Evolutionary Speculation About Tuberculosis and the Metabolic and Inflammatory Processes of Obesity

This Commentary explores the possibility that the tuberculosis epidemic during previous centuries generated selective pressures that intensified the metabolic syndrome and the inflammatory processes now associated with obesity. These proinflammatory defenses (with immune systems that are especially robust and more easily triggered) in partnership with the metabolic syndrome (insulin resistance, dyslipidemias, and hypertension),¹ may have provided an advantage during the tuberculosis pandemic when food availability was limited and average life span was short. Currently, in developed countries, tuberculosis is relatively uncommon, food is abundant, and life expectancy beyond the reproductive years is substantial; the evolutionarily enhanced immune and metabolic elements now act possibly to intensify the pathological consequences of obesity.

One hypothesis for the obesity pandemic posits that thrifty genes, mutations incorporated into the genome during millennia of lean times to protect against starvation, produce obesity in times of plenty.² If the evolutionary goal is to store extra calories to prevent death from starvation, the thrifty gene hypothesis fails to explain why obesity predisposes to the metabolic syndrome. Equally puzzling is the increase in circulating cytokine levels associated with obesity-related inflammation, despite the absence of a microbial threat.³

If calorie conservation is overriding, why does a calorie-wasting process of inflammation occur? What factors explain the well-recognized minority of individuals with simple obesity in whom accumulation of fat occurs with limited metabolic and inflammatory complications? If prevention of starvation is a dominant evolutionary drive, simple obesity should be the dominant not the minority model.⁴ Moreover, metabolic disturbances and inflammation associated with obesity produce widespread damage to macromolecules, cell organelles, cells, and tissues that predispose to certain diseases, such as diabetes, myocardial infarction, certain cancers, and cognitive decline and a shortened life span.^{1 - 2}

Because the body is programmed to benefit self, seemingly harmful responses prompt searches for benefit for other scenarios. For example, in mice, the homozygous ob mutation produces leptin deficiency, massive obesity, and infertility when homozygous, whereas heterozygote ob mice are fertile and weigh the same as normal littermates but store more fat and survive starvation longer.^{5 - 6} Could the metabolic and inflammatory process associated with obesity, currently disadvantageous, have been important in attempts to survive tuberculosis?

At one point in history, tuberculosis was recognized as the most dreaded disease of the human race.⁷ Optimism about eradication, brought on by discovery of the first antituberculosis drugs, has been replaced by the sober recognition that tuberculosis (alone and in combination with drug resistance and AIDS) worldwide is second only to AIDS among the leading causes of death from infectious diseases.⁸ It is estimated that one-third of the world's population is infected with latent tuberculosis with about 9 million new cases and 1.6 million deaths occurring annually.⁸

Historically, it is estimated that tuberculosis has been responsible for more than 1 billion deaths,⁷ exceeding the 40 million deaths from the influenza pandemic of 1918 and the millions of deaths from bubonic plague. The social deterioration and crowding that accompanied the industrial revolution, as well as major wars, ignited tuberculosis epidemics.⁷ In 19th-century Europe, 25% of all deaths were attributed to tuberculosis. Human populations newly exposed to the bacillus were often decimated.⁷ The devastation caused by tuberculosis thereby could have provided powerful pressure for darwinian adaptations.

In general, the initial defense against microbes is the innate immune system—an array of cells, cytokines, and other antimicrobial peptides—that prevents or controls infection until the adaptive immune system can forge pathogen-specific responses. Innate immune elements along with adaptive immunity, involving B cells, T cells, and macrophages, can forestall infection and even provide immunity from reinfection. Tuberculosis exposure generally provokes full bidirectional innate and adaptive immune responses, with cell-mediated elements more important than humoral factors.⁸ Although these responses are essential, once tuberculosis is contracted, they are insufficient to produce a cure or to guarantee protection from recrudescence.

Initial infection with tubercle bacillus can result in rapid death or prolonged illness leading to death in some individuals, can progress without causing death, or might be halted or arrested.⁹ However mycobacteria remain in the host, capable of reactivating the disease. Before the introduction of specific antimycobacterial agents, tuberculosis typically was only arrested and rarely resolved spontaneously.⁹ Compromise of the immune system—as with human immunodeficiency virus infection, certain drugs, aging, and malnutrition—substantially increases the likelihood of a recrudescence. While malnutrition predisposes to tuberculosis, obesity appears to be associated with decreased risk.¹⁰

When starvation occurs, growth, puberty, and reproduction are markedly attenuated to conserve nutrients. Immune responses also are diminished by starvation, and the 2 are linked: starvation weakens immunity, and with starvation, the mode of death is often an infection. Conversely, overeating and physical inactivity promote weight gain, predispose to the metabolic syndrome, and up-regulate multiple proinflammatory elements.^{1 - 4} A 20% to 25% weight gain typically doubles body fat.² The enlarged fat mass increases circulating levels of leptin and resistin, proinflammatory adipokines, and decreases levels of adiponectin, an anti-inflammatory peptide.^{1 - 4}

Adipocytes in subcutaneous fat (and in brown fat) are low in proinflammatory influences and are largely bypassed in the deposition of the excess fat. Adipocytes in visceral fat, the favored site, in addition to storing fat, secrete adipokines and also attract and activate macrophages that release enzymes and cytokines that further drive the proinflammatory state.^{2 - 4} Inflammation is also promoted by ectopic fat, triglycerides deposited inappropriately in liver, skeletal muscle, and pancreatic islets.^{2 - 4}

In most individuals with excess weight, levels of the cytokine tumor necrosis factor (TNF) are elevated, along with levels of other proinflammatory markers. The importance of TNF as a strong innate antituberculosis factor has been illustrated by patients who receive new therapies that inhibit TNF activity. These therapeutic agents ameliorate symptoms of rheumatoid arthritis and Crohn disease but are associated with increased risk of reactivation of tuberculosis.¹¹

Khovidhunkit et al¹² suggested that “[b]esides their role in lipid transport, lipoproteins also are involved in innate immunity. Many changes in lipoproteins during infection/inflammation help protect the host. . . . If prolonged, these changes in . . . lipoproteins will contribute to atherogenesis.” The metabolic syndrome, associated with calorie excess and sedentary behavior, is characterized by increased levels of low-density lipoprotein, a proinflammatory lipoprotein, and decreased levels of high-density lipoprotein, an antiinflammatory moiety.¹²

In recent centuries, essentially everyone in Europe harbored the mycobacterium,⁷ and many died or were impaired by the disease. Even for individuals with robust immune systems, cures were rare. Tuberculosis microbes survived intracellularly and could reactivate clinical disease that could be fatal. Lapses in immunity associated with calorie deprivation may have predisposed individuals to recrudescence of clinical disease. The endogenous in vivo metabolic-inflammatory process and commonly used therapies for tuberculosis in the preantibiotic era⁹ overlap in bolstering the immune system. For instance, in the preantibiotic era, physicians advised patients with tuberculosis to curtail severely physical activity and to adhere to a calorie-, protein-, and micronutrient-laden diet, maneuvers now known to enhance proinflammatory processes. Daily doses of cod-liver oil greatly augmented intake of (the then not yet discovered) vitamins A and D, which also boost immunity.^{13 - 14} Sunshine, also prescribed, enhances the transformation in skin of endogenous precursors into fully active vitamin D. High altitudes were also recommended for patients with tuberculosis. Hypoxia, induced by high elevations, up-regulates hypoxia-inducible transcription factor 1α (HIF 1α), which in turn promotes a major proinflammatory cascade, another potential beneficial immune response against tuberculosis.

According to Baldwin,^{15 (p 143)} “The greatest mortality from tuberculosis is between the fifteenth and forty-fourth years of life, when it causes one third of all deaths occurring during that period.” Evolutionarily, the reproducing population was in greatest need of the potential antimycobacterial effects of the metabolic-inflammatory process associated with obesity and seldom experienced the undesirable effects. Myocardial infarction, stroke, and type 2 diabetes generally occur later in life, following the reproductive years. In European populations, when life expectancy was relatively short and tuberculosis was a serious threat, it may have been biologically advantageous for an individual's calorie balance, even when just above a starvation threshold, to sustain the metabolic-inflammatory process. Immediate benefits, on balance, may have exceeded long-term risks.

Individuals and populations vary widely in the set point, the magnitude of caloric balance, for activating the immune response with its metabolic-inflammatory components.^{1 - 4} For instance, inhabitants of India and Japan may develop metabolic-inflammatory aspects of obesity at levels of adiposity considered normal by European standards, supporting the idea that the metabolic syndrome is not simply intrinsic to fat accumulation. Rather, fat accumulation may provide a set point that acts as a trigger.^{1 - 4} With high rates of tuberculosis, evolution would favor individuals with easily triggered metabolic and inflammatory processes of obesity. That the Inuits, historically free of tuberculosis, now have extraordinarily high rates of clinically serious tuberculosis and extraordinarily low rates of atherosclerotic cardiovascular disorders would be consistent with that observation.

Prosperous residents of wealthy countries, with the ready availability of high-calorie food, the diminished need for physical exertion, and the near disappearance of tuberculosis, have inverted the equation. For them, the metabolic-inflammatory processes are an evolutionary anachronism that brings serious adverse effects at earlier ages to a longer-living overfed population with little off-setting benefit.

These hypotheses suggest the existence of 1 (or a few) upstream switches that may regulate most or all of the downstream undesirable metabolic and inflammatory processes associated with fat accumulation in visceral fat. Possibly in the future, 1 or 2 newly introduced medications that control the upstream switches could dampen the panoply of unwanted downstream processes and thereby replace the multiple agents now used to control hypertension, dysglycemia, dyslipidemia, and inflammation.

Speculation that the previous tuberculosis pandemic may have intensified the metabolic syndrome and inflammatory processes associated with obesity suggests a plausible, though hypothetical, evolutionary process. Although these associations might be coincidental, it is important to recognize that theoretical constructs, no matter how logical, may yield conclusions that are not correct.