The World Health Organization (WHO) has identified type 2 diabetes (T2DM) as a neglected, important, and re-emerging risk factor for tuberculosis (TB), especially in low and middle-income countries where TB is endemic. In this clinical trial study, oral liposomal glutathione supplementation (L-GSH) or placebo was given to individuals with T2DM to investigate the therapeutic effects of L-GSH supplementation. We report that L-GSH supplementation for 3 months in people with T2DM was able to reduce the levels of oxidative stress in all blood components and prevent depletion of glutathione (GSH) in this population known to be GSH deficient. Additionally, L-GSH supplementation significantly reduced the burden of intracellular mycobacteria withinin vitrogranulomas generated from peripheral blood mononuclear cells (PBMCs) of T2DM subjects. L-GSH supplementation also increased the levels of Th1-associated cytokines, IFN-γ, TNF-α, and IL-2 and decreased levels of IL-6 and IL-10. In conclusion our studies indicate that oral L-GSH supplementation in individuals with T2DM for three months was able to maintain the levels of GSH, reduce oxidative stress, and diminish mycobacterial burden withinin vitrogenerated granulomas of diabetics. L-GSH supplementation for 3 months in diabetics was also able to modulate the levels of various cytokines.

Glutathione (GSH) is an antioxidant in human cells that is utilized to prevent damage occurred by reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. Due to its immunological role in tuberculosis (TB), GSH is hypothesized to play an important part in the immune response against M. tb infection. In fact, one of the hallmark structures of TB is granuloma formation, which involves many types of immune cells. T cells, specifically, are a major component and are involved in the release of cytokines and activation of macrophages. GSH also serves an important function in macrophages, natural killer cells, and T cells in modulating their activation, their metabolism, proper cytokine release, proper redox activity, and free radical levels. For patients with increased susceptibility, such as those with HIV and type 2 diabetes, the demand for higher GSH levels is increased. GSH acts as an important immunomodulatory antioxidant by stabilizing redox activity, shifting of cytokine profile toward Th1 type response, and enhancing T lymphocytes. This review compiles reports showing the benefits of GSH in improving the immune responses against M. tb infection and the use of GSH as an adjunctive therapy for TB.

Tuberculosis (TB) remains a pervasive global health threat. A significant proportion of the world’s population that is affected by latent tuberculosis infection (LTBI) is at risk for reactivation and subsequent transmission to close contacts. Despite sustained efforts in eradication, the rise of multidrug-resistant strains of Mycobacteriumtuberculosis (M. tb) has rendered traditional antibiotic therapy less effective at mitigating the morbidity and mortality of the disease. Management of TB is further complicated by medications with various off-target effects and poor compliance. Immunocompromised patients are the most at-risk in reactivation of a LTBI, due to impairment in effector immune responses. Our laboratory has previously reported that individuals suffering from Type 2 Diabetes Mellitus (T2DM) and HIV exhibited compromised levels of the antioxidant glutathione (GSH). Restoring the levels of GSH resulted in improved control of M. tb infection. The goal of this review is to provide insights on the diverse roles of TGF- β and vitamin D in altering the levels of GSH, granuloma formation, and clearance of M. tb infection. We propose that these pathways represent a potential avenue for future investigation and development of new TB treatment modalities.

Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), is responsible for causing significant morbidity and mortality, especially among individuals with compromised immune systems. We have previously shown that the supplementation of liposomal glutathione (L-GSH) reduces M. tb viability and enhances a Th-1 cytokine response, promoting granuloma formation in human peripheral blood mononuclear cells in vitro. However, the effects of L-GSH supplementation in modulating the immune responses in the lungs during an active M. tb infection have yet to be explored. In this article, we report the effects of L-GSH supplementation during an active M. tb infection in a mouse model of pulmonary infection. We determine the total GSH levels, malondialdehyde (MDA) levels, cytokine profiles, granuloma formation, and M. tb burden in untreated and L-GSH-treated mice over time. In 40 mM L-GSH-supplemented mice, an increase in the total GSH levels was observed in the lungs. When compared to untreated mice, the treatment of M. tb-infected mice with 40 mM and 80 mM L-GSH resulted in a reduction in MDA levels in the lungs. L-GSH treatment also resulted in a significant increase in the levels of IL-12, IFN-γ, IL-2, IL-17, and TNF-α in the lungs, while down-regulating the production of IL-6, IL-10, and TGF-β in the lungs. A reduction in M. tb survival along with a decrease in granuloma size in the lungs of M. tb-infected mice was observed after L-GSH treatment. Our results show that the supplementation of mice with L-GSH led to increased levels of total GSH, which is associated with reduced oxidative stress, increased levels of granuloma-promoting cytokines, and decreased M. tb burden in the lung. These results illustrate how GSH can help mitigate M. tb infection and provide an insight into future therapeutic interventions.

Diversity-generating retroelements (DGRs) accelerate evolution by rapidly diversifying variable proteins. The human gastrointestinal microbiota harbors the greatest density of DGRs known in nature, suggesting that they play adaptive roles in this environment. We identified >1100 distinct DGRs among human-associated Bacteroides species and discovered a subset that diversify adhesive components of type V pili and related proteins. We show that Bacteroides DGRs are horizontally transferred across species, display activity levels ranging from high to low, and preferentially alter the functional characteristics of ligand-binding residues on adhesive organelles. Specific variable protein sequences are enriched when Bacteroides strains compete with other commensal bacteria in gnotobiotic mice. Analysis of >2700 DGRs from diverse phyla in mother-infant pairs shows that Bacteroides DGRs are disproportionately transferred to vaginally delivered infants where they actively diversify. Our observations provide a foundation for understanding the potential roles of targeted genome plasticity in shaping host-associated microbial communities.

Tuberculosis (TB) caused by Mycobacterium tuberculosis ( M. tb ) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects’ blood was drawn pre- and post-L-GSH/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.