Potential Role of Microbiome in Tuberculosis (Micro-STOP)

Exploring the Role of Microbiome in Susceptibility, Treatment Response and Outcome Among Tuberculosis Patients; a Prospective Cohort Study

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a deadly infectious disease and major global public health problem. Recent evidence from animal studies suggests that the microbiome plays a role in TB pathogenesis and immune response. However, until now, no similar study has been performed in humans and thus any influence of the microbiota on TB or vice versa remains unknown.

Study Overview

• Status: Completed
• Conditions: Tuberculosis

Detailed Description

Tuberculosis is among one of the most difficult to treat infections that require multidrug therapy for prolonged periods, in most cases 6-9 months. Treatment failure is still common and frequently observed (even where adherence to antibiotic therapy is maintained) in 15% of drug-susceptible infections and 31% for drug-resistant cases. Although poor patient compliance and the emergence of drug-resistant Mtb strains are generally implicated as a major cause of TB treatment failure, other factors such as the role of the microbiome in TB pathogenesis and reactivation are poorly considered.

The human microbiome is a consortium/collection of all microorganisms (bacteria, archaea, viruses, and fungi) colonizing different habitats in the human body such as skin, gut, and mucosal surfaces and living in a commensal relationship with each other. Emerging evidence suggests a crucial role of the microbiome in hosts physiology, nutritional status, and development of the functional immune system. Microbial dysbiosis is the change in microbial composition or functional potential that has been implicated both in infectious diseases status as well as the development of non-communicable disease in hosts ranging from immune mediated diseases to intergenerational obesity and even cancers. Microbial dysbiosis at different body sites has also been reported in TB-associated comorbidities such as diabetes mellitus and malnutrition. However, to date, the role of the microbiome and microbial dysbiosis is not clear in the context of TB infections in humans.

Therefore, this study aims to dissect the relationship between the microbiomes and its interaction with the immune system during TB infection, and anti-tuberculosis therapy in humans.

• Study Type: Observational
• Enrollment (Actual): 450

Contacts and Locations

Study Locations

• Pakistan
  • KP
    • Peshawar, KP, Pakistan, 23061
      • DTO Peshawar
    • Peshawar, KP, Pakistan, 25110
      • Khyber Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study will be conducted primarily in three district levels (Peshawar, Mardan and Swat) TB diagnostic and treatment centers of Khyber Pakhtunkhwa province of Pakistan. These centers have been selected based on the highest TB prevalence in the year 2020

Description

Inclusion Criteria:

1. Diagnosed with TB after detailed history collection, clinical examination and laboratory assessment (sputum culture positive).
2. Aged 18 - 65 years.
3. Willing to participate in the study.
4. Healthy controls are those who are free of TB symptoms, healthy on physical examination and with a negative sputum culture result.

Exclusion Criteria:

1. Already on anti-TB treatment or previously treated for TB.
2. Severely anemic (Hb < 10g/dL).
3. Having diarrhea or other major gastrointestinal disorders.
4. Using or have used aminoglycoside or quinolones antibiotics in the past one month.
5. Using a medically prescribed diet or nutrition supplement.
6. Pregnant or lactating women.
7. Patients with liver or renal dysfunction, or having any other chronic disease condition.
8. Multidrug resistance TB patients

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Tuberculosis Patients; Diagnosed with pulmonary TB after detailed history collection, clinical examination, and laboratory assessment (sputum culture positive).; Aged 18 years or above.; Willing to participate in the study.
Healthy Volunteers; Healthy subjects with no symptoms or history of pulmonary TB; Negative sputum culture; Matched for sex and age (±5 years) with the TB patient group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiome diversity and functional potential	To explore the effect of TB infection and anti-tuberculosis therapy on gut microbiome diversity, functional potential and immune response in newly diagnosed TB patients from Pakistan.	2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Gut microbiome	To determine gut microbiome diversity and functional potential at baseline and compare with healthy controls	1 year
Baseline Oral microbiome	To determine oral microbiome diversity and functional potential at baseline and compare with healthy controls	1 year
Gut microbiome and associated factors	3. To assess the relationship between gut microbiome and socio-demographic characteristics and dietary intake in TB patients at baseline, before the start of anti-tuberculosis treatment.	1 year
Microbial dysbiosis	To describe the occurrence of gut microbial dysbiosis and its association with adverse reaction and treatment failure in TB patients.	Two years
Microbial signatures	5. To identify specific oral and gut enterotypes associated with adverse reaction and unfavorable treatment outcomes.	2 years

Collaborators and Investigators

• Sponsor: Khyber Medical University Peshawar
• Collaborators: University of Reading; TB Control Program Khyber Pakhtunkhwa
• Investigators: Principal Investigator: Muhammad Shahzad, Khyber Medical University

Publications and helpful links

General Publications

• Shahzad M, Andrews SC, Ul-Haq Z. Exploring the role of Microbiome in Susceptibility, Treatment Response and Outcome among Tuberculosis Patients from Pakistan: study protocol for a prospective cohort study (Micro-STOP). BMJ Open. 2022 Jun 7;12(6):e058463. doi: 10.1136/bmjopen-2021-058463.

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2021
• Primary Completion (Actual): March 31, 2024
• Study Completion (Actual): August 31, 2024

Study Registration Dates

• First Submitted: July 22, 2021
• First Submitted That Met QC Criteria: July 22, 2021
• First Posted (Actual): August 2, 2021

Study Record Updates

• Last Update Posted (Actual): October 10, 2024
• Last Update Submitted That Met QC Criteria: October 9, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Microbiome; Nutrition; Immunity; Tuberculosis; Treatment response; Gut microbiome; Treatment Outcome; Pulmonary TB; Dietary intake; Oral Microbiome
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: DIR/KMU-EB/PR/000858; 10289/KPK/NRPU/R&D/HEC/2019 (Other Grant/Funding Number: Higher Education Commission Pakistan)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to the trial IPD can be requested by qualified researchers with research or academic interests in Tuberculosis or Microbiome research. The individual researchers will be required to send an email to the principal investigator describing the need and rationale for IPD. However, the access will be provided only after the proposal and statistical analysis plan is reviewed by the principal investigator and ORIC office of Khyber Medical University. The party requesting the access will also be required to sign Data Sharing agreement and or Material transfer agreement. Before sharing, the principal investigator will make sure that the samples and data are coded and all the personal information are removed.
• IPD Sharing Time Frame: Within one year after the data is published
• IPD Sharing Access Criteria: The information request should be send directly to the principal investigator by email.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Study Data/Documents

1. Study Protocol
   Information comments: Complete study protocol has been published and can be accessed through the URL given above.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No