About one tenth of the 1.7 billion individuals infected with Mycobacterium tuberculosis
(Mtb) will progress to active tuberculosis (TB). This probability increases in people
with human immunodeficiency virus (HIV) and other risk co-morbidities such as
malnutrition, diabetes and substance abuse. Chronic microbial colonisation with unrelated
bacteria are associated with TB pathogenesis (e.g., mice colonised with Helicobacter
hepaticus exhibit poor control of TB), indicating that the gut microbiota may modulate
progression to active TB. Furthermore, first-line TB treatment (Isoniazid, Rifampicin,
Ethambutol, Pyrazinamide; HREZ) depletes gut commensal bacteria (Ruminococcus,
Coprococcus and Bifidobacterium) with immunomodulatory roles [interleukin (IL)-1,
interferon (IFN)-γ and Th17 responses, respectively).
Recent work identified heat-killed Mycobacterium manresensis (hkMm), a harmless member of
the fortuitum complex naturally found in drinking water, as a promising candidate for
reducing the risk of active TB. Mtb-infected mice treated with hkMm had significantly
reduced lung pathology (fewer and smaller lesions,) bacillary load and proinflammatory
cytokines (TNF-α, IFN-γ, IL-6, and IL-17) compared to untreated control mice, and in mice
receiving hkMm with HREZ, survival rates were significantly increased. Moreover, mice
treated with hkMm had increased microbial diversity and an altered gut microbial
composition relative to untreated mice. This could prove beneficial for TB patients
during prolonged antibiotic treatment as supplementation with hkMm may help protect gut
microbiota, and potentially improve clinical outcome.
In individuals with and without latent M. tuberculosis infection, two weeks of daily oral
doses of Nyaditum resae® (a preparation of hkMm approved as a food supplement by
Manremyc) demonstrated enhanced effector and memory specific regulatory T-cell responses.
Similar clinical trials with Nyaditum resae® are currently being done in paediatrics
(NCT02581579) and close contacts of active TB cases in Tbilisi, Georgia (NCT02897180;
2017-2023). The probiotic is also being registered as a food supplement in several
countries.
In the proposed study, the efficacy of Nyaditum resae® in reducing antibiotic-associated
gut dysbiosis and disease progression in patients with active TB will be tested. To do
this, the investigators will assess changes in the microbiota during treatment (with or
without Nyaditum resae® supplementation) and attempt to identify genera associated with a
favourable or unfavourable treatment outcome in TB patients.
