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Review
. 2016 Jan;2016(1):338-357.
doi: 10.1093/emph/eow028. Epub 2016 Sep 25.

Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?

Michael D Gurven  1 , Benjamin C Trumble  2 , Jonathan Stieglitz  3 , Aaron D Blackwell  4 , David E Michalik  5 , Caleb E Finch  6 , Hillard S Kaplan  7
Affiliations
Review

Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?

Michael D Gurven et al. Evol Med Public Health. 2016 Jan.

Abstract

Heart disease and type 2 diabetes are commonly believed to be rare among contemporary subsistence-level human populations, and by extension prehistoric populations. Although some caveats remain, evidence shows these diseases to be unusual among well-studied hunter-gatherers and other subsistence populations with minimal access to healthcare. Here we expand on a relatively new proposal for why these and other populations may not show major signs of these diseases. Chronic infections, especially helminths, may offer protection against heart disease and diabetes through direct and indirect pathways. As part of a strategy to insure their own survival and reproduction, helminths exert multiple cardio-protective effects on their host through their effects on immune function and blood lipid metabolism. Helminths consume blood lipids and glucose, alter lipid metabolism, and modulate immune function towards Th-2 polarization - which combined can lower blood cholesterol, reduce obesity, increase insulin sensitivity, decrease atheroma progression, and reduce likelihood of atherosclerotic plaque rupture. Traditional cardiometabolic risk factors, coupled with the mismatch between our evolved immune systems and modern, hygienic environments may interact in complex ways. In this review, we survey existing studies in the non-human animal and human literature, highlight unresolved questions and suggest future directions to explore the role of helminths in the etiology of cardio-metabolic disease.

Keywords: atherosclerosis; diabetes; ecological immunology; helminths; hygiene hypothesis; old friends hypothesis.

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Figures

Figure 1.
Figure 1.
Summary of mechanisms by which helminths affect CAD and T2DM. ‘Lipid and Glucose Metabolism’: Helminths promoting Th2 immune bias induce systemic elevations in eosinophils and alternatively activated macrophages (AAMs or M2), especially in white adipose tissue. AAMs producing resistin-like molecule alpha (REMα) inhibit adipogenesis, while increased anti-inflammatory cytokines (e.g. IL-10) downregulate pro-inflammatory cytokines, increasing insulin sensitivity [34]. Together these factors reduce obesity and insulin resistance, lowering risk of T2DM. Direct ‘Nutritional Costs of Helminths’: Helminths can directly consume blood lipids, but may also decrease lipid levels by inhibiting their intestinal absorption, depending on species and density of infection. ‘Trade Offs: Costs of Immune Function’: Immune activation is energetically expensive, and results in increased RMR, which can lead to less adipose storage, or possible consumption of existing adipose tissue to generate eosinophils, macrophages and other immune components. ‘Classically Activated Macrophages (CAMs) and LDL’: In hygienic populations, CAMs or M1 cluster at the site of arterial injuries and bind with LDL cholesterol, resulting in calcified lesions that progress with repeated exposure. In presence of helminths, LDL is lower, and immunity is Th2-polarized with anti-inflammatory M2 macrophages recruited to fight infection; the net effect is decreased atherosclerotic lesion progression. ‘Immune Modulation and Regulation and Atherosclerosis’: Th2-biased immunity increases AAMs and regulatory T-cells, which release cytokines (IL-4, IL-5, IL-13, IL-10) that impact signaling pathways within adipose tissue (e.g. PPAR, STAT-6). T regulatory cells inhibit Th-17 responses (e.g. IL-17), and produce other anti-inflammatory cytokines (e.g. IL-10) that result in immunomodulation disfavoring atherosclerotic lesions, plaque vulnerability or insulin resistance [35]. Note: regular arrowhead suggests promotion, whereas flat arrowhead signifies inhibition
Figure 2.
Figure 2.
Contemporary preindustrial study populations. (a) Three Ende women at a health clinic (Photo credit: Aprilianto Eddy Wiria). (b) Two elderly Tsimane from a remote Tsimane village along the Maniqui River (Photo credit: Michael Gurven). (c) An older Bimoba woman in upper east Ghana (Photo credit: David van Bodegom). (d) Elderly Kitava man and woman (Photo credit: Staffan Lindeberg). Note: all photos were obtained with permission and consent for use
Figure 3.
Figure 3.
Difference in cardiometabolic risk factors between Ende infected (n = 446) and uninfected (n = 229) with at least one soil-transmitted helminth. Cross-sectional representative sample of adults age 18+ in a semi-urban area of Nangapanda on Flores Island were collected from May to August 2009. Most prevalent helminths include N. Americanus, A. lumbricoides, T. trichiura. Error bars are the 95% CI for the mean difference. Results are similar but attenuated when adjusting for age, sex and BMI. Based on [120]
Figure 4.
Figure 4.
Relationships between indicators of infection and immune activation on blood lipids. Sample of 418 adults age 20+ from 17 Tsimane villages in 2004, collected as part of the Tsimane Health and Life History Project. Low hemoglobin, high CRP and IL-6, high IgE and eosinophil count are all associated with lower total blood cholesterol, and to some extent with lower HDL cholesterol. Results based on multiple regression analyses of total-C (n = 345) and HDL (n = 318) that also control for age, sex, BMI. Low Hb refers to first quartile, high eosinophils refers to fourth quartile. Based on [119]
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