Does adipose tissue have a role in tuberculosis?

KEYWORDS:

• Tuberculosis
• body composition
• fat mass
• lean mass
• adipose tissue

1. Introduction

Adipose tissue is best understood from the body composition perspective, where body weight is divided into two functional component parts referred to as fat mass (mainly composed of adipose tissue) and lean mass [1]. Adipose tissue is an aggregate of discrete forms of non-essential fat whereas lean mass contains all non-adipose elements including minerals, protein, and body water [2]. Among healthy adults, males have 15% (8–25%) whereas females have 27% (20–38%) of their weight as adipose tissue [2]. In addition to sex, these proportions of adipose tissue may change depending one’s age, ethnic background, and level of physical activity. Studies have found that at the same body mass index, old people tend to have a higher proportion of adipose tissue than young people due to loss of lean mass as age increases [3] and Asians tend to have a higher degree of stored adipose tissue than Caucasians [4]. Similarly, people who are physically active tend to have less adipose tissue, but more lean mass [5]. Adipose tissue can be found either in subcutaneous tissues (comprising of 80% of all adipose tissue) and in visceral organs where it surrounds intestines, kidneys, heart, peritoneum, and mesenteric systems [6]. Adipose tissue has a critical role in energy homeostasis and immunomodulation and may alter the risk of both communicable and non-communicable diseases [7].

2. Functions of adipose tissue

Adipose tissue is made of two cell types, namely, adipocytes and stromal vascular fraction which are surrounded by extracellular matrix [6]. Although adipose tissue was considered principally an energy storage organ, this perspective has changed in recent years and is now acknowledged to be an important immune organ linking energy metabolism and immune functions as well as playing a critical role in mounting an immune response against infections [6]. Adipocytes produce adipokines including adiponectin, Tumor Necrosis Factor-alpha (TNF-α), and several cytokines and chemokines which are key to the mounting of local inflammatory response and tissue remodeling. In addition, other adipokines like leptin, Interleukin-1 (IL-1), IL-6, IL-8 and interferon-gamma (IFN-γ) and chemokines such as monocyte chemotactic protein-1 and macrophage inflammatory protein-1 are critical to both innate and adaptive immunity and in metabolic regulation of immune systems [6]. On the other hand, the stromal vascular fraction contains significant immune cellular components including macrophages, lymphocytes, neurophils, eosinophilis, mast cells, B cells and others and may contribute to the immune response to infections [6]. Thus, these immune components provide adipose tissue with the potential to act against infections by mounting local immune response as well as contributing to systemic immune response.

3. TB and adipose tissue

About a quarter of the world population is thought to be infected with Mycobacterium tuberculosis (Mtb), an infectious agent causing tuberculosis (TB) [8]. However, 90% of those infected will only have latent TB infection (LTBI), an inactive form of TB and 5–15% of recently Mtb infected populations will be at an increased risk developing active TB due to reduced immunity associated with various host, environmental and Mtb factors [8]. Thus, globally there are about 10 million incident active TB cases and two million deaths annually [9] particularly in middle and low-income countries in Asia and Africa. Adipose tissue is known to harbor infectious agents including HIV, cytomegalovirus, and tuberculosis (TB) [6] and is probably one of the largest reservoirs of Mtb in human body [10,11] and may play an important role in the pathogenesis of TB disease.

Epidemiological studies suggest that undernutrition which is commonly associated with loss of adipose tissue may have a bi-directional relationship with TB. In German’s prisoner of war camps, where all prisoners were subjected to the same living conditions, but British prisoners received more nutritional supplies than Russian prisoners, subsequent TB assessment found that the incidence of TB was higher among wasted Russian than British prisoners [12]. During the first world war, in Denmark, massive export of fish and dairy products to Germany probably leading to undernutrition was followed by an increase in TB incidence, but the incidence dropped as protein and vitamin-rich foods became available after the exports were blocked [13]. Among individuals aged ≥14 years who were prospectively followed for 12 years in Norway, it was found that the incidence of TB declined with increasing body mass index [14] and a prospective study in the United States found that children who had low subcutaneous fat had double the risk of developing active TB compared with those with sufficient amounts of subcutaneous fat [15]. Furthermore, among TB patients reduced adipose tissue at the beginning of treatment is associated with severe clinical TB and increased mortality [16] while predominant regain of adipose rather than lean was associated with higher mortality in Uganda [17]. On the other hand, studies have found TB is associated with weight deficit which is both lean and adipose tissue and during recovery patients particularly females regain adipose tissue rather than lean mass [18]. The loss of adipose tissue during TB is probably related to decreased intake but increased utilization of nutrients during TB disease. However, the increased risk of TB associated with the loss of adipose tissue is due to mechanisms that are only begining to emerge.

Laboratory studies provide insights on how adipose tissue interacts with Mtb. In 2006, Neyrolles et al. in autopsy studies found that Mtb could be detected in adipose tissue of kidneys, stomach, lymph nodes, heart, and the skin in (6/19) individuals from Brazil and (6/20 individuals) France who had died from causes other than TB and in in-vitro studies they found Mtb could easily enter adipocytes and survive in non-replicating state where they could avoid anti-TB drugs [19]. There have been several animal studies further supporting that adipose tissue could be one of the Mtb reservoirs. In one Swiss study, investigators performed experiments to assess how Mtb bacilli were disseminated from lungs to adipose tissue and back to lungs in immunocompetent mice. In this study, mice were infected with various doses of Mtb bacilli intra-nasally and by 7-weeks Mtb could be detected in various adipose depots distal to the lungs [20]. In the same study, Mtb-containing pre-adipocytes implants were inserted subcutaneously to Mtb-free mice. At 5 weeks after insertion, Mtb infection was detected in the lungs. Thus, indicating that Mtb can easily be disseminated from lungs to adipose tissue and back to lungs. Interestingly, in yet another study, Mtb infection in adipose tissue was associated with infiltration of mononuclear phagocytes, Mtb-specific CD8⁺ T cells and NK cells which became activated suggesting that adipose tissue undergoes significant mild inflammatory changes during Mtb infection to help stay in a dormant form in adipocytes [21]. There has been limited work looking at how the loss of adipose tissue influences the development of TB. In transgenic mice studies in the US, loss of adipocytes was associated with decreased Mtb load in the adipose tissue but increased Mtb burden as well as worsened pathology in the lungs. Thus, suggesting that loss of fat mass may contribute in changing immune homeostasis and increasing the vulnerability of LTBI re-activation or progression of primary TB infection to full blown TB [22], but further work will be needed to replicate these findings and elucidate exact mechanisms [23].

Taken together, these reviewed studies suggest that in an environment where there is Mtb exposure, infection of adipose tissue with Mtb may be common and disseminated from lungs and may be associated with low-grade adipose tissue inflammation. Furthermore, Mtb infection may be unleashed to lungs due to loss of adipose tissue and reduced immunity. This is likely to be associated with increased Mtb burden in lungs and associated pathology. This is an important observation likely explaining why during periods of rapid adipose tissue loss humans develop active TB and why the degree of adipose tissue loss is associated with both severity of TB infection and mortality. Nevertheless, results from mice studies should be taken cautiously, since due to species difference as well as the complexity of TB immunology in humans, mice TB can not accurately mimic human TB [24]. Although limited work in human tissues has confirmed adipose tissue as a reservoir of TB, further clinical studies particularly among high-risk TB populations are needed to investigate adipose tissue-TB dynamics in order to exploit this understanding in the development of tools for prevention or treatment of TB. For example, studies among diabetes or HIV patients who are known to have a higher risk of developing TB conducted using novel disease markers to assess the impact of adipose tissue changes over short or long period of time on TB development could help increase our understanding of these host-disease dynamics. In addition, besides TB work, this knowledge could be used to improve understanding of the biology of other diseases. For example, it will be crucial to study the role of adipose tissue inflammation among populations with latent TB to give insights on how this impacts insulin resistance and metabolic syndrome-related diseases like diabetes.

4. Conclusion

There seems to be some evidence based on mice and human studies that adipose tissue may be a reservoir for Mtb infection and that loss of adipose tissue unleashes Mtb infection to lungs and worsen lung pathology. However, appropriate clinical studies using novel methods are needed to exploit this understanding in developing tools for the prevention and treatment of TB. Furthermore, studies exploring the links between adipose tissue changes due to Mtb infection with metabolic syndrome will help shed more light on the complexity of Mtb biology in humans.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

G PrayGod is funded by the National Institute for Medical Research (NIMR) & European & Developing Countries Clinical Trials Partnership (EDCTP).