Research Progress on the Immunomodulatory Effect of Trace Element Selenium and Its Effect on Immune-Related Diseases

Yao Lin,Li-Qin Jiang＊

1College of Pharmaceutical Sciences,Zhejiang Chinese Medical University,Hangzhou 310053,China

Abstract Selenium,one of the essential trace elements in the body,has a variety of biological functions including antioxidant activity,immunity enhancement and anti-tumor effect,and has the potential to be further developed into new drugs.In this paper,the research progress on the immunomodulatory effect of selenium and its mechanism and the effects of immune-related diseases in recent years were reviewed,and its future research and application were prospected.It is hoped to provide reference for further exploring the immune regulation effect and application of selenium.

Keywords:Selenium,Immunity,Obesity,Diabetes,Inflammatory Bowel Disease

Background

Selenium(Se)has been considered a toxic element for nearly 150 years since its discovery in 1817 by Swedish chemist Jons Jacob Berzelius.It wasn't until 1953,when Klaus Schwartz and Calvin Foltz discovered that dietary selenium protected rats from liver necrosis,that people realized how important it was[1].Selenium has a variety of biological effects,such as anti-oxidation,improving body immunity,anti-tumor and so on,and has therapeutic effects on cardiovascular diseases,low immunity,cancer and other diseases[2,3].The immune system is an important line of defense against pathogens.The existing form and intake level of selenium affect the immune function of the body,and therefore affect the occurrence and development of immune-related diseases.What is the effect of selenium on immunity?What is the immunomodulatory mechanism of selenium?What is the effect on immune-related diseases?Many scholars have carried out basic research on these aspects and accumulated some research results.This paper collates and summarizes it in order to provide theoretical support for the research,development and application of selenium.

The existing form and physiological function of selenium in vivo

Selenium is generally absorbed by the human body in two forms(inorganic forms:selenite and selenate;organic form:selenoamino acid,selenoprotein)from food or supplements.The absorption rate of inorganic selenium in human body is about 50%,while that of organic selenium is about 80%[4].After selenium intake,it is absorbed by the gastrointestinal tract and non-specifically bound with plasma albumin or lipoprotein to produce selenoprotein,selenium polysaccharide and selenium nucleic acid in organic form.Selenium forms selenoprotein by covalent binding with cysteine and methionine,which is the main form of selenium in mammals[5].There are dozens of selenoproteins in mammals,including glutathione peroxidase(GSH-Px/GPx)family,thioredoxin reductase(TrxR)family,selenoprotein P(SeP),selenoprotein K(SelK)and so on.Most of these selenoproteins take selenocysteine(SeCys)as the active center and exist in human blood,muscle,liver,kidney and other tissues and organs,participate in the regulation of various physiological processes of body,play an important biological function,and can directly or indirectly affect the occurrence and development of a variety of diseases[6].

Selenoenzyme such as GPx and TrxR,which are composed of selenoproteins,maintain the normal morphology and function of cells and achieve antioxidant effect mainly by scavenging the excess free radicals in the body[7,8].Selenoenzyme can also drive innate and acquired immune response cells(such as T cells,B cells)to activation,proliferation and differentiation,inhibit the production of inflammatory factors and activate inflammatory pathways,playing the role of anti-inflammation and promote immunity[9].Therefore,selenium,which is listed as one of the 15 daily dietary nutrients by the Chinese Nutrition Association and one of the essential nutrients of infant formula by the Food and Drug Administration(FDA),plays a significant part in human health.

We can not synthesize selenium independently,so it needs external intake and supplementation.According to incomplete statistics,there are 42 countries in the world that lack selenium,including China,New Zealand,Europe and Russia[10].China,about 72% of the regions are deficient in selenium,among which the severely deficient areas account for 30%,is one of the countries which are urgently lack of selenium[11].In addition,with the improvement of living standards,food processing is becoming more and more refined,resulting in a considerable loss of nutrients in food.Furthermore,with the rapid development of society,people work and live in a "fast pace",and their bodies are often under pressure,sleeplessness and so on.Therefore,under the interference of environmental selenium deficiency,unreasonable diet structure,irregular daily life,age and other factors,it is easy to cause modern people to be in a state of selenium deficiency for a long time(i.e.,daily selenium intake of adults is less than 40 μg).Selenium deficiency will lead to body dysfunction,affect physiological and metabolic function,resulting in low immune function,and cause more than 40 kinds of diseases such as Keshan disease,Kaschin-Beck disease,diabetes,immunodeficiency,cancer,cardiovascular disease and thyroiditis[11-14].Keshan disease has been broken out in Keshan County,Heilongjiang Province,China,which was a selenium-deficient area.After determining that the cause of the disease is related to selenium deficiency,Keshan disease was finally cured by supplementing selenium reasonably.

Selenium and immunity

Not only are dietary selenium and selenoproteins a necessary for activating or boosting immunity,but it may also participate in immune regulation,which is essential for warding off chronic inflammation[15].When selenium intake is insufficient,the immune system will be damaged to a certain extent,making the body in a state of low immune function and causing a variety of immune problems.Statistics show that 75%of the people in China are in a state of sub-health,and the core problem of sub-health is the low immune function caused by a variety of internal and external factors.When the human body is suffering from malnutrition(insufficient intake of protein and trace elements)for a long time,failing to inject the relevant vaccine in accordance with the regulations,environmental pollution,or excessive pressure,it will lead to low immune function,and cause immune-related problems such as fatigue,insomnia,dreaminess,gastrointestinal dysfunction,while the resulting imbalance of intestinal flora will inhibit the mucosal barrier and further aggravate the damage of immune function[16,17].As shown by Novel coronavirus pneumonia(NCP)outbreak in Wuhan,Hubei Province in December 2019,the elderly are the susceptible and high-risk population in this epidemic,and most of the patients who died were the elderly with weak immunity[18,19].Long-term low immune function will greatly damage the body's health and increase the risk of human disease.

It has been found that selenium exists in almost all immune cells,such as macrophages,neutrophils,T lymphocytes and natural killer cells(NK).Selenium can protect thymus,maintain lymphocyte activity and promote antibody formation[9,15].Supplementation of selenium not only promotes the immunity of the normal body,but also has a certain regulatory effect on the immune deficiency caused by selenium deficiency or other causes(radiotherapy and chemotherapy,heavy metals).The mechanism of regulating immunity is shown in Figure 1,mainly in the following three aspects:

(1)Nonspecific immunity.The first line of defense of the human body is composed of skin and mucous membrane,and the intestinal tract,as the largest immune organ of animals,mainly protects against foreign pathogenic bacteria through intestinal mucosa and intestinal flora.Intestinal mucosal epithelial cells and metabolites secreted by intestinal flora(such as short-chain fatty acids)also play a major part in regulating immunity,and they jointly maintain intestinal immunity[20].However,studies have hinted that dietary selenium deficiency for a long time can easily lead to a variety of intestinal diseases,and moderate selenium supplementation can improve intestinal damage.Gu et al.[21]showed that low molecular-weight seleno-aminopolysaccharides(LSA)could dramatically increase the level and gene expression of immune factors such as tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-10 and inducible nitric oxide synthase(iNOS)in intestinal porcine epithelial cells,and had immunomodulatory effect on intestinal porcine epithelial cells.He and his colleagues[22]found that 0.3 mg/kg aflatoxin B1 could reduce the number of IgA+cells,decrease the content of secretory immunoglobulin A(sIgA),immunoglobulin A(IgA),IgG and IgM in broilers,and suppress the humoral immune function of ileum mucosa,while the addition of 0.4mg/kg dietary Se could protect the mucosal humoral immune function from aflatoxin B1-induced damage.In the body's second line of defense,it is mainly defended by bactericidal substances and phagocytes in body fluids.Selenium affects the production of immune cytokines and plays an immunomodulatory role by enhancing the killing activity and phagocytic efficiency of macrophages and neutrophils.The study by Khoso et al.[23]found that selenium deficiency inhibited the expression of selenoprotein,decreased the contents of interferon-α(IFN-α),IFN-β,IL-2,IL-10,IL-17 and IL-1β,and increased the contents of IL-6,IL-8,IFN-γ and TNF-α,which may result in oxidative stress in the thymus of chicken,which may lead to immunological changes and immune stress response.Yang et al.[24]conducted experiments to determine whether selenium deficient,high energy diet can contribute to oxidative stress and deregulate the erythroid-derived nuclear factor-2(Nrf2)pathway and phagocytic dysfunction of neutrophils.The results showed that the selenium deficient and high energy diet significantly decreased the phagocytic activity of neutrophils compared to the control group.A previous research by Hall et al.[25]examined the effect of supranutritional selenium supplementation in footrot sheep on immune function and found that selenium supplementation does not prevent footrot,but does recover the negative effect of footrot on innate and humoral immune functions.The bacterial killing percentages of neutrophils in diseased mice was greatly increased after selenium supplementation,which was almost equal to that in the normal control group.

(2)Specific immunity.As the third line of defense of the human body,specific immunity is composed of immune organs and immune cells,including cellular immunity and humoral immunity.In cellular immunity,selenium plays a positive role in the proliferation and differentiation of cluster of differentiation(CD)4+helper T(Th)cells.The study by Xue et al.[26]showed that Se supplementation can increase the percentage of CD4+CD25+forkhead box p(Foxp)3+regulatory T(Treg)cells in an iodine-induced autoimmune thyroiditis(AIT)model mice.Compared with the AIT model mice,the serum thyroglobulin antibody titers was reduced and the infiltration of thyroid lymphocytes was decreased in the se-supplemented mice.Selenium deficiency can decrease the number of mature T cells in lymphoid tissue,impair T cell dependent antigen antibody response or inhibit T cell proliferation,resulting in impaired immune function[15].It can also reduce the killing activity of NK cells.Li et al.[27]found that methylmercury(MeHg)exposure significantly inhibited the lymphoproliferation and the functions of NK cells in mice,while Se-rich yeast partly or even completely restored the lymphocyte proliferation of both T and B cells in spleen and thymus,and enhanced the activities of NK cells,indicating the protective effect of selenium against MeHg-induced immunosuppression in mice.Selenium deficiency will also affect the production of immune factors,bring about the increase of proinflammatory cytokine and the reduction of antiinflammatory cytokine.Adegoke et al.[28]proves that supplemented with 0.50 mg/L of selenium significantly promoted cell viability,up-regulate the gene expression of toll-like receptor-4(TLR-4),IL-4,IL-10 and transforming growth factor-β1(TGF-β1)),and modulated the expression of proinflammatory factors(TNF-α,IL-1β,IFN-γ).

In humoral immunity,selenium promotes the proliferation of lymphocytes,makes lymphocytes produce antibodies and stimulates the formation of immunoglobulins,improving the ability of the body to synthesize antibodies such as IgM and IgG.When selenium is deficient,the immune function of the body is weakened and the production of Ig and antibody is inhibited.The results of the study by Rossi and his companion[29]showed that supplementation of organic selenium ameliorated the growth performance of beef cattle and increased bobine herpesivirus-1(BHV-1)antibody titre after vaccination,emphasizing a positive impact of selenium-enriched yeast on immune system function.Umaya et al.[30]studied and analyzed the effects of diet containing organic selenium on humoral immunity and selenoprotein gene expression of lambs.The results showed that feeding 1.5 ppm organic selenium could significantly improve the antibody effect of small ruminant virus vaccine in lamb serum and improve its humoral immune response.Wen et al.[31]investigated the immunomodulatory effect of LSA on cyclophosphamide-induced immunosuppressive mice and related mechanism.The experiment results demonstrated that LSA could observably promote the spleen and thymus indices,the proliferation of splenic lymphocyte,the secretion of IL-2,IL-4,IL-10 and INF-γ in serum and ileum,and the sIgA content of gut.LSA has a remarkably role in promoting the gene expression of IL-2,IL-4,IL-10 and INF-γ in gut.

(3)Antioxidant activity.Selenium supplementation protects immune cells from oxidative damage caused by stimulation by increasing the activity of selenium-containing enzymes and enhancing the antioxidant effect.Antioxidant refers to the elimination of excessive reactive oxygen species(ROS)produced by oxidative stress in the body.Once the body produces oxidative stress,it will lead to inflammatory infiltration of neutrophils and increase the secretion of protease,resulting in a large number of peroxides.GPx,as an important member of antioxidant kinases in organisms,can reduce toxic peroxides to harmless hydroxyl compounds,so as to protect the structure and function of cell membrane from interference and damage by oxides.GPx is also engaged in T cell differentiation and regulates immunity.It is worth mentioning that the GPx activity center is composed of selenium[7,15].Therefore,selenium supplementation can improve the activity of GPx,enhance the ability of scavenging peroxides and protect immune cells.Jiao et al.[32]investigated the improvement of selenium on lead(Pb)-induced oxidative stress and immune damage in the chicken bursa of Fabricius.It was found that the presence of Pb inhibited total antioxidant capacity(T-AOC),GPx,glutathione S-transferase(GST),superoxide dismutase(SOD),and catalase(CAT)activities;the contents of glutathione(GSH)was decreased;the contents of malondialdehyde(MDA)and hydrogen peroxide(H2O2)was increased.It inhibited the expression of IL-2 and IFN-γ mRNA,and increased the expression of IL-4,IL-6,IL-10,IL-12β,and IL-17 mRNA.The presence of selenium alleviated the Pb-induced changes mentioned above.This indicated that selenium reduced the oxidative stress and immune damage caused by lead in chickens.Other research have found that selenium promotes GPx1 and TrxR1 expression and increases antioxidant capacity in porcine splenocytes,which enhances T cell receptor(TCR)or concanavalin A(Con A)-induced T-cell activation[33].Since activating neutrophils produces a large number of ROS to stimulate the Nrf2 pathway,Yang et al.[24]studied the effects of Se-deficient,high-energy diet on phagocytic activity in neutrophils,the production of ROS,protein levels of Nrf2 and Nrf2 downstream target genes,and the mRNA levels of 25 selenoproteins,heat shock proteins and cytokines.The results showed that Se deficiency and high energy diet inhibits the Nrf2 pathway and its regulation of oxidative stress,and prompted a pleiotropic mechanism that suppresses phagocytosis.It also reveals a special link between selenium-antioxidant-immunity.

Interestingly,many researchers studying the immune effects of selenium often add the antioxidant vitamin E to compare the effects of selenium and/or vitamin E.For example,a study evaluated the ameliorator property of selenium and/or vitamin E in the biochemical,immunological and histological damage induced by sodium azide(SA)induced in mice.The experimental results was found that there is synergy between selenium and vitamin E,which is most powerful in decreasing the SA-induced toxicity and increasing the humoral immune response of mice.Selenium ameliorated the effect of vitamin E with SA and normalized IgM and IgG levels[34].Dawood et al.[35]studied the feed additives to meet the nutritional needs of fish growth.The study found that the addition of nano selenium and vitamin E alone or in combination can improve the growth performance,intestinal tissue morphology,oxidation state and immune-related gene expression of fish,and their effects seemed to be similar to immunostimulants to upregulates pro-inflammatory cytokines.After consulting the literature,it was concluded that selenium and antioxidant vitamin E were more effective in combination than in isolation,which may also suggest that the mechanism of selenium in immune regulation may be similar to that of vitamin E,which is related to antioxidant.

At present,the immunomodulatory mechanism of selenium is still in the exploratory stage.However,previous studies have shown that the mechanism is complex and changeable,and different diseases,objects or ages will have different regulatory mechanisms,and even different selenium doses will cause different results.Therefore,it is necessary to keep exploring in it to provide more reliable research support.

Figure 1.Immune regulation mechanism of selenium.In nonspecific immunity(a),selenium mainly protects against foreign pathogenic bacteria through intestinal mucosal barrier,intestinal mucosal epithelial cells and metabolites secreted by intestinal flora(such as SCFA)maintain intestinal immunity,selenium can enhance the killing activity and phagocytosis efficiency of macrophages and neutrophils,affect the production of immune cytokines such as IFN-α,TNF-α,IL-1 and IL-6,play a role in regulating immunity.In specific immunity(b),selenium regulates the cellular immune function by promoting the proliferation and differentiation of CD4+ helper T cells and T cells,and reducing the killing activity of NK cells.In humoral immunity,selenium promotes the proliferation of lymphocytes,produces antibodies and stimulates the formation of immunoglobulins such as IgA,IgG,IgM.In antioxidant activity(c),selenium,as the main component of selenium-containing enzyme GPx active center,can increase GPX activity,enhance antioxidant and reduce ROS content through selenium supplementation,so as to protect immune cells and organs(liver,spleen,thymus,etc.)from oxidative damage caused by stimulation.SCFA,short-chain fatty acids.IFN-α,interferon-α.TNF-α,tumor necrosis factor-α.IL-1,interleukin-1.IL-6,interleukin-6.CD,cluster of differentiation.NK,natural killer cells.IgA,immunoglobulin A.IgG,immunoglobulin G.IgM,immunoglobulin M.GPx,glutathione peroxidase.ROS,reactive oxygen species.

Regulatory effect of selenium on immune-related diseases and gut

There are about 1013-1014bacteria in a human adult,which is similar to the total human somatic and germ cells[36].Under normal physiological conditions,small molecules produced by gut microbes stimulate metabolites,which act on different areas of the body through the circulatory system,and the concentration of these secondary metabolites in the blood can reach or exceed the maximum safe dose37.Gut microbiota is a dynamic balanced ecosystem.Once the balance is destroyed,the diversity,composition and structure of gut microbiota will also be changed,affecting the normal immune function,increasing the risk of health problems,bring about a wide variety of immune diseases such as obesity,diabetes,inflammatory bowel disease and hepatitis[38,39].

Selenium is mainly digested and absorbed through the gastrointestinal tract,which can affect the intestinal barrier,gut microbiota diversity and structure to play an immune role.The research by Zhai et al.[40]compared the effects of three doses and two forms of Se supplementation on the gut physiology of untreated,dextran sodium sulfate treated,and Salmonella typhimurium infected mice.It was found that Se-deficiency(<0.01 mg/kg Se)supplementation had adverse effects on the gut barrier and gut immune responses in the untreated mice.In addition,Se-supranutritional(0.40 mg/kg Se)supplementation improved gut physiology compared with Se-adequate(0.15 mg/kg Se)supplementation in mice.Zhai et al.[41]found that deficient Se supplementation could change the composition of gut microbiota,and the abundance ofDoreainduced by Se deficiency diet was significantly higher than that in Se sufficient diet at the genus level.Doreais a bacterium associated with irritable bowel syndrome and non-alcoholic fatty liver whose overgrowth may have adverse health effects[42-44].TuricibacterandAkkermansiaabundance increased significantly and the level ofMucispirillumdecreased in mice supplied with Se(0.40 mg/kg Se).Turicibactershowed potential anti-inflammatory activity in the gut,and high abundance ofTuricibacterwas also observed in mutant mice that were resistant to colitis[45,46].Akkermansiahas been proven to protect the gut barrier,play a vital role in immune and metabolic regulation,and is negatively correlated with the occurrence of inflammatory intestinal disease,obesity and diabetes[47].The increase ofMucispirillumis associated with helminth infection[48].In conclusion,selenium is absolutely necessary to maintain intestinal homeostasis and regulate immunity.

Effect of selenium on obesity and gut

Obesity,caused by excessive accumulation of fat and abnormal body weight,is a chronic metabolic disease that causes pathophysiological changes in the human body.It is generally caused by energy intake exceeding energy consumption,or metabolic changes.Immunologically,obesity is characterized by mild chronic inflammation,accompanied by abnormal production of cytokines and activation of various inflammation.Obesity affects the phenotypic polarization of Th17 cells,especially secondary lymphoid organs(e.g.spleen,lymph nodes).It also affects the number of Tregs cell and regulates systemic metabolism,promoting the development of other chronic inflammatory diseases[49,50].Some studies have shown that,compared with other tissues,lean mice are rich in visceral adipose tissue and have a unique Foxp3+CD4+Tregs population[51].The imbalance of intestinal flora may also lead to weight gain and obesity,which can lead to changes inGammaproteobacteria,Verrucomicrobia,as well as an increase inFirmicutes/Bacteroidetesratio[52].

Selenium participates in the process of energy metabolism and maintains human metabolism and normal physiological activities.Previous studies have shown that changes in serum selenium may have some relationship with obesity.Wang et al.[53]measured the dietary selenium intake and body composition of 3214 subjects.The dietary selenium intake of obese men and women was 24 to 31 percent lower than that of the corresponding normal weight men and women.In addition,subjects with the highest dietary selenium intake had the lowest body mass index(BMI),waist circumference,trunk,android,gynoid and total body fat percentages,and there was a significant dose-dependent negative correlation in groups.Selenium deficiency in the human body will lead to a decline in immunity,slow down the rate of metabolism,leading to the absorption of energy is more than its consumption,resulting in fat accumulation and obesity.Some studies suggest that selenium may have an inhibitory effect on adipocyte hypertrophy and lipogenesis[54].Kim et al.[55]observed that the levels of lipid metabolism-related factors in obese mice rats were all decreased after 2 weeks of administration of sodium selenite,and the pathology of fatty liver was slowed down.The results indicate that Se may inhibit adipocyte hypertrophy and abdominal fat accumulation,as well as reduce the probability of fatty liver formation by the differential regulation of the gene expression for fatty acid β-oxidation in the obese mice.

There are also studies to explore the effect of selenium on the gut of obesity.Gao et al.[56]tested the body fat accumulation,serum lipids and glucose levels,serum metabolic related hormone levels,gut barrier function and the composition of gut microbiota of Sprague-Dawley rats fed with normal diet,fatty diet,fatty diet containing Se-rich black tea or fatty diet containing Se-deficient black tea for 4 weeks,respectively.Although both types of black tea have been shown to improve body weight gain,serum triglyceride reduction and gut barrier dysfunction caused by fatty diet,Se-rich black tea showed greater activity in reducing fasting serum glucose,and a greater protective effect on the liver.After analyzing the gut microbiota of rats,it was found that Se-rich black tea group was rich inPrevotellaandDesulfovibrio,which were positively correlated with obesity,while the Se-rich black tea group inhibitedRomboutsiaandCorynebacterium,which were associated with a reduced risk of obesity.It may be partly responsible for the difference in preventing fat accumulation between Se-rich black tea and Se-deficient black tea[57-60].This may be used as a direction of future research to provide more verification for the hypothesis that selenium improves the physique of obese patients by regulating gut microbiota.

Effect of selenium on diabetes and gut

As an autoimmune disease,diabetes is usually caused by genetic factors,immune system disorders and other problems resulting in islet function decline[61].A type 1 diabetes mellitus(T1D)prediction and prevention project analyzed the gut microbiome of 76 Finnish children aged 4 to 26 months,and found that the abundance ofBacteroides doreiin the gut of children who seroconverted to T1D-related showed autoantibodies was higher than that of children without seroconversion[62].Kostic et al.[63]assessed the composition of the gut microbiota of 33 infants from birth until three years of age,who were genetically predisposed to T1D.Compared with the control group,the α diversity in children who progress to T1D decreased by 25%,and identified changes in the phylogenetic and metabolic pathway composition of the microbiome during this time,which are characteristic of the proinflammatory environment.Their results demonstrate that the microbial community of children with T1D may be related to the inflammatory environment that is conducive to human immunity.

Previous studies have suggested that high Se content in the body improve the risk of diabetes.Lu et al.[64]and Bleys et al.[65]investigated 847 adults over 40 years old in Taiwan and 8876 adults over 20 years old in the United States respectively,and the results indicated that the level of serum selenium was correlated positively with the prevalence of diabetes.Laclaustra et al.[66]analyzed the prevalence of diabetes in 917 adults over the age of 40 in the United States,and measured their fasting plasma glucose and glycosylated hemoglobin levels.The results showed that the prevalence of diabetes and the levels of glucose and glycosylated hemoglobin increased to 160 g/L with increasing selenium concentration.It is suggested that high selenium concentration in serum is related to higher rates of diabetes,as well as higher fasting plasma glucose and glycosylated hemoglobin levels.But other studies have linked low selenium intake to diabetes.Park et al.[67]found that individuals with higher toenail selenium content levels are at lower risk for T2D.Roman et al.[68]shows that patients with diabetes demonstrate significantly lower levels of GPx and seleno-albumin with respect to healthy subjects.Akbaraly et al.[69]found that high blood selenium levels in men over 9-year were tightly tied to a reduced risk of hyperglycemia.The key factor that needs to be emphasized is the U-shaped link between diabetes and selenium dosage[70].Before considering supplement,the nutritional status of the patient should be assessed first.The effect of selenium supplement in selenium deficiency may be different from that in selenium adequacy.When the level of blood selenium is lower than a certain range,with the increase of blood selenium concentration,the concentration of blood antioxidant enzyme and anti-endoplasmic reticulum kinase increases,which helps to protect the body and reduce the risk of diabetes.As the blood selenium level continues to increase,the excessive concentration of peroxidase may lead to the excessive clearance of the insulin signal hydrogen peroxide,affecting the insulin signal transduction.Animal experiments have also shown that overexpression and deletion of selenoprotein may lead to the appearance of T2D characterization in mice[71].Yuan et al.[72]fed normal rice(N R),normal rice with high anti-starch content or selenium-rich rice with high anti-starch content to fat diet induced obesity and diabetic mice.

In order to study the effect of selenium on diabetes and gut,Yuan et al.[72]fed four different types of rice to obese and diabetic mice induced by a high-fat diet.The results showed that both normal rice with a high resistant starch content(NRRS)and selenium-enriched rice with a high resistant starch content(SRRS)could significantly improve the imbalance of gut microbiota in diabetic mice,reduce the pH value of feces,stimulate the production of SCFA in cecal digestion,and promote the development ofBifidobacteriumandLactobacillus.Regarding the inflammatory factor levels,the SRRS and NRRS-treated mice had lower levels of TNF-α,IL-6 and nuclear factor kappa-B(NF-κB)and higher levels of adiponutrin compared to diabetic and normal rice treated mice.These results suggest that rice high in resistant starch and selenium treatment plays a beneficial role by improving intestinal disorders and chronic inflammation.Furthermore,selenium and RS may play a synergistic role in chronic inflammation.Deng et al.[73]made selenium nanoparticles(SeNPs)into insulin loaded SeNPs(INS-SeNPs)and studied their synergistic hypoglycemic effect and mechanism.The results revealed that the synthesized INS-SeNPs showed controllable insulin release and excellent stability in the digestive juice,and had a marked hypoglycemic effect in both healthy and diabetic rats.Interestingly,SeNPs also has hypoglycemic effect,and the synergistic effect of insulin and SeNPs promotes the hypoglycemic effect of INS-SeNPs.In vitro intestinal imaging and cell experiments showed that INS-SeNPs had excellent performance in gut permeability.INS-SeNPs could relieve oxidative stress,ameliorate pancreatic islet function,and promote glucose utilization.The correlation between selenium and diabetes and gut microbiota,and whether selenium can play a role in the treatment of diabetes by altering gut microbiota,which need to be confirmed by continuous research in the future.

Effect of selenium on inflammatory bowel disease and gut

Inflammatory bowel disease(IBD),a chronic and recurrent inflammatory bowel disease,includes Crohn disease(CD)and ulcerative colitis(UC),which may develop into colon cancer.It is known that the inflammatory response caused by the abnormal response of the intestinal immune system plays an integral role in the pathogenesis of IBD.The dysfunction of the interaction between the gut microbiota and the host may lead to excessive inflammatory response,resulting in IBD,functional dyspepsia and other problems[74].Some research have shown that there are fewer antiinflammatory bacteria(such asFirmicutes)and/or more proinflammatory bacteria in patients with IBD[75].The results of Joossens et al.[76]indicated that the abundance of antiinflammatoryFaecalibacterium prausnitzii,Bifidobacterium adolescentisandDialister invisusin the fecal microbial community of CD patients decreased,while the abundance ofRuminococcus gnavuswith potential proinflammatory effect increased.These changes in gut microbiota observed in the gastrointestinal tract of IBD patients may exacerbate inflammation and oxidative stress,leading to severe illness.

The research of epidemiology reveals that there is a negative correlation between selenium and IBD.A particularly large number of studies have shown that IBD patients have lower average selenium levels.Poursadegh et al.[77]evaluated the serum micronutrient levels of 112 UC patients(average age of 34.6 years)in three hospitals,and evaluated the relationship between serum micronutrients levels and UC activity.Experimental results show that the levels of total protein,zinc,and selenium in serum of patients with UC were significantly decreased.Aguilar-Tablada et al.[78]measured the selenium level,BMI and inflammatory biomarker(α-1-antitrypsin)in 106 IBD patients(53 patients with UC and 53 patients with CD)and 30 normal control subjects.The results showed that the serum selenium concentration of patients with UC and CD was significantly lower than that of normal controls.This suggests that adequate selenium status minimizes the cardiovascular risk associated with inflammatory biomarkers,which is especially important in patients with IBD.Han et al.[79]assessed the prevalence of micronutrient deficiency in Korean IBD patients,and identified the risk factors for the disease.Serum zinc and selenium levels were lower in IBD patients with than in healthy controls,and the proportion of patients were 39.0% and 30.9%,respectively.Patients under 40 years of age had an increased risk of zinc deficiency.This suggesting that many Korean IBD patients are deficient in vitamin D,zinc,and selenium,and it is necessary to monitor levels of these micronutrients.

The selenium content in IBD patients is generally low,and it will also aggravate the process of IBD when the body is in a state of selenium deficiency[80,81].Therefore,people try to explore whether selenium supplementation can reduce the risk of IBD and improve a series of inflammatory damage and gut damage.Zhu et al.[82]found that ULP-SeNPs,SeNPs decorated with Ulva lactuca polysaccharide(ULP),has a remarkably protective effect on DSS-induced acute colitis mice,including alleviation of weight loss and colonic inflammatory damage.It also improves the infiltration of macrophage,and inhibits NF-κB to suppress macrophage activation,which drives the transcription of proinflammatory factors,such as IL-6 and TNF-α.Kaur et al.[83]demonstrated that compared with Se deficient,dietary Se supplementation changed oxidative stress markers,morphology,histopathology,and biochemical indexes and expression of proinflammatory and antiinflammatory factors to relieve inflammation.Petronilho et al.[84]found that diphenyl diselenide 2 improved the infiltration of neutrophil in DSS rats,reduced the oxidative damage in lipids and proteins,and recovered the levels of SOD and CAT in DSS rats.Soliman et al.[85]showed that sodium selenite could markedly ameliorated colitis,alleviated oxidative stress in the colon by normalizing the contents of nitric oxide and MDA,reducing the contents of GSH and the activity of CAT and SOD.Furthermore,it signally increased colonic myeloperoxidase content and the pro-inflammatory factors.This study shows that sodium selenite ameliorates the intestinal and parenteral manifestations in acetic acid-induced colitis effectively through antioxidant,anti-inflammatory,and immunomodulatory.In summary,supplementation of selenium can reduce inflammatory response,relieve gut damage and improve IBD in experimental animals.

Application and prospect

Selenium is an essential trace element for the human body,so it should be ingested timely and appropriately to achieve the selenium intake recommended by the Chinese Nutrition Association(50-200 μg/d for adults).The items that should be paid attention to in selenium supplement are as follows:(1)Scientific selenium supplementation.Not all people are suitable to supplement selenium,we should go to the hospital to determine the level of trace elements in the body,and under the guidance of doctors to supplement selenium.(2)Strictly control the dose of selenium supplement.The range between the lowest dose and the highest toxic dose of selenium is narrow,too much or too little selenium will affect human health,leading to disease and even death.The effective dose of selenium is also different for different diseases and different populations.The dose of selenium that has the therapeutic effect on cancer is used to treat immune deficiency,which may be the toxic dose.The dose of selenium supplement for diabetic patients is about 300-400 μg/d to protect and improve pancreatic function.For those who have not been cured for a long time,the dose of selenium supplement is about 100-200 μg/d to enhance immunity,repair damaged cells and enhance self-healing.Selenium supplementation dose for pregnant women and nursing mothers is about 50-100 μg/d to improve immunity,prevent infection,and ensure the selenium intake of fetuses and nursing children.Therefore,selenium dosage should be strictly controlled for different patients and diseases.(3)There are many ways to supplement selenium:①The general population can consume selenium by eating selenium-containing foods(seafood,cereals,dairy products),together with fruits and vegetables containing vitamins to promote selenium absorption and enhance immunity.Selenium can also be supplemented by eating selenium-rich products(such as selenium-rich rice[86],selenium-rich fruits and vegetables[87],selenium-rich tea[56]).②Under the guidance of doctors,patients can take targeted medicines containing selenium certified by the state(e.g.,Ebselen has anti-inflammatory,antioxidant,neuroprotective and immune system diseases[88])to cure diseases.

Nowadays,people's understanding of the function of selenium is deepening,and it has been supported by a large number of experimental studies in agriculture,animal husbandry and pharmaceutical industry.However,the toxicity and dose range of selenium are still controversial.Therefore,further basic research is needed to study the toxicity mechanism of selenium by means of multi-group study,molecular biology and bioinformatics,in order to ensure the safety of selenium consumption.It is necessary to explore the absorption and metabolism mechanism and immune regulation mechanism of selenium to provide reference for selenium to play a safe,effective and definite role in improving disease and maintaining human health.