafish (Zheng et al., 2023). Another study has also shown that Nos2-produced ROS have an important role in maintaining homeostasis of the gut microbiota and defense against bacterial translocation (Matziouridou et al., 2018). Therefore, regulating the Nos2–ROS pathway may enhance the host’s defense ability against pathogens.

β-defensin-1 is an antimicrobial peptide, which is mainly produced by various epithelial cells and is an important part of the innate immune response (Flores Saiffe Farías et al., 2015). Defb1 is also expressed in the respiratory epithelium cells and protects the airways from respiratory pathogens (Diamond et al., 2008). Previous research has found that Defb1 has 98% killing activity against active Mtb H37Rv (Álvarez et al., 2018), and also has an effective antibacterial effect against dormant mycobacteria (Sharma et al., 2017). Consistent with the above results, our data revealed that there was a strong negative correlation between Defb1 gene expression and MS colonization in A549 cells. The present study was mainly performed at the gene level and lacked verification at the protein level. We will verify the role of the Nos2–Defb1 pathway on MS colonization at the protein levels in future studies.

Altogether, the crosstalk between the gut microbiome and the lungs through the ‘gut–lung axis’ is complex and may involve multiple mechanisms, including immune response, metabolic disorders, cytokines, inflammation, etc. However, in the present study, we found that gut microbiome dysbiosis induced by clindamycin disturbs the gut equilibrium between bacteria and fungi, alters the lung transcriptome, and increases Nos2 expression. Then, the microbiota dysbiosis could enhance the pulmonary colonization of MS in mice by regulating the Nos2–NO, Nos2–ROS, and Nos2–Defb1 pathways (Figure 7). In the future, we need more experiments to explore the relationship between the intestinal microbiome and the Nos2-associated pathways in the lung and to further explore new targets for the prevention and treatment of TB.

Figure 7

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16s RNA / ITS and transcriptome sequencing data have been deposited in NCBI under the accession codes PRJNA1091926 and PRJNA1099882. All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for the figures and figures supplements.

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Author details

1. MeiQing Han

   1. Department of Tuberculosis, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
   2. Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Investigation, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

2. Xia Wang

   Department of Tuberculosis, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China

   Contribution

   Conceptualization, Resources

   Competing interests

   No competing interests declared

3. Lin Su

   Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

4. Shiqi Pan

   Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

5. Ningning Liu

   Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

6. Duan Li

   Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Liang Liu

   Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Software

   Competing interests

   No competing interests declared

8. JunWei Cui

   Department of Tuberculosis, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China

   Contribution

   Software, Supervision

   Competing interests

   No competing interests declared

9. Huajie Zhao

   Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

   Contribution

   Funding acquisition, Writing – review and editing

   For correspondence

   zhaohuajiebest@163.com

   Competing interests

   No competing interests declared

10. Fan Yang

    1. Department of Tuberculosis, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
    2. Department of Pathogenic Biology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China

    Contribution

    Conceptualization, Funding acquisition, Writing – review and editing

    For correspondence

    yangf77@163.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-9582-1394

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