Helminth Infections, Type-2 Immune Response, and Metabolic Syndrome

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Published in the journal: . PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004140
Category: Pearls
doi: 10.1371/journal.ppat.1004140


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The Association between Metabolic Syndrome and Inflammation

Metabolic syndrome (MetS), a disorder of energy utilization and storage, manifests as a cluster of conditions such as hypertension, dyslipidemia, abdominal obesity, and altered glucose metabolism, which increases the risk of type-2 diabetes (T2D) and cardiovascular diseases (CVD). A lifestyle that consists of overeating, high-calorie food intake, and no or irregular physical activity is a risk factor for developing MetS. Therefore, treatment for MetS comprises regular physical activity, diet modification to reduce weight and/or blood glucose, and the use of lipid-lowering drugs.

Recently, evidence is emerging that innate and/or adaptive inflammatory responses might be associated with MetS [1]. Obese people with MetS have higher concentrations of circulating inflammatory markers [2]. Nevertheless, the incidence of CVD is also found to be higher in patients with inflammatory diseases such as asthma [3] or rheumatoid arthritis [4]. It has been shown in vitro that an inflammatory milieu, with pro-inflammatory cytokines and high levels of interleukin (IL) 17 and tumor necrosis factor (TNF), can lead to the development of a prothrombotic state in human endothelial cells [5]. Several studies have shown that controlling inflammation might be linked to improved MetS. A T2D drug, thiazolidinedione (pioglitazone), can improve insulin sensitivity by activation of peroxisome proliferator-activated receptor (PPAR) γ, a type-2 nuclear receptor that regulates fatty-acid storage and glucose metabolism [6]. It was noted that the expression of PPARγ in Foxp3+CD4+ regulatory T cells (Treg) in visceral adipose tissue was essential for the restoration of insulin sensitivity in obese mice after pioglitazone treatment [6]. In addition, subcutaneous injection of adjuvant-free apolipoprotein B100-derived peptides, as atherosclerosis-related antigens, can induce accumulation of atherosclerosis-specific Treg in lymph nodes and prevent development and progression of atherosclerosis in C57BL/6J apoE−/− mice [7]. Along with the finding that statin, a lipid-lowering drug that has beneficial effects on CVD, has an anti-inflammatory role [8], there seems to be a real case for further studies into alternative therapies that interfere with inflammatory processes to combat MetS [9].

Are Helminth Infections Associated with Metabolic Syndrome?

In high-income countries (HICs), infectious diseases such as helminths (usually associated with bad hygiene or sanitation) are relatively well controlled compared to developing or low-to-middle-income countries (LMICs), especially the rural areas of LMICs. The health problems in the HICs are instead commonly related to MetS. There is increasing evidence that improvements in the infrastructure and control of infectious diseases in LMICs, which are often followed by a decline in infections (including helminth infections), are paralleled by increasing prevalence of various inflammatory diseases such as allergies and autoimmunities as well as of T2D and CVD [10].

Numerous studies have shown an inverse association between helminth infections and inflammatory diseases such as allergies, autoimmunities, and inflammatory bowel disease, but importantly there is emerging evidence that helminths seem to also be associated with a lower incidence of MetS [10]. A study in India has indicated an inverse association between lymphatic filariasis and T2D [11], while a recent report from a rural community in China, which was previously endemic for schistosomiasis, has indicated that past infection with Schistosoma japonicum was associated with lower MetS prevalence [12]. The fasting plasma glucose, postprandial blood glucose, HbA1c, and insulin resistance, as well as the level of triglyceride and low-density cholesterol, were inversely associated with self-reported past S. japonicum infection. In support of this, we have also found that in Indonesia helminth infections are associated with improved insulin sensitivity (Wiria et al., article, unpublished).

In a study in rural Indonesia, we have shown that intestinal helminth infections in adults were negatively associated with risk factors for CVD, such as body mass index (BMI), waist-to-hip ratio (WHR), and lipid levels [13]. In the same study, we did not find any association between current helminth infections and carotid intima media thickness (cIMT) [13]. This might not be surprising as the cIMT of individuals in this area was very low compared to individuals of the same age living in HICs [14], which would make it difficult for any beneficial effect to be detected. Our finding is supported by another study that investigated atherosclerosis in cadavers [15]. The authors reported that Opistorchis felineus infection was associated with lower serum total cholesterol and was a negative predictor of aortic atherosclerosis.

Taken together, it is tempting to hypothesize that helminth infections can protect against MetS, therefore decreasing the risk for subsequent development of T2D and/or CVD.

What Is the Possible Mechanism behind the Association between Helminths and Metabolic Syndrome?

The ability of helminth parasites to influence the immune system of their host is evident from the association between these infections and immune hyporesponsiveness and the skewing of the immune system toward modified type-2 responses [10]. These characteristic responses are thought to ensure the long-term survival of worms in the human host while benefiting the host by preventing immune pathological reactions [10]. Recent studies have shown that there might be a link between the immune responses that helminths can induce and glucose metabolism. In Table 1, a summary of the expanding body of research on the effect of helminths on various aspects of MetS is presented. Ricardo-Gonzales et al. have elegantly shown that when IL-4 is injected into mice fed a high-fat diet, the signal transducer and activator of transcription 6 (STAT-6) was activated in the liver and attenuated adipose tissue inflammation which in turn lead to improvement of insulin action [16]. Furthermore, Wu and colleagues showed in a landmark study that the nematode Nippostrongylus brasiliensis infection in mice could improve insulin sensitivity associated with adipose tissue eosinophilia [17]. In the same report, using noninfected mice, the authors describe eosinophils as the major IL-4 producers in the adipose tissue that sustains alternatively activated macrophages (AAM). These AAMs are able to maintain insulin sensitivity in adipose tissue partly through the production of the anti-inflammatory cytokine IL-10, a mechanism that has been previously demonstrated to counter the effect of TNF on inducing insulin resistance [18].


In a study using apoE−/− mice, it was shown that factors released from S. mansoni eggs have lipid-lowering effects [19]. Recently, a report in another model (c57BL/6 LDLR−/− mice) showed that S. mansoni-soluble egg antigen (SEA) treatment induces anti-inflammatory macrophages, which may reduce systemic inflammation, attenuates atherosclerosis development, and inhibits plaque necrosis [20]. Moreover, Bhargava et al. [21] have demonstrated that lacto-N-fucopentose III, an immunomodulatory glycan that can be found in human milk and its Lewis-X moiety on parasitic helminths (in SEA), could improve insulin sensitivity by enhancing white-adipose-tissue insulin signaling through induction of IL-10 production. Whether helminth infections lead to similar changes in humans still requires further investigation. In a recent study, we found that total immunoglobulin E (IgE), which is associated with helminth infections, was associated with decreased fasting blood glucose and lipid levels [13]. The scheme that shows the role of inflammation in the development of T2D and CVD in the absence and presence of helminth infections is given in Figure 1.


Is There More to IgE and CVD?

The association between total IgE and CVD in the absence of helminths has been investigated in animal models. Wang et al. have reported that IgE is associated with CVD by its binding to FcεR1α on macrophages to promote plaque instability [22]. They also reported that IgE levels were higher in subjects with CVD, especially in those with unstable angina and acute coronary events. In an urban area in China, a higher level of IgE and chymase, a mast cell protease, has been reported to be a potential risk factor for T2D [23], [24]. These studies seem to be in contrast to our findings that high total IgE is associated with decreased fasting glucose and lipids [13]. However, recent work has suggested that there are two types of IgE, which provoke different responses when bound to Fcε receptors on mast cells [25]. One is IgE that has a high affinity and can initiate mast cells' degranulation and anaphylaxis when bound to its antigen, whereas another is low-affinity IgE that is functionally less active. Investigating how IgE is involved in the pathogenesis of MetS and how the biological activities of IgE differ in the absence or presence of helminth infections might generate new insights into possible MetS pathogenesis and treatments.

The Emerging Area of Helminth Infections and MetS

It is tempting to speculate that the possible protective effect against MetS of living in areas where helminths are highly endemic is based on the presence of strong anti-inflammatory and modified responses (Figure 1). To test this hypothesis, sufficiently powered longitudinal studies are needed in the form of a randomized, double-blind, anthelmintic-placebo-controlled trial that can reveal whether deworming leads to MetS. Another method would be to infect patients with MetS with helminths to assess whether the treatment can improve MetS. Only then will it be possible to bridge the gap between the findings in animal models and the situation in humans. Next, it might be interesting to test which helminths or which of their products can be used to modify inflammatory responses as a treatment for T2D or CVD, as is currently being done in the field of allergy, autoimmunity, and inflammatory bowel diseases [10].


1. OdegaardJI, ChawlaA (2013) Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339: 172–177 doi:10.1126/science.1230721

2. Van GuilderGP, HoetzerGL, GreinerJJ, StaufferBL, DesouzaCA (2006) Influence of metabolic syndrome on biomarkers of oxidative stress and inflammation in obese adults. Obesity (Silver Spring) 14: 2127–2131 doi:10.1038/oby.2006.248

3. IribarrenC, TolstykhIV, MillerMK, SobelE, EisnerMD (2012) Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts. Am J Epidemiol 176: 1014–1024 doi:10.1093/aje/kws181

4. OngKL, WuBJ, CheungBM, BarterPJ, RyeKA (2013) Arthritis: its prevalence, risk factors, and association with cardiovascular diseases in the United States, 1999 to 2008. Ann Epidemiol 23: 80–86 doi:10.1016/j.annepidem.2012.11.008

5. HotA, LeniefV, MiossecP (2012) Combination of IL-17 and TNFalpha induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells. Ann Rheum Dis 71: 768–776 doi:10.1136/annrheumdis-2011-200468

6. CipollettaD, FeuererM, LiA, KameiN, LeeJ, et al. (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486: 549–553 doi:10.1038/nature11132

7. HerbinO, Ait-OufellaH, YuW, FredriksonGN, AubierB, et al. (2012) Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice. Arterioscler Thromb Vasc Biol 32: 605–612 doi:10.1161/ATVBAHA.111.242800

8. BelalcazarLM, HaffnerSM, LangW, HoogeveenRC, RushingJ, et al. (2013) Lifestyle intervention and/or statins for the reduction of C-reactive protein in type 2 diabetes: From the look AHEAD study. Obesity (Silver Spring) 21: 944–950 doi:10.1002/oby.20431

9. TabasI, GlassCK (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339: 166–172 doi:10.1126/science.1230720

10. WiriaAE, DjuardiY, SupaliT, SartonoE, YazdanbakhshM (2012) Helminth infection in populations undergoing epidemiological transition: a friend or foe? Semin Immunopathol 34: 889–901 doi:10.1007/s00281-012-0358-0

11. AravindhanV, MohanV, SurendarJ, MuralidharaRM, PavankumarN, et al. (2010) Decreased prevalence of lymphatic filariasis among diabetic subjects associated with a diminished pro-inflammatory cytokine response (CURES 83). PLoS Negl Trop Dis 4: e707 doi:10.1371/journal.pntd.0000707

12. ChenY, LuJ, HuangY, WangT, XuY, et al. (2013) Association of previous schistosome infection with diabetes and metabolic syndrome: a cross-sectional study in rural china. J Clin Endocrinol Metab 98: E283–E287 doi:10.1210/jc.2012-2517

13. WiriaAE, WammesLJ, HamidF, DekkersOM, PrasetyaniMA, et al. (2013) Relationship between Carotid Intima Media Thickness and Helminth Infections on Flores Island, Indonesia. PLoS One 8: e54855 doi:10.1371/journal.pone.0054855

14. SolimanEZ, DingJ, HsuFC, CarrJJ, PolakJF, et al. (2010) Association between carotid intima-media thickness and pericardial fat in the Multi-Ethnic Study of Atherosclerosis (MESA). J Stroke Cerebrovasc Dis 19: 58–65 doi:10.1016/j.jstrokecerebrovasdis.2009.03.008

15. MagenE, BychkovV, GinovkerA, KashubaE (2013) Chronic Opisthorchis felineus infection attenuates atherosclerosis - An autopsy study. Int J Parasitol 43: 819–824 doi:10.1016/j.ijpara.2013.04.008

16. Ricardo-GonzalezRR, RedEA, OdegaardJI, JouihanH, MorelCR, et al. (2010) IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 107: 22617–22622 doi:10.1073/pnas.1009152108

17. WuD, MolofskyAB, LiangHE, Ricardo-GonzalezRR, JouihanHA, et al. (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332: 243–247 doi:10.1126/science.1201475

18. LumengCN, BodzinJL, SaltielAR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175–184 doi:10.1172/JCI29881

19. StanleyRG, JacksonCL, GriffithsK, DoenhoffMJ (2009) Effects of Schistosoma mansoni worms and eggs on circulating cholesterol and liver lipids in mice. Atherosclerosis 207: 131–138 doi:10.1016/j.atherosclerosis.2009.04.037

20. WolfsIM, StogerJL, GoossensP, PottgensC, GijbelsMJ, et al. (2013) Reprogramming macrophages to an anti-inflammatory phenotype by helminth antigens reduces murine atherosclerosis. FASEB J 28: 288–299 doi:10.1096/fj.13-235911

21. BhargavaP, LiC, StanyaKJ, JacobiD, DaiL, et al. (2012) Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways. Nat Med 18: 1665–1672 doi:10.1038/nm.2962

22. WangJ, ChengX, XiangMX, Alanne-KinnunenM, WangJA, et al. (2011) IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe−/− mice. J Clin Invest 121: 3564–3577 doi:10.1172/JCI46028

23. WangZ, ZhangH, ShenXH, JinKL, YeGF, et al. (2011) Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus. PLoS One 6: e28962 doi:10.1371/journal.pone.0028962

24. WangZ, ZhangH, ShenXH, JinKL, YeGF, et al. (2013) Immunoglobulin E and mast cell proteases are potential risk factors of impaired fasting glucose and impaired glucose tolerance in humans. Ann Med 45: 220–229 doi:10.3109/07853890.2012.732234

25. XiongH, DolpadyJ, WablM, Curotto de LafailleMA, LafailleJJ (2012) Sequential class switching is required for the generation of high affinity IgE antibodies. J Exp Med 209: 353–364 doi:10.1084/jem.20111941

26. DoenhoffMJ, StanleyRG, GriffithsK, JacksonCL (2002) An anti-atherogenic effect of Schistosoma mansoni infections in mice associated with a parasite-induced lowering of blood total cholesterol. Parasitology 125: 415–421 doi:}10.1017}S0031182002002275

27. La FlammeAC, HarvieM, KenwrightD, CameronK, RawlenceN, et al. (2007) Chronic exposure to schistosome eggs reduces serum cholesterol but has no effect on atherosclerotic lesion development. Parasite Immunol 29: 259–266 doi:10.1111/j.1365-3024.2007.00942.x

28. YangZ, GrinchukV, SmithA, QinB, BohlJA, et al. (2013) Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity. Infect Immun 81: 1905–1914 doi:10.1128/IAI.00053-13

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