Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy (original) (raw)
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Scientific Reports
Tuberculosis (TB) preventive therapy (TPT) is an effective strategy to eliminate TB in low-incidence settings. Shorter TPT regimens incorporating the antimicrobial class of rifamycins are designed to improve adherence and completion rates but carry the risk of modifications to the gut microbiota. We enrolled six subjects diagnosed with latent TB infection (LTBI) who accepted to initiate TPT. We also enrolled six healthy volunteers unexposed to the rifamycins. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region) to document the immediate effect of rifamycin-based TPT on the gut microbiota composition and tracked recovery to baseline two months after TPT. Overall, TPT accounted for 17% of the variance in gut microbial community dissimilarity. This rifamycin-based TPT induced dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacte...
Scientific Reports
Mycobacterium tuberculosis, the cause of Tuberculosis (TB), infects one third of the world's population and causes substantial mortality worldwide. In its shortest format, treatment of TB requires six months of multidrug therapy with a mixture of broad spectrum and mycobacterial specific antibiotics, and treatment of multidrug resistant TB is longer. The widespread use of this regimen makes this one of the largest exposures of humans to antimicrobials, yet the effects of TB treatment on intestinal microbiome composition and long-term stability are unknown. We compared the microbiome composition, assessed by both 16S rDNA and metagenomic DNA sequencing, of TB cases during antimycobacterial treatment and following cure by 6 months of antibiotics. TB treatment does not perturb overall diversity, but nonetheless dramatically depletes multiple immunologically significant commensal bacteria. The microbiomic perturbation of TB therapy can persist for at least 1.2 years, indicating that the effects of TB treatment are long lasting. These results demonstrate that TB treatment has dramatic effects on the intestinal microbiome and highlight unexpected durable consequences of treatment for the world's most common infection on human ecology. Each year, up to 3-4% of all deaths worldwide from any cause are attributable to infection with the bacterial pathogen Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB) disease, which amounts to almost 5,000 TB-related deaths each day 1. This colossal disease burden necessitates a thorough understanding of both the pathogenic strategies Mtb uses to cause disease, as well as the host susceptibilities Mtb has evolved to exploit. Individuals can be Mtb uninfected, infected with latent Mtb, have active TB disease, or be cured through antibiotic therapy. Many factors can influence the probability that some individuals transition from one of these stages to another, but most defined risk factors compromise immune function 2. For example, untreated HIV infection, which depletes CD4+ T cells, is associated with elevated risk of TB disease. Overall, immune status is also affected by age-the elderly and young infants are at a disproportionately high risk of Mtb infection and subsequent TB disease. Furthermore, individuals with germline mutations in pathways involved in controlling mycobacterial infection, such as IFNγ and TNFα, have an increased risk of active TB disease 3. Despite these examples, known immune deficiencies are not sufficient to explain why the incidence of new active TB cases hovers over 10 million people each year, with a mortality rate between 1.5-2 million people 1. Furthermore, it is
Background: Latent tuberculosis infection (LTBI) treatment is an effective strategy to eliminate TB in low-incidence settings. Shorter LTBI regimens incorporating the antimicrobial class of rifamycins are designed to improve treatment completion rates. Recent evidence suggests that the rifamycins could induce irreversible gut microbiota changes that impact future anti-TB immunity. Methods: To document the immediate effect of the rifamycins on the gut microbiota, we followed six patients with LTBI initiating four months of monotherapy with rifampin (4R; n=4) or three months of rifapentine in combination with isoniazid (3HP; n=2) and tracked recovery to baseline two months posttreatment completion. We collected stool samples parallel to the LTBI group from healthy volunteers (N=6) unexposed to the rifamycins. We used a questionnaire to collect diet, antibiotics, and lifestyle changes during follow-up. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region). Re...
BMC Pulmonary Medicine
Background Anti-tuberculosis therapy requires at least six-month treatment with continuous administration of combined antibiotics, including isoniazid, rifampicin, pyrazinamide, and ethambutol. The long-term exposure to antibiotics could cause consequent changes in gut microbiota, which may alter the gastrointestinal function and drug absorption in patients, thereby affect the outcome of treatment. The study aims to characterize the longitudinal changes of gut microbiota among tuberculosis (TB) patients under standardized first-line treatment and provide an understanding of the association between alterations in gut microbiota composition and unfavorable clinical outcomes. Methods The study is a multicenter, observational prospective cohort study. Three study sites are purposively selected in the western (Sichuan Province) and eastern (Jiangsu Province and Shanghai) parts of China. Three-hundred patients with bacteriologically confirmed pulmonary TB are enrolled. All eligible patien...
The host microbiome and impact of tuberculosis chemotherapy
Tuberculosis, 2018
The treatment of Mycobacterium tuberculosis infection is often viewed in isolation from other human microbial symbionts. Understandably, the clinical priority is eliminating active or latent tuberculosis (TB) in patients. With the increasing resolution of molecular biology technologies, it is becoming apparent that antibiotic treatment can perturb the homeostasis of the host microbiome. For example, dysbiosis of the gut microbiota has been associated with an increased risk of the development of asthma, obesity and diabetes. Therefore, the fundamental question is: Does TB chemotherapy cause disruption of the human microbiome and adverse effects in patients, and are there signature taxa of dysbiosis following TB treatment. In this review, we examine recent research on the detection of changes in the microbiome during antibiotic administration and discuss specific findings that relate to the impact of anti-tubercular chemotherapy.
Microbiome Changes during Tuberculosis and Antituberculous Therapy
Clinical microbiology reviews, 2016
The critical role of commensal microbiota in the human body has been increasingly recognized, and our understanding of its implications in human health and disease has expanded rapidly. The lower respiratory tract contains diverse communities of microbes known as lung microbiota, which are present in healthy individuals and in individuals with respiratory diseases. The dysbiosis of the airway microbiota in pulmonary tuberculosis (TB) may play a role in the pathophysiological processes associated with TB disease. Recent studies of the lung microbiome have pointed out changes in lung microbial communities associated with TB and other lung diseases and have also begun to elucidate the profound effects that antituberculous drug therapy can have on the human lung microbiome composition. In this review, the potential role of the human microbiome in TB pathogenesis and the changes in the human microbiome with Mycobacterium tuberculosis infection and TB therapy are presented and discussed.
Objective: We present 16s rRNA gene sequencing (V1-V2 region) and sample data from a pilot observational cohort study to describe the gut microbiota dynamics in patients with latent tuberculosis infection (LTBI) treated with a three to four-month course of a rifamycin-based regimen. Our objectives were to (1) document changes to the gut microbiota following exposure to the rifamycins and (2) document recovery to baseline two months after treatment completion.Data description: Six LTBI patients were followed for 5 – 6 months. Each patient provided stool samples before, during, and two months after treatment. Six healthy controls were sampled in parallel with the LTBI patients. We report amplicon sequence variants (ASVs) and taxonomic assignments for 60 stool samples. Also provided are the raw amplicon sequences, and data on diet, medication, and lifestyle changes over the follow-up period. Additionally, phosphate buffer washes of the stool samples from the LTBI participants were anal...
Antibiotic therapy cures infection predominantly by killing the infecting pathogen, but for infections such as tuberculosis (TB), which are accompanied by chronic inflammation, the salutary effects of antibiotic therapy may reflect a combination of pathogen killing and microbiome alteration. This question has not been examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic induced pathogen clearance and microbiome alteration. We analyzed sputum TB bacterial load, microbiome composition, and peripheral blood transcriptomics from a clinical trial (NCT02684240) comparing two antimicrobial therapies for tuberculosis, only one of which was clinically effective. We confirm that standard TB therapy (HRZE) rapidly depletes Clostridia from the intestinal microbiota. The antiparasitic drug nitazoxanide (NTZ), although ineffective in reducing Mycobacterium tuberculosis (Mtb) bacterial load in the sputum, caused profound alterations to host microbiome comp...
The Lancet Respiratory Medicine, 2019
The diverse microbial communities within our bodies produce metabolites that modulate host immune responses. Even the microbiome at distal sites has an important function in respiratory health. However, the clinical importance of the microbiome in tuberculosis, the biggest infectious cause of death worldwide, is only starting to be understood. Here, we critically review research on the microbiome's association with pulmonary tuberculosis. The research indicates five main points: (1) susceptibility to infection and progression to active tuberculosis is altered by gut Helicobacter co-infection, (2) aerosol Mycobacterium tuberculosis infection changes the gut microbiota, (3) oral anaerobes in the lung make metabolites that decrease pulmonary immunity and predict progression, (4) the increased susceptibility to reinfection of patients who have previously been treated for tuberculosis is likely due to the depletion of T-cell epitopes on commensal gut non-tuberculosis mycobacteria, and (5) the prolonged antibiotic treatment required for cure of tuberculosis has long-term detrimental effects on the microbiome. We highlight knowledge gaps, considerations for addressing these knowledge gaps, and describe potential targets for modifying the microbiome to control tuberculosis.
Aerosol Mycobacterium tuberculosis Infection Causes Rapid Loss of Diversity in Gut Microbiota
PLoS ONE, 2014
Mycobacterium tuberculosis is an important human pathogen, and yet diagnosis remains challenging. Little research has focused on the impact of M. tuberculosis on the gut microbiota, despite the significant immunological and homeostatic functions of the gastrointestinal tract. To determine the effect of M. tuberculosis infection on the gut microbiota, we followed mice from M. tuberculosis aerosol infection until death, using 16S rRNA sequencing. We saw a rapid change in the gut microbiota in response to infection, with all mice showing a loss and then recovery of microbial community diversity, and found that pre-infection samples clustered separately from post-infection samples, using ecological beta-diversity measures. The effect on the fecal microbiota was observed as rapidly as six days following lung infection. Analysis of additional mice infected by a different M. tuberculosis strain corroborated these results, together demonstrating that the mouse gut microbiota significantly changes with M. tuberculosis infection.