Metabolic syndrome (MS) refers to a group of co-morbidities which include central obesity, hypertension, hyperglycemia and dyslipidemia (1). Patients with MS have an increased risk of developing cardiovascular, cerebral and hepatic disorders (1). MS being a metabolic disorder is associated with three types of hormonal dysregulation, namely: 1. Pancreatic hormones, 2. Incretins and 3. Adipokines. Insulin and glucagon are the major pancreatic hormones which control blood glucose levels, lipid storage and protein synthesis (2). Incretins are a group of low molecular weight peptides secreted by the intestine which control insulin secretion and action (3). Ghrelin, Gastric Inhibitory Peptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) are the major incretins implicated in obesity and diabetes (3). Finally, adipokines are a group of peptides secreted by the adipose tissue and control various aspects of metabolism (4). Adiponectin, adipsin, leptin, resistin, visfatin and Plasminogen Activator Inhibitor (PAI)-1 are the major adipokines which control insulin secretion and action (4). Recently, a systematic meta-analysis of fourteen studies showed that fasting blood glucose and HbA1c were significantly lower in persons with helminth infection, and the prevalence of metabolic syndrome and type-2 diabetes was lower among those who were infected (5).

Helminth infections affect approximately one-quarter of the world’s population and are widespread in lower to middle-income countries (6). The prevalence of MS is predominant in urbanized countries where most helminth infections have been eliminated (7, 8). Recent data in both animal and human studies have shown a reciprocal relationship between helminth infection and metabolic disorders like obesity, insulin resistance and type-2 diabetes (9–13), suggesting that helminth infection may have a role in the prevention or delay of these diseases (metabolic hygiene hypothesis). In previous studies, we have shown that glycemic factors, hormone and cytokine levels in T2DM were modulated by Strongyloides stercoralis infection, which is partially reversed following anti-helmintic therapy (14). However, the mechanisms of how helminth infections mediate protection against MS is unknown.

In our previous studies, we found out that childhood lymphatic filariasis (LF) infection can confer significant protection against both type-1 (15) and type-2 diabetes (16), but not against the related coronary artery disease (17), largely by suppressing the metainflammation (18). However, the effect of LF in regulating endocrine dysfunction in these diseases is not known. Following our initial studies, several studies have reported the therapeutic utility of helminth products against metabolic disorders (7–9, 12, 13). Immunoendocrinology is a fast upcoming interdisciplinary field wherein several immunomodulatory agents were shown to either directly or indirectly alter hormone levels (11). Towards this end, in the present study, we have quantified the levels of pancreatic hormones, incretins and adipokines in MS and non-MS subjects (both LF infected and uninfected) cohort, at baseline and after 10 years of follow-up. The hormone levels were correlated with the clinical parameters and their association with the disease phenotype was studied.

Previously, we have shown an immunomodulatory effect of LF infection on serum cytokine profile in type-2 diabetes patients (16). Recently, we have reported the effect of chronic diabetes on anti-filarial immunity (19). In the present paper, we have studied the effect of LF infection on serum hormone levels in MS patients. Our major findings were: 1. MS patients have significant insulin resistance, which is not modulated by LF infection; LF⁺ MS subjects had high glucagon levels compared to the LF^-MS group. 2. LF infection increases incretin levels in MS subjects and 3. Adipsin levels were significantly increased in MS subjects who were LF⁺. The beneficial effect of LF infection, in reducing the morbidity associated with MS, seems to be, largely due to the upregulation of incretins, which increase both insulin secretion and decrease IR ( Figure 3 ). However, this was a transient effect which was seen only during an active infection, since no long-term effect on serum hormone levels was noted in those, who have cleared the infection.

The serum levels of ghrelin, GLP-1 and GIP were found to be significantly elevated in the MS-LF⁺, compared to MS-LF^- group. The increased GIP levels (but not GIP-1 levels) were in accordance, with our recent study on obese subjects infected with Strongyloides stercoralis (20). The most unexpected finding of the study is that compared to pancreatic hormones and incretins, there was no major difference in the levels of the adipokines (except adipsin) between NMS-LF^- and MS-LF^- groups, which is in contrast to previous studies (21–26). In our previous study, we saw increased levels of adiponectin and decreased levels of resistin, visfatin, leptin and PAI-1 in obese individuals with Strongyloides stercoralis infection (20). Recently there had been renewed interest in understanding helminth-mediated endocrine regulation, which can confer protection against metabolic disorders (27). In fact, recent studies have indicated that the sudden drop in the prevalence of helminth infections, due to mass drug administration, may have fueled metabolic disorders in developing countries, which require urgent attention (28). In this respect, to the best of our knowledge, this is the first study to document filariasis-mediated modulation of hormonal levels in MS subjects.

The exact mechanism by which helminth infection modulates immunoendocrine functions is not clearly known. However, in a recent study in a high-fat diet-induced obese mice model, helminth Strongyloides venezuelensis infection, resulted in the alteration of gut microbiota, decreased gut permeability, decreased metabolic endotoxemia and decreased inflammation, which overall increased insulin sensitivity (29). Our study indicates that, apart from these effects, helminth infections might also induce the secretion of gut hormones, which adds one more level of complexity to the helminth-host interaction. The modulatory effect of LF on hormone profile was not seen after the follow-up period, within which all the infected individuals have cleared their infection. This observation is well in accordance with the outcome of a recent meta-analysis, which indicates that active helminth infection is more beneficial compared to past infection, since, constant taming of the immune system, by the worm, is needed in order to maintain metabolic homeostasis (5). In this connection, recently several novel helminth antigens with strong immunomodulatory effect have been identified. Mukherjee et al., have recently identified several filarial proteins which are capable of directly binding to TLR4 in macrophages (30, 31) and dendritic cells (32, 33). It is important to note that, apart from immune cells, adipocytes, hepatocytes, myocytes and pancreatic beta cells all express TLRs. However, whether the filarial products can directly bind to TLRs, present in these cells and modulate the cellular metabolism, is not known. While most of the helminth products induce metabolic homeostasis through immunomodulation, immunomodulatory glycan Lacto-N-fucopentaose III (LNFPIII), which is abundantly present in helminths, can directly bind to cell surface lectins present on hepatocytes and strongly suppress ectopic lipogenesis (34). By this mechanism, it can confer significant protection against steatohepatitis which is a major complication seen in MS (34).

The major limitations of this study are the limited sample size which could not be avoided due to the low prevalence of LF among the South Indian population. The major strength of the study is that, it was conducted in a filarial endemic population wherein the prevalence of MS is rapidly increasing. Further, all the important hormones which are implicated in MS have been quantified. Overall, LF infection offers some short-term benefits against MS, which needs further validation, in a large cohort study. To conclude, LF infection confers some immunoendocrine benefits against MS which seem to diminish, once the infection is cleared.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by MDRF institutional ethical committee. The patients/participants provided their written informed consent to participate in this study.

VM, SB and VA conceived the idea. JS did the experiments. JS and VA did the analysis. MD was involved in sample collection and analysis. All authors contributed to the article and approved the submitted version.

The Dept. of Genetics, University of Madras has received funds for infrastructural support from DST-FIST and UGC-SAP programs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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