Tuberculosis Progression Research Articles

Tuberculosis Diagnoses Following Wildfire Smoke Exposure in California.

Rationale: Wildfires are a significant cause of exposure to ambient air pollution in the United States and other settings. Although indoor air pollution is a known contributor to tuberculosis reactivation and progression, it is unclear whether ambient pollution exposures, including wildfire smoke, similarly increase risk. Objectives: To determine whether tuberculosis diagnosis was associated with recent exposure to acute outdoor air pollution events, including those caused by wildfire smoke. Methods: We conducted a case-crossover analysis of 6,238 patients aged ⩾15 years diagnosed with active tuberculosis disease between 2014 and 2019 in 8 California counties. Using geocoded address data, we characterized individuals' daily exposure to <2.5 μm-diameter particulate matter (PM2.5) during counterfactual risk periods 3-6 months before tuberculosis diagnosis (hazard period) and the same time 1 year previously (control period). We compared the frequency of residential PM2.5 exposures exceeding 35 μg/m3 (PM2.5 events) overall and for wildfire-associated and nonwildfire events during individuals' hazard and control periods. Measurements and Main Results: In total, 3,139 patients experienced 1 or more PM2.5 events during the hazard period, including 671 experiencing 1 or more wildfire-associated events. Adjusted odds of tuberculosis diagnosis increased by 5% (95% confidence interval, 3-6%) with each PM2.5 event experienced over the 6-month observation period. Each wildfire-associated PM2.5 event was associated with 23% (19-28%) higher odds of tuberculosis diagnosis in this time window, whereas no association was apparent for nonwildfire-associated events. Conclusions: Residential exposure to wildfire-associated ambient air pollution is associated with an increased risk of active tuberculosis diagnosis.

Promising Roles of Circular RNAs as Biomarkers and Targets for Potential Diagnosis and Therapy of Tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains one of the most threatening infectious diseases worldwide. A series of challenges still exist for TB prevention, diagnosis and treatment, which therefore require more attempts to clarify the pathological and immunological mechanisms in the development and progression of TB. Circular RNAs (circRNAs) are a large class of non-coding RNA, mostly expressed in eukaryotic cells, which are generated by the spliceosome through the back-splicing of linear RNAs. Accumulating studies have identified that circRNAs are widely involved in a variety of physiological and pathological processes, acting as the sponges or decoys for microRNAs and proteins, scaffold platforms for proteins, modulators for transcription and special templates for translation. Due to the stable and widely spread characteristics of circRNAs, they are expected to serve as promising prognostic/diagnostic biomarkers and therapeutic targets for diseases. In this review, we briefly describe the biogenesis, classification, detection technology and functions of circRNAs, and, in particular, outline the dynamic, and sometimes aberrant changes of circRNAs in TB. Moreover, we further summarize the recent progress of research linking circRNAs to TB-related pathogenetic processes, as well as the potential roles of circRNAs as diagnostic biomarkers and miRNAs sponges in the case of Mtb infection, which is expected to enhance our understanding of TB and provide some novel ideas about how to overcome the challenges associated TB in the future.

Two decades of tuberculosis surveillance reveal disease spread, high levels of exposure and mortality and marked variation in disease progression in wild meerkats.

Infections with tuberculosis (TB)-causing agents of the Mycobacterium tuberculosis complex threaten human, livestock and wildlife health globally due to the high capacity to cross trans-species boundaries. Tuberculosis is a cryptic disease characterized by prolonged, sometimes lifelong subclinical infections, complicating disease monitoring. Consequently, our understanding of infection risk, disease progression, and mortality across species affected by TB remains limited. The TB agent Mycobacterium suricattae was first recorded in the late 1990s in a wild population of meerkats inhabiting the Kalahari in South Africa and has since spread considerably, becoming a common cause of meerkat mortality. This offers an opportunity to document the epidemiology of naturally spreading TB in a wild population. Here, we synthesize more than 25 years' worth of TB reporting and social interaction data across 3420 individuals to track disease spread, and quantify rates of TB social exposure, progression, and mortality. We found that most meerkats had been exposed to the pathogen within eight years of first detection in the study area, with exposure reaching up to 95% of the population. Approximately one quarter of exposed individuals progressed to clinical TB stages, followed by physical deterioration and death within a few months. Since emergence, 11.6% of deaths were attributed to TB, although the true toll of TB-related mortality is likely higher. Lastly, we observed marked variation in disease progression among individuals, suggesting inter-individual differences in both TB susceptibility and resistance. Our results highlight that TB prevalence and mortality could be higher than previously reported, particularly in species or populations with complex social group dynamics. Long-term studies, such as the present one, allow us to assess temporal variation in disease prevalence and progression and quantify exposure, which is rarely measured in wildlife. Long-term studies are highly valuable tools to explore disease emergence and ecology and study host-pathogen co-evolutionary dynamics in general, and its impact on social mammals.

Heterogeneous impact of Covid-19 response on tuberculosis burden by age group

Apart from the incidence and mortality caused by it, Coronavirus disease (COVID-19) has had a significant impact on other diseases. This study aimed to estimate the influences of COVID-19 pandemic on the incidence of tuberculosis (TB) and the number of TB-associated deaths in Republic of Korea. A dynamic compartment model incorporating age-structure was developed for studying TB transmission and progression using the Korean population data. After calibration with notification of incidence data from South Korea, the TB burden over 6 years (2020–2025) was predicted under the nine different scenarios. Under the scenario of strong social distancing and low-level health service disruption, new TB cases were reduced by 761 after 1 year in comparison to the baseline. However, in the elderly population, social distancing had little impact on TB incidence. On the other hand, the number of TB-related deaths mainly depends on the level of health service disruption for TB care. It was predicted that with a high degree of health service disruption, the number of TB-related deaths would increase up to 155 in 1 year and 80 percent of the TB-related deaths would be in the elderly population. The decrease of tuberculosis incidence is significantly affected by social distancing, which is owing to reduction of contacts. The impact of health service disruption is dominant on TB-related deaths, which occurs mainly in the elderly. It suggests that it is important to monitor TB-related deaths by COVID-19 because the TB burden of the elderly is high in the Republic of Korea.

Mathematical Model of the Immunopathological Progression of Tuberculosis

Tuberculosis is a worldwide persistent infectious disease. It is caused by bacteria from the Mycobacterium tuberculosis complex that mainly affects the lungs and can be fatal. Using an integrative systems biology approach, we study the immunopathological progression of this disease, analyzing the key interactions between the cells involved in the different phases of the infectious process. We integrated multiple in vivo and in vitro data from immunohistochemical, serological, molecular biology, and cell count assays into a mechanistic mathematical model. The ordinary differential equation (ODE) model captures the regulatory interplay between the phenotypic variation of the main cells involved in the disease progression and the inflammatory microenvironment. The model reproduces in vivo time course data of an experimental model of progressive pulmonary TB in mouse, accurately reflecting the functional adaptations of the host–pathogen interactions as the disease progresses through three phenotypically different phases. We used the model to assess the effect of genotypic variations (encoded as changes in parameters) on disease outcomes. For all genotypes, we found an all-or-nothing response, where the virtual mouse either completely clears the infection or suffers uncontrolled Tb growth. Results show that it is 84% probable that a mouse submitted to a progressive pulmonary TB assay will end up with an uncontrolled infection. The simulations also showed how the genotypic variations shape the transitions across phases, showing that 100% of the genotypes evaluated eventually progress to phase two of the disease, suggesting that adaptive immune response activation was unavoidable. All the genotypes of the network that avoided progressing to phase 3 cleared the infection. Later, by analyzing the three different phases separately, we saw that the anti-inflammatory genotype of phase 3 was the one with the highest probability of leading to uncontrolled bacterial growth, and the proinflammatory genotype associated with phase 2 had the highest probability of bacterial clearance. Forty-two percent of the genotypes evaluated showed a bistable response, with one stable steady state corresponding to infection clearance and the other one to bacteria reaching its carrying capacity. Our mechanistic model can be used to predict the outcomes of different experimental conditions through in silico assays.

Tuberculosis in pregnancy.

Due to COVID-19 pandemic, the latest progress of the End Tuberculosis (TB) Strategy was far from optimal and services for TB needs to be quickly restored. Pregnancy is a unique opportunity to screen and manage TB, and it is an essential step in TB eradication. Early diagnosis and treatment for active disease can reduce maternal and neonatal morbidities and mortality. The more widespread utilization of newer rapid molecular assays with drug-susceptibility testing has significantly shortened the diagnostic process for active TB disease. First-line anti-TB drugs are proven to be safe in pregnancy. Management of latent TB infection (LTBI) during pregnancy is controversial, but puerperium is a period of increased susceptibility to progress to active disease. Extrapulmonary TB (EPTB), multidrug-resistant TB (MDR-TB) and HIV co-infection remain significant issues surrounding TB management during pregnancy and often require input from a multidisciplinary team including TB experts.

COMPARATIVE STUDY OF CLINICO-RADIOLOGICAL AND MYCOBACTERIAL PROFILE OF PULMONARY TB IN DIABETIC VS. NON DIABETIC PATIENTS AT TERTIARY CARE HOSPITAL

Background: Tuberculosis (TB) is a disease most commonly affecting the lungs caused by mycobacterium tuberculosis, may also affect any parts of the body. Diabetes mellitus (DM) is recognized as a major risk factor for the progression of active pulmonary tuberculosis (PTB). The prole of pulmonary tuberculosis is variable in diabetic vs non diabetic patients .There is scarcity of published comparative literature, therefore this study carried out. This is hospital based prospective observational and comparative study was conducted in admitted patients of MahatmaMethod: Gandhi Medical College &amp; Hospital, Jaipur. All the new cases of pulmonary tuberculosis diagnosed on the basis of clinic-radiological and mycobacterial. All the tuberculosis patients were also screened for diabetes as per criteria and divided in 2 groups PTB-DM &amp; PTB-NDM respectively. Total number of cases of pulmonary tuberculosis in the study was 150, out of which 50 cases with diabetic and 100 casesResults: without diabetic. Male's predominance was in both the groups (70%vs78%). Maximum cases of PTB were in middle age (41-60 years) in both the groups (54% vs51%). There was no signicant difference in respiratory symptoms, mycobacterial positivity and various type parenchymal lesions. However there was signicantly more grade 3 positivity on Z.N staining, lower zone predominance, multiple cavitations and far advance disease in diabetic PTB patients Diabetes is a risk factor &amp; potentially may affect serious implications in management of tuberculosis and TB. Conclusion: control program. Therefore, early detection of diabetes in suspect cases of pulmonary tuberculosis &amp;vice-versa is important in clinical practice &amp; TB control program.

Mathematical modelling of the progression of active tuberculosis: Insights from fluorography data.

Little is known about the dynamics of the early stages of untreated active pulmonary tuberculosis: unknown are both the rates of progression and the model “scheme”. The “parallel” scheme assumes that infectiousness of tuberculosis cases is effectively predefined at the onset of the disease, and the “serial” scheme considers all cases to be non-infectious at the onset, with some of them later becoming infectious.Our aim was to estimate the progression of the early stages of pulmonary tuberculosis using data from a present-day population. We used the routine notification data from Moscow, Russia, 2013–2018 that contained the results and time of the last fluorographic screening preceding the detection of tuberculosis cases. This provided time limits on the duration of untreated tuberculosis.Parameters of TB progression under both models were estimated. By the goodness of fit to the data, we could prefer neither the “parallel”, nor the “serial” model, although the latter had a bit worse fit. On the other hand, the observed rise in the fraction of infectious tuberculosis cases with the time since the last screening was explained by the “serial” model in a more plausible way – as gradual progression of some cases to infectiousness. The “parallel” model explained it through less realistic quick removal of non-infectious cases and accumulation of the infectious ones.The results demonstrate the potential of using such detection data enriched with reassessments of the previous screenings.

Spatial bacterial subpopulations of a human lung lobe and their potential impact on the progression of pulmonary tuberculosis

Better understanding the spatial variation in resident pulmonary bacteria can help to link the disease severity of pulmonary tuberculosis (TB) with lung bacteriomes. This study aimed to investigate bacterial compositions in subniches of a lung lobe from pulmonary TB patient with two separate visible lesions. There were no significant differences between the bacterial compositions in normal tissue and TB lesions, but the bacterial compositions of the two TB lesions differed significantly (P = 0.009). Interestingly, 52 OTUs (relative abundance >1%) that specifically inhabiting certain lung niches were observed and they were affiliated with five phyla. Specific OTUs affiliated with Firmicutes mainly inhabited normal tissues. The dominant phylum in the lung subniches was Proteobacteria, with a relative abundance between 67.03% and 99.99%. Ralstonia, Achromobacter, and Pseudomonas were the most abundant genera, collectively accounting for 34.02% of total bacterial species. A total of 667 of the 700 bacterial connections in a co-correlation network of 145 OTUs (Operational Taxonomic Unit) were positive, indicating a cooperative relationship between bacterial members. Using PICRUSt tool, we do predict bacterial MetaCyc functions responsible for lipid synthesis and heme biosynthesis across the lung lobe that are essential for generation of caseous necrosis and TB disease pathology. MetaCyc pathways responsible for the degradation of aromatic biogenic amines, sulfur oxidation, and denitrification were all related to M.tb growth status, and they were significantly enriched in the lesion with necrosis than that with inflammation. These results open a new insight for us to comprehend the spatial profile of bacteriomes in a pulmonary TB human lung lobe, and shed light on the design of future diagnosis and treatment for pulmonary TB disease.

Glutamine Is Required for M1-like Polarization of Macrophages in Response to Mycobacterium tuberculosis Infection.

ABSTRACTIn response to Mycobacterium tuberculosis infection, macrophages mount proinflammatory and antimicrobial responses similar to those observed in M1 macrophages activated by lipopolysaccharide (LPS) and interferon gamma (IFN-γ). A metabolic reprogramming to hypoxia-inducible-factor 1 (HIF-1)-mediated uptake of glucose and its metabolism by glycolysis is required for M1-like polarization, but little is known about other metabolic programs driving the M1-like polarization during infection. We report that glutamine serves as a carbon and nitrogen source for the metabolic reprogramming to M1-like macrophages. Widely targeted metabolite screening identified an association of glutamine and/or glutamate with highly affected metabolic pathways of M1-like macrophages. Moreover, stable isotope-assisted metabolomics of U13C glutamine and U13C glucose revealed that glutamine, rather than glucose, is catabolized in both the oxidative and reductive tricarboxylic acid (TCA) cycles of M1-like macrophages, thereby generating signaling molecules that include succinate, biosynthetic precursors such as aspartate, and itaconate. U15N glutamine-tracing metabolomics further revealed participation of glutamine nitrogen in synthesis of intermediates of purine and pyrimidine metabolism plus amino acids, including aspartate. These findings were corroborated by diminished M1 polarization from chemical inhibition of glutaminase (GLS), the key enzyme in the glutaminolysis pathway, and by genetic deletion of GLS in infected macrophages. Thus, the catabolism of glutamine is an integral component of metabolic reprogramming in activating macrophages and it coordinates with elevated cytosolic glycolysis to satisfy the cellular demand for bioenergetic and biosynthetic precursors of M1-like macrophages. Knowledge of these new immunometabolic features of M1-like macrophages should advance the development of host-directed therapies for tuberculosis.

Higher native Peruvian genetic ancestry proportion is associated with tuberculosis progression risk

SUMMARYWe investigated whether ancestry-specific genetic factors affect tuberculosis (TB) progression risk in a cohort of admixed Peruvians. We genotyped 2,105 patients with TB and 1,320 household contacts (HHCs) who were infected with Mycobacterium tuberculosis (M. tb) but did not develop TB and inferred each individual’s proportion of native Peruvian genetic ancestry. Our HHC study design and our data on potential confounders allowed us to demonstrate increased risk independent of socioeconomic factors. A 10% increase in individual-level native Peruvian genetic ancestry proportion corresponded to a 25% increased TB progression risk. This corresponds to a 3-fold increased risk for individuals in the highest decile of native Peruvian genetic ancestry versus the lowest decile, making native Peruvian genetic ancestry comparable in effect to clinical factors such as diabetes. Our results suggest that genetic ancestry is a major contributor to TB progression risk and highlight the value of including diverse populations in host genetic studies.

Transcriptional Analysis for Tuberculosis in Pregnant Women From the PRegnancy Associated Changes In Tuberculosis Immunology (PRACHITi) Study.

A new tuberculosis (TB) diagnostic cartridge assay, which detects a 3-gene TB signature in whole blood, was not diagnostic in women with maternal TB disease in India (area under the curve [AUC] = 0.72). In a cohort of pregnant women, we identified a novel gene set for TB diagnosis (AUC = 0.97) and one for TB progression (AUC = 0.96).

Evaluating the diversity of circulating natural killer cells between active tuberculosis and latent tuberculosis infection

Tuberculosis (TB) is a leading global public health problem; however, the mechanisms underlying the immunopathology of TB progression are not well understood. It is currently believed that Mycobacterium tuberculosis (Mtb) infection can modify natural killer (NK) cell phenotypic signatures. Hence, our study was designed to investigate the diversity of circulating NK cells in patients with different TB infection status. NK subsets, as well as their expression of activating and inhibitory receptors between active TB (ATB) and latent TB infection (LTBI) were evaluated. There were significant differences in NK cell phenotypes between ATB, LTBI and healthy controls. Notably, the proportion of KLRG1 in NK cells (P = 0.036), as well as in their subsets CD56DimCD16+ (P = 0.046) and CD27+ (P = 0.027) NK cells, increased significantly in LTBI group than in ATB group; while Mtb specific IFN-γ+CD56BrightCD16Dim NK cells expressed higher KLRG1 in ATB than in LTBI (P = 0.027). However, the expression of activating receptor NKG2D in NK subsets showed no significant difference among the study groups. Our results suggest that different TB infection status are coupled with the diversity of NK cell compartments, and the expression of KLRG1 in NK cells may be a specific phenotype that modulates the progression of TB from latent to active.

Clinical and laboratory specific parameters of COVID-19 in patients with TB/HIV co-infection

The objective: to study clinical and laboratory specific parameters of the COVID-19 course in patients with TB/HIV co-infection, to analyze changes in the lungs caused by COVID-19 in patients with pulmonary tuberculosis and concurrent HIV infection.Subjects and Methods. 68 HIV-infected patients aged 18-66 years old were included in the study, they all were admitted to the Novosibirsk State Regional Clinical Tuberculosis Hospital, Novosibirsk, with confirmed COVID-19 from May 2020 to May 2021. Clinical manifestations, CD4 count and HIV RNA level, and the presence of secondary infections were assessed.Results. In patients with severe and profound immunodeficiency, coronavirus infection was more often mild to moderate, and in immunocompetent patients – moderate to severe. However, patients with profound immunodeficiency were at greater risk of an adverse outcome due to lymphohematogenic progression of tuberculosis and concurrent opportunistic infections.Conclusion. When diagnosing and treating COVID-19 in patients with comorbid HIV infection and tuberculosis, it is important to consider the form of tuberculosis and CD4+ count.

The tuberculosis resistance protein TOLLIP prevents disease progression by regulating the integrated stress response in alveolar macrophages.

Abstract Genetic variation associated with decreased TOLLIP expression in macrophages is a tuberculosis (TB) risk factor. However, the fundamental mechanisms underlying TOLLIP’s role in TB pathogenesis and macrophage function are unknown. To understand why TOLLIP strongly influences Mtb-macrophage interactions, we infected B6 mice lacking Tollip (Tollip−/−) with Mtb and evaluated lung-resident macrophage function and clinical response. Tollip−/− mice developed worsened Mtb disease with profuse lipid-laden foamy macrophages in their lungs. This phenotype was intrinsic to AM, as Tollip−/− AM, but not other lung-resident macrophage subtypes, from mixed bone marrow chimeras selectively harbored excessive Mtb bacilli and intracellular lipid. Global gene expression analysis of Mtb-infected, Tollip−/− AM demonstrated alteration in dozens of genes consistent with the integrated stress response (ISR), which adapts cells to variable environmental conditions and is associated with TB progression. Administration of mycolic acid, an Mtb cell wall lipid, to Tollip−/− macrophages induced lipid accumulation, ISR, and increased intracellular Mtb burden. Pharmacologic ISR inhibition restored host defense in Tollip−/− mice and improved Mtb outcomes overall. In humans, TOLLIP mRNA expression was increased in caseous TB granulomas, providing translational relevance for our observations. Taken together, TOLLIP deficiency in AMs induces foam cell formation and ISR after Mtb infection, which permits increased replication and drives immunopathology. These findings illustrate a major mechanism by which TOLLIP-deficient individuals are susceptible to TB disease and suggest novel targets for TB host-directed therapy.

Association Between Genetic Polymorphisms of lncRNA NEAT1 and Pulmonary Tuberculosis Risk, Clinical Manifestations in a Chinese Population.

BackgroundRecent studies have shown that abnormal expression of lncRNA NEAT1 is associated with the progression of pulmonary tuberculosis (PTB). The aim of our study was to analyze the relationship between single nucleotide polymorphisms (SNPs) of NEAT1 gene and susceptibility to PTB.MethodsFour SNPs (rs2239895, rs3741384, rs3825071, rs512715) in NEAT1 gene were genotyped in 479 patients with PTB and 476 controls by improved multiple ligase detection reaction (iMLDR) in a Chinese population.ResultsWe found no significant differences in allele and genotype frequencies of NEAT1 gene rs2239895, rs3741384, rs3825071, rs512715 between PTB patients and controls (all P > 0.05). There was no statistically significant association between genotype frequency distribution of dominant model, as well as recessive model, and genetic susceptibility to PTB patients (all P > 0.05). The TT genotype, T allele frequencies of rs3825071 were significantly increased in sputum smear-positive PTB patients when compared to sputum smear-negative PTB patients (P = 0.010, P = 0.003, respectively). Haplotype analysis shown that NEAT1 haplotype frequency was not associated with PTB susceptibility.ConclusionNEAT1 gene polymorphisms were not associated with the risk of PTB in Chinese population, and rs3825071 polymorphism might be related to sputum smear-positive in PTB patients.

CHARACTERIZING TUBERCULOSIS PROGRESSION IN WILD MEERKATS (SURICATA SURICATTA) FROM FECAL SAMPLES AND CLINICAL SIGNS.

Tuberculosis (TB) is an increasing threat to wildlife, yet tracking its spread is challenging because infections often appear to be asymptomatic, and diagnostic tools such as blood tests can be invasive and resource intensive. Our understanding of TB biology in wildlife is therefore limited to a small number of well-studied species. Testing of fecal samples using PCR is a noninvasive method that has been used to detect Mycobacterium bovis shedding amongst badgers, yet its utility more broadly for TB monitoring in wildlife is unclear. We combined observation data of clinical signs with PCR testing of 388 fecal samples to characterize longitudinal dynamics of TB progression in 66 wild meerkats (Suricata suricatta) socially exposed to Mycobacterium suricattae between 2000 and 2018. Our specific objectives were 1) to test whether meerkat fecal samples can be used to monitor TB; 2) to characterize TB progression between three infection states (PCR-negative exposed, PCR-positive asymptomatic, and PCR positive with clinical signs); and 3) estimate individual heterogeneity in TB susceptibility, defined here as the time between TB exposure and detection, and survival after TB detection. We found that the TB detection probability once meerkats developed clinical signs was 13% (95% confidence interval 3-46%). Nevertheless, with an adapted test protocol of 10 PCR replicates per sample we detected hidden TB infections in 59% of meerkats before the onset of clinical signs. Meerkats became PCR positive approximately 14 mo after initial exposure, developed clinical signs approximately 1 yr after becoming PCR positive, and died within 5 mo of developing clinical signs. Individual variation in disease progression was high, with meerkats developing clinical signs from immediately after exposure to 3.4 yr later. Overall, our study generates novel insights into wildlife TB progression, and may help guide adapted management strategies for TB-susceptible wildlife populations.

A Clinical Case of the Personalized Approach to Surgical Treatment of Drug-Resistant Bilateral Fibrous Cavernous Pulmonary Tuberculosis Complicated by Pyopneumothorax and Pleural Cavity Empyema

A clinical case shows the complexity of the choice of surgical strategy for treatment in drug-resistant bilateral fibrous cavernous pulmonary tuberculosis complicated by pyopneumothorax and empyema of the pleural cavity. A non-standard personalized approach to the patient with initially compromised cardiorespiratory system resulted not only in cure of tuberculosis complications but also improved pulmonary functional parameters and allowed avoiding progression of pulmonary tuberculosis.

Alterations in the Gut Microbiome of Individuals With Tuberculosis of Different Disease States

ObjectiveThere is evidence that the gut microbiota play a regulatory role in the occurrence and progression of tuberculosis. The purpose of the current study was to explore the alterations in gut microbiome under different tuberculosis disease stages in the Uyghur population, clarify the composition of microbial taxonomy, search for microbial biomarkers and provide innovative ideas for individual immune prevention and for control strategies.DesignA case–control study of Uyghur individuals was performed using 56 cases of pulmonary tuberculosis (PTB), 36 cases of latent tuberculosis infection (LTBI) and 50 healthy controls (HC), from which stool samples were collected for 16S rRNA gene sequencing.ResultsThe results showed that the alpha diversity indexes of the PTB group were lower than those of the other two groups (P <0.001), while only observed species were different between LTBI and HC (P <0.05). Beta diversity showed differences among the three groups (P = 0.001). At the genus level, the relative abundance of Bifidobacterium and Bacteroides increased, while Roseburia and Faecalibacterium decreased in the PTB group, when compared with the other two groups, but the changes between the LTBI and HC groups were not significant. The classifier in the test set showed that the ability of the combined genus to distinguish between each two groups was 81.73, 87.26, and 86.88%, respectively, and the validation efficiency was higher than that of a single screened genus.ConclusionThe gut microbiota of PTB patients was significantly disordered compared with LTBI and HC, while the changes of LTBI and HC were not significant. In the future, gut microbiota could be used as a non-invasive biomarker to assess disease activity.

The gut microbiota mediates protective immunity against tuberculosis via modulation of lncRNA

ABSTRACT The gut-lung axis has been implicated as a potential therapeutic target in lung disorders. While increasing evidence suggests that gut microbiota plays a critical role in regulating host immunity and contributing to tuberculosis (TB) development and progression, the underlying mechanisms whereby gut microbiota may impact TB outcomes are not fully understood. Here, we found that broad-spectrum antibiotics treatment increased susceptibility to Mycobacterium tuberculosis (M. tuberculosis) infection and modulated pulmonary inflammatory responses in mouse M. tuberculosis infection model. We then identified a commensal gut bacteria-regulated lncRNA, termed lncRNA-CGB, which was down-regulated by dysbiosis of gut microbiota during TB infection. Furthermore, we found that Bacteroides fragilis (B. fragilis) was a direct regulator of lncRNA-CGB, and oral administration of B. fragilis enhanced expression of lncRNA-CGB and promoted anti-TB immunity. Genomic knock-out of lncRNA-CGB led to reduced IFN-γ expression and impaired anti-TB immunity, therefore leading to detrimental effects on M. tuberculosis infection. Mechanistically, lncRNA-CGB interacted with EZH2 and negatively regulated H3K27 tri-methylation (H3K27Me3) epigenetic programming, leading to enhanced IFN-γ expression. Thus, this work not only uncovered previously unrecognized importance of gut bacteria-lncRNA-EZH2-H3K27Me3 axis in conferring immune protection against TB but also identified a potential new paradigm to develop a microbiota-based treatment against TB and potentially other diseases.