Metabolic syndromes, carbohydrate and lipid metabolism disorders in helminthic infections: review of the literature

Metabolic syndrome is a common pathological condition based on an increase of the mass of visceral fat, insulin resistance with hyperinsulinemia, carbohydrate, lipid and protein disorders. The natural course of the metabolic syndrome can be affected by the presence of intercurrent diseases connected with metabolic disorder, and helminthic infections are among them. This review presents an analysis of the results of current epidemiological and experimental studies of metabolic syndrome and abnormalities of carbohydrate and lipid metabolism associated with helminth infections.

The main risk factors for MS are genetic predisposition, sedentary lifestyle, a diet high in * Ekaterina A. Golovach, carbohydrates and lipids [13][14][15]. At the same time, the presence of concomitant diseases, combined with metabolic disorders, can have a significant impact on the formation and course of MS. These factors include parasitic infections found in various regions of the world, including Russia.
In the world, up to 56 million people suffer from trematodiasis, including opisthorchiasis [16]. The Ob-Irtysh basin is the global hotbed for Opisthorchis felineus (O. felineus) infection, responsible for up to 80% of known cases [17][18][19]. In 2017, opisthorchiasis in Russia accounted for 78.5% of the number of biohelminthoses cases (18.7 thousand cases of infection) [20]. Thus, an increase in the risk of metabolic diseases should be considered in the context of continuing high loads of parasitic infections.
The aim of this literature review is to analyze the results of modern epidemiological and experimental studies regarding the effect of helminth infections on the formation and course of MS, as well as associated disorders of carbohydrate and lipid metabolism.

EPIDEMIOLOGICAL STUDIES
The data of epidemiological studies aimed at studying changes in carbohydrate and lipid metabolism associated with helminth infections are extremely scarce ( Table 1). Most of these studies were carried out in the regions of Southeast Asia, endemic to various helminth infections.
For example, as part of an epidemiological study (n = 646, Indonesia, 2013), the effect of geohelminths (Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Strongyloides stercoralis) on insulin sensitivity was analyzed in infected individuals. It was found that a lower body mass index (BMI 22.5 vs. 23.2 kg / m2) and a lower insulin resistance index (HOMA-IR 0.81 vs. 0.97) were observed in infected individuals compared to uninfected participants. In the presence of co-infection with other geohelmintosis, the HOMA-IR index decreased by 0.10, mainly due to a decrease in the level of insulin with each additional infection. Also, a decrease in BMI of 0.3 kg / m2 was detected with each subsequent type of geohelminth found in an individual [21].
In another study (n = 259, Australia, 2013), the enzyme immunoassay (ELISA) was used to detect Strongyloides stercoralis infection in participants. They also measured hemoglobin levels, glycated hemoglobin levels, serum lipid concentration, blood pressure, and BMI. The results suggest that strongyloidiasis reduces the risk of developing type 2 diabetes in adults by 61% [22].
A similar study (China, 2015) included participants living in a territory with a high prevalence of S. japonicum 40 years ago. Among the participants, there were 465 people with a history of previous infection and 1,132 people representing the control group. An association has been established between prior schistosomiasis and a lower prevalence of MS and its associated conditions (central obesity, hypertriglyceridemia, a low HDL level) [24].
One of the first epidemiological studies on the relationship between obesity and hepatic trematodoses infection is a one-step study in the O. viverrini endemic region (n = 730, Thailand, 2015). The study established an association between opisthorchiasis and the presence of 1 st and 2 nd degree obesity [26].
In contemporary literature, the results of studies carried out by local authors are available in regions endemic to O. felineus infection. Thus, during the study of autopsy materials (n = 319, 2013), the number of adult O. felineus helminths in the bile ducts of the studied liver was estimated.
The results indicate that, as a result of O. felineus infection, a lower level of serum cholesterol was observed in comparison with samples without infection. Chronic opisthorchiasis was shown to be a negative predictor of atherosclerosis: the degree of infection was negatively correlated with the area of aortic damage [27].
In one study (n = 77, 2001), liver biopsy specimens from patients with type 1 and type 2 diabetes associated with O. felineus infections revealed manifestations of hepatocyte cellinvolutive degeneration, intracellular cholestasis syndrome, and focal lipid infiltration, as well as periportal, pericentral and perigepatocellular fibrosis. Electron microscopy revealed degenerative changes in hepatocytes with nucleic alteration associated with impaired carbohydrate metabolism and high cytoplasmic glycogen content [28].
In a case-control study (n = 99, 2003), a higher level of glycemia was found in the group of patients with both type 1 diabetes and opisthorchosis as compared to uninfected type one diabetic patients (19.6 vs. 16.7 mmol / l) required to compensate for the insulin dose (0.88 vs. 0.71 U / kg). In the case of infected patients, an increase in liver size  Обзоры и лекции according to ultrasound data was three times more frequent than in the group with isolated type 1 diabetes, severity of bile ducts was observed, and the walls with periportal echogenicity were thickened [29]. Similar results were obtained in a study performed with the participation of children (n = 90, 2006) with type 1 diabetes in combination with opisthorchiasis. There was a higher level of glycemia, glycated hemoglobin, and insulin dose than in the comparison group. Ultrasound signs of fatty hepatosis were determined in 68% of patients with concomitant pathology [30]. It should be noted that according to the World Health Organization and the International Diabetes Federation, type 1 diabetes is less common in countries in Asia and Africa, which are characterized by high rates of helminth infections in the population [31]. Also, other population studies suggest that helminth infection does not interfere with the development and course of type 1 diabetes [32].

EXPERIMENTAL STUDIES
Currently, accumulated experimental data indicate a change in carbohydrate and lipid metabolism linked to helminthiasis (Table 2). Thus, when studying the effect of Nippostrongylus brasiliensis nematodosis (USA, 2013) on the development of metabolic disorders, it was found that in affected animals compared to controls: adipose tissue weight was lowered , fatty degeneration of the liver slowed, and carbohydrate metabolism improved, accompanied by changes to the metabolic hormone profile. Authors note the preventive and therapeutic effect of N. brasiliensis infection on the development of obesity and associated metabolic disorders in mice [33].
In another study (Germany, 2016), infection by Litomosoides sigmodontis was shown to increase the number of eosinophils and activated macrophages in the gonadal epididymal adipose tissue. Improvement in glucose tolerance (in the glucose tolerance test) in mice with experimental obesity was also noted [34].
In an experimental model with the line of apolipoprotein E defective mice (ApoE -/ -), the effect of S. mansoni infection on the progression of atherosclerosis was studied (United Kingdom, 2002). The development of aortic and brachiocephalic artery plaque was reduced by 50% in ApoE -/ -mice infected with S. mansoni compared to the control [35]. A decrease in serum cholesterol was observed in the effects of excretory-secreto-ry products and S. mansoni eggs, but not adult worms [36].
In another study (Netherlands, 2013), S. mansoni infection in mice resulted in the reduced size of atherosclerotic plaques by 44% as compared with the control. With the introduction of helminth excretory-secretory products, the number of circulating neutrophils and inflammatory monocytes Ly6C decreased and the content of interleukin 10 increased. Also, inflammation inside the plaques (decreased?) as inflammatory markers decreased: (tumor necrosis factor alpha (TNF-№), monocytic chemotactic factor 1 (MCP-1), factor cell-cell adhesion 1 (ICAM-1), adhesion factor of vascular endothelium type 1 (VCAM-1), CD68), neutrophil cell count, and macrophage cell count [37].
An experimental study (Netherlands, 2015) showed that chronic infection by S. mansoni (12 weeks) reduces weight gain (-62%), adipose tissue (-89%), and adipocyte size. Also noted was a decrease in insulin resistance (-23%) and an improvement in peripheral absorption of glucose (+ 25%) and insulin sensitivity of white adipose tissue. The authors note that the injection of soluble S. mansoni antigens prevents metabolic disorders by activating the Th2 immune response, activating eosinophilia, and activating the M2 macrophage of white adipose tissue [38].
The infection by trematode S. japonicum in animals modeling obesity and insulin resistance (China, 2018) was associated with a decrease in body weight 7 weeks after infection, a decrease in fasting blood glucose, and an improvement in glucose tolerance. In addition, when the line of mice spontaneously developing obesity and diabetes was infected, a decrease in body weight and an improvement in glucose tolerance were recorded along with the pronounced expression of proinflammatory cytokines in visceral adipose tissue compared to controls [25].
In the available literature, there are a limited number of studies performed on models of hepatic trematodosis. In a study of O. viverrini infected hamsters (Thailand, 2013), scientists studied the relationship between damage to bile ducts and metabolic changes in the liver using magnetic resonance imaging and 1H magnetic resonance spectroscopy. In the group of infected hamsters, intrahepatic and extrahepatic dilations of the ducts in the liver were dependent on the duration of infection. The ratio of choline-lipids in the group of infected animals increased by 2, 3 and 4 times after 7-11, 13-15, 17-21 weeks of the Т а б л и ц а 2 T a b l e 2

Experimental study of carbohydrate and lipid metabolism disorders in helminthic infections
Автор
Обзоры и лекции study, respectively. Choline-lipid coefficients are associated with the degree of cell infiltration in the periductal space in animals infected by O. viverrini [39].
In another study (Thailand, 2018) on the combined course of type 1 diabetes and O. viverrini infection, an experiment revealed jaundice and hepatomegaly, an increase in transaminase levels, alkaline phosphatase, hepatocyte damage, hypertrophy, and proliferation. This study also suggests that the combination of type 1 diabetes and opisthorchiasis increases the expression of pro-inflammatory interleukins 6, 12, 13 by aggravating liver fibrosis and oxidative damage to deoxyribonucleic acid [40].
In an experimental study carried out at Siberian State Medical University, it was shown that O. felineus infection is accompanied by accumulation of cholesterol in the liver. Eight weeks after infection, histological analysis of liver samples revealed impaired hepatic architectonics, hepatocyte size variability, periductal and periportal fibrosis, and dilation of intrahepatic bile ducts. There was also an increase in ALT, gamma-glutamyl transpeptidase, TC, TG, and LDL in the serum of infected hamsters compared to the control group of animals. Biochemical analysis of liver tissue showed a statistically significant increase in cholesterol level, the ratio of cholesterol to phospholipids, in O. felineus infected animals [41].

CONCLUSION
Studies in recent years indicate a relationship between helminth infections and MS, diabetes, and obesity, which are accompanied by impaired carbohydrate and lipid metabolism [21,22,38,42]. Helminths are natural inducers of the Th2 immune response. MS, diabetes and obesity are accompanied by a Th1 immune response, while helminth infection shifts the immunological vector towards the Th2 immune response with a change in the production of interleukins, as well as polarization of M2 adipose tissue and activation of eosinophils, basophils, and mast cells [31, 41 , 43].
Inflammation associated with obesity, insulin resistance, diabetes, and MS is known to be characterized by the abnormal formation of cytokines, an increase in the concentration of acute phase proteinsand other mediators, and an activation of the network of inflammatory signaling pathways [44]. It is possible that a change in the Th1 immunological vector in the direction of Th2 with MS during helminth infection contributes to a decrease in insulin resistance and adipose tissue mass, an improvement in the peripheral absorption of glucose and insulin sensitivity of white adipose tissue, and a decrease in the likelihood of development and severity of diabetes (Tables 1, 2 ). At the same time, reactive oxygen species play an important role in the pathogenesis of diabetes in initial stages (destruction of pancreatic islets) and in the period of late complications. Numerous studies in this area indicate that the damaging effects of hyperglycemia are mediated by free radicals [45].
Chronic inflammation during helminth infection leads to increased generation of reactive oxygen and nitrogen species, leading to the development of oxidative and carbonyl stress [46,47]. This may cause a increased hyperglycemia and glycated hemoglobin levels and glycated hemoglobin in patients with concomitant type 1 diabetes and opisthorchosis infection [30]. It is known that MS and obesity are accompanied by oxidative stress, mainly in adipose tissue due to activation of the production of reactive oxygen species by adipocytes and cells of the immune system [48]. Thus, the inflammatory process and oxidative stress associated with helminthic infection can exacerbate the severity of MS and contribute to the complexity of its clinical manifestations.

CONFLICT OF INTEREST
The authors declare the absence of obvious and potential conflicts of interest related to the publication of this article.

SOURCE OF FINANCING
The study was supported by the Russian Foundation for Basic Research (grant "Fundamental approaches to optimizing the diagnosis and therapy of natural focal infection of Opisthorchis felineus in endemic regions" No. 16-44-700148); Russian Science Foundation (grant "Metabolic changes reflect the interaction in the parasitehost system at the level of the target organ and the whole organism" No. 14-15-00247).