Impact of diabetes on tuberculosis and MDRTB susceptibility
- Impaired immune function
- Altered microbial genomics
- Uncontrolled glucose levels, increasing susceptibility to MDR-TB
- Compromised phagocytic activity and reduced chemotactic response
- Increased oxidative species and microbe proliferation
- Altered drug disposition
- Higher likelihood of non-adherence to treatment
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Ssekamatte P, Sande OJ, van Crevel R and Biraro IA (2023). Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility. Front. Immunol. 14:1122255.
See also: Lin TB Lab
Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, accounting for 90-95% of all cases worldwide, with the highest prevalence in low- and middle-income countries. While the direct causes of T2DM are not fully understood, there are strong associations with factors such as overweight, obesity (especially visceral adiposity), aging, alcohol abuse, ethnicity, and a family history of diabetes. T2DM results from a combination of genetic predisposition and environmental triggers.
See also: Post-TB DM and Stroke
Obesity-related insulin resistance, a precursor to T2DM, involves a failure of pancreatic β-cells to compensate, leading to chronic hyperglycemia. Abdominal obesity is linked to low-grade chronic inflammation, which may contribute to metabolic disorders, including T2DM. Markers of inflammation, such as elevated white blood cell count, pro-inflammatory cytokines (TNF, IL-1β, IL-6), chemokines (MCP-1, IL-8, IP-10), and other markers (CRP, fibrinogen, sialic acid, PAI-1), are predictors of T2DM.
See also: CV mortality on TB patients
In obesity and T2DM, adipose tissue becomes enriched with macrophages and T-cells, shifting from an anti-inflammatory to a pro-inflammatory state. This imbalance increases chemokine and cytokine production, promoting systemic inflammation and insulin resistance.
Natural infection with Mycobacterium tuberculosis (Mtb) occurs through inhalation of aerosols containing bacilli, which settle in the primary alveolus. The bacilli initially invade alveolar macrophages, the primary site for early replication. Once inside, the bacilli secrete the 6kDa early secretory antigenic target (ESAT-6), which prevents phagosome-lysosome fusion and apoptosis, facilitating bacillus multiplication and necrosis of the macrophages. The bacilli spread extracellularly and are phagocytosed by additional macrophages from surrounding alveoli, generating a significant inflammatory response.
See also: NCD and TB
This inflammation recruits polymorphonuclear (PMN) cells and monocytes, enhancing phagocytosis and drainage into lymph nodes, where myeloid dendritic cells (mDCs) can transport the bacilli. mDCs process the Mtb and present antigens, including ESAT-6 and the antigen 85 complex, to stimulate CD4+ T-cell proliferation (Th1, Th17, and Tregs) and, to a lesser extent, CD8+ T cells. These T cells migrate to the lungs and produce IFN-γ to activate macrophages and other immune cells like neutrophils, NK cells, B cells, and DCs, leading to the formation of granulomas to restrict Mtb replication.
See also: Prediabetes and TB
If the immune system or granulomas fail to control the initial spread, primary active tuberculosis (ATB) may develop, particularly in immunocompromised individuals. If Mtb is contained but not eliminated, latent TB infection (LTBI) occurs, which can progress to ATB later. Immunosuppression may reactivate Mtb within granulomas, resulting in pulmonary TB, extrapulmonary TB, or miliary TB.
Type 2 diabetes mellitus (T2DM) is a primary risk factor for Mycobacterium tuberculosis (Mtb) infection. Patients with T2DM or pre-diabetes have a significantly higher risk of latent TB infection (LTBI) and are more likely to develop active tuberculosis (ATB). T2DM is also linked to an increased risk of multi-drug-resistant TB (MDR-TB), with higher rates of resistance to isoniazid, ethionamide, and fluoroquinolones.
See also: Glycemic control and TB
T2DM patients with ATB tend to have more severe disease, with chest X-rays and CT scans often showing cavities, bilateral pulmonary involvement, extensive lesions, and more advanced disease. Poorly controlled T2DM is associated with all-lobe involvement and adverse TB treatment outcomes, including early mortality and increased overall risk of death during TB treatment.
Innate immune cells, including macrophages, innate lymphoid cells (ILCs), neutrophils, and dendritic cells (DCs), play a crucial role in identifying Mycobacterium tuberculosis (Mtb) and initiating immune responses like autophagy, apoptosis, and phagocytosis to eliminate the pathogen. Macrophages are central in controlling Mtb by producing reactive nitrogen and oxygen species, and cytokines. However, in T2DM patients, macrophage function is impaired, with decreased expression of HLA-DR and increased expression of PD-L1, which inhibits T cell proliferation and weakens the immune response, increasing susceptibility to Mtb. T2DM also alters macrophage receptor expression, reducing their ability to recognize and respond to Mtb, and induces lysosomal dysfunction, which supports Mtb survival.
See also: Health care visit and TB
Neutrophils, abundant in early Mtb infection, show increased levels but reduced adhesion and phagocytic abilities in ATB-T2DM patients. Chronic low-grade inflammation, a characteristic of T2DM, further impairs immune responses to TB. Elevated IL-8 and resistin levels in TB-T2DM patients are associated with increased proinflammatory cytokines and impaired neutrophil function, promoting Mtb growth. Resistin also inhibits reactive oxygen species (ROS) and IL-1β production by macrophages, suppressing the inflammasome.
Dendritic cells (DCs) are essential for presenting antigens and initiating adaptive immune responses by activating T cells. In TB-T2DM patients, DC frequencies are reduced, impairing their ability to prime T cells, which affects the host's capacity to clear Mtb. ILC3 cells, which produce IL-22 critical for early innate immunity and granuloma formation, may have reduced IL-22 production in T2DM, suggesting a potential therapeutic target for TB-T2DM. Natural killer (NK) cells (ILC1s) are elevated in ATB-T2DM patients, with CD16 and CD56 expression decreasing after anti-TB treatment, highlighting their potential role in monitoring treatment response. Additionally, NK cells produce IL-6, which can inhibit CD4+ T cell proliferation.
In ATB-T2DM patients, there is an imbalance in T cell populations, with an increase in Th2 and Th17 cells and a reduction in Th1 cells, leading to a decreased Th1/Th2 ratio. These patients also show elevated levels of CD4+ Th1 and Th17 cells, but reduced regulatory T (Treg) cells compared to ATB patients without T2DM. Additionally, in LTBI-T2DM patients, there is a reduction in CD4+ Th1, Th2, and Th17 cells.
T2DM is associated with lower Mtb antigen-specific IFN-γ production in ATB patients due to decreased levels of IL-12, which is crucial for promoting IFN-γ production by Th1 cells. Elevated IL-10 levels in ATB-T2DM patients further inhibit the Th1 response. Increased expression of PD-L1 in Mtb-infected macrophages in T2DM patients also suppresses the Th1 response, reducing IFN-γ production and impairing the ability to control Mtb infection.
ATB-T2DM patients have higher frequencies of central memory CD4+ and CD8+ T cells, but lower frequencies of naïve and effector T cells at baseline and after two months of treatment, with restoration observed after six months of treatment. In LTBI-T2DM patients, there is a reduction in type 1 (TNF, IL-2, IFN-γ), type 17 (IL-17F), pro-inflammatory (IL-1, IL-18), and anti-inflammatory (IL-10) cytokines. Upon Mtb antigen stimulation, these patients show lower frequencies of CD8+ Tc1, Tc2, and Tc17 cells with increased cytotoxic markers (perforin and granzymes), which reverse upon progression to ATB.
Overall, T2DM impairs the Th1 response, reducing the host's ability to eliminate TB.
In poorly controlled diabetes, the presence of highly glycated proteins and advanced glycation end products (AGEs) impairs immune responses by reducing complement activation, phagocytosis, and the killing of bacteria, thereby promoting the spread of Mycobacterium tuberculosis (Mtb). AGEs can induce oxidative stress and hinder wound healing by causing excessive mitochondrial ROS production. Similarly, oxidized low-density lipoprotein (oxLDL), which is elevated in T2DM, contributes to Mtb survival by inducing lysosomal dysfunction in macrophages.
Metformin, a common treatment for T2DM, has anti-mycobacterial benefits. It enhances the function of CD8+ T cells, increases oxidative phosphorylation, and upregulates genes related to ROS production and phagocytosis while downregulating genes involved in inflammation. T2DM and obesity are also linked to gut microbiome dysbiosis, affecting the balance of bacteria that produce short-chain fatty acids (SCFAs), which are critical in regulating immune and inflammatory responses. T2DM patients typically have increased Lactobacillus species (associated with higher glucose levels) and decreased Clostridium species (associated with better glucose and lipid control). TB infection can further reduce microbial diversity, particularly SCFA-producing bacteria.
Patients with ATB-T2DM show elevated levels of haem oxygenase-1 (HO-1), which correlates with increased glucose, LDL, and HbA1c levels. They also have higher levels of inflammatory cytokines and vascular endothelial growth factors (VEGFs), which are associated with HbA1c levels. Certain amino acids (e.g., citrulline, histidine, tryptophan) are decreased in ATB-T2DM patients compared to healthy controls, while specific biomarkers (choline, serine, putrescine) and metabolite ratios (phenylalanine/histidine, kynurenine/tryptophan) have shown potential as discriminative or predictive markers for TB diagnosis, regardless of diabetes status. The kynurenine/tryptophan ratio is particularly significant as it reflects enhanced activity of the immunoregulatory enzyme IDO, supporting Mtb infection.
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