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MAP  >  Food Materials Research
2022 Volume 2
Article Contents
Abstract
Introduction
Structure and distribution of main bioactive constituents of lonicera
Biosynthesis and regulation of the main bioactive constituents of lonicera
Biosynthesis of chlorogenic acids and flavonoids
Biosynthesis of iridoids and triterpene saponins
Metabolic engineering of the main bioactive compounds of the lonicera genus
Metabolic engineering of chlorogenic acid, luteolin and their glycosides
Metabolic engineering of iridoids and triterpene saponins
Pharmacological activities of the main bioactive compounds of lonicera
Anti-inflammatory effects
Antimicrobial effects
Anti-oxidative stress effect
Hepatoprotection
Other pharmacological effects
Chloroplast genomic and phylogenetic relationships of lonicera species
Conclusions and future perspectives
Author contributions
Data availability
Acknowledgments
Conflict of interest
Rights and permissions
References
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ARTICLE   Open Access    

The Association between Vitamin D and Hashimoto Thyroiditis: An Up-to-date Systematic Review and Meta-analysis

  • 1.

    The Out Patient Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • 2.

    Psychology Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • 3.

    The Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • 4.

    Office of The Standardized Residents Training in Hospitals, Graduate School, Southern Medical University, Guangzhou 510515, China

More Information
  • The objective of the surrent study was to summarize the up-to-date studies to investigate the relationship between vitamin D and Hashimoto thyroiditis (HT). An online search of English and Chinese databases was performed. The studies concerned the investigation of the relationship between vitamin D and HT including meta-analysis, meanwhile the heterogeneities were revealed by subgroup analysis. Fourty six elated studies containing 15,336 participants (HT: 6,138 versus control: 9,198) were included. HT patients had lower levels of 25(OH)D3 (standardised mean difference, −1.09; 95%CI: [−1.42, −0.75]; P < 0.01), and were more likely to be deficient in 25(OH)D3 (OR, 2.77; 95%CI, [1.88, 3.91]; P < 0.05). Obvious heterogeneities in the results of meta-analysis were down to the difference of detection methods and criteria of vitamin D insufficiency among studies. Vitamin D deficiency was colncluded to have a significant relation with HT.

  • Introduction

    The Lonicera Linn. genus is a constituent member of the Caprifoliaceae family[1]. It is the largest genus in this family and comprises at least 200 species with a notable presence in North Africa, North America, Asia, and Europe[1]. Members of the Lonicera genus possess a wide range of economic benefits from their use as ornamental plants to food and as plants credited with numerous health benefits. Conspicuous among the numerous members of this genus with known medicinal uses are L. japonica, L. macranthoides, L. hypoglauca, L. confusa, and L. fulvotomentosa[2]. Though these species feature prominently in the Chinese Pharmacopoeia, other species such as L. acuminata, L. buchananii, and L. similis are recognized as medicinal resources in certain parts of China[1]. Among the aforementioned species, L. japonica takes precedence over the rest due to its high medicinal and nutritional value[3,4]. For instance, the microRNA MIR2911, an isolate from L. japonica, has been reported to inhibit the replication of viruses[5−7]. Also, the water extract of L. japonica has been used to produce various beverages and health products[8]. The Lonicera genus therefore possesses huge prospects in the pharmaceutical, food, and cosmetic industries as an invaluable raw material[9].

    The main active constituents of the Lonicera genus include organic acids, flavonoids, iridoids, and triterpene saponins. Chlorogenic acids, iridoids, and flavones are mainly credited with the anti-inflammatory, antiviral, anticancer, and antioxidant effects of the various Lonicera species[10−13]. Their hepatoprotective, immune modulatory, anti-tumor and anti-Alzheimer’s effects are for the most part ascribed to the triterpene saponins[14−16]. As stated in the Chinese Pharmacopoeia and backed by the findings of diverse research groups, the plants of the Lonicera genus are known to possess high amounts of organic acids (specifically chlorogenic acid) and pentacyclic triterpenoid saponins[2,17−19]. The flower and flower bud have traditionally served as the main medicinal parts of the Lonicera genus even though there is ample evidence that the leaves possess the same chemical composition[20]. A perusal of the current scientific literature reveals the fact that little attention has been devoted to exploring the biosynthesis of the chemical constituents of the Lonicera genus with the view to finding alternative means of obtaining higher yields. It is therefore imperative that priority is given to the exploration of the biosynthesis of these bioactive compounds as a possible means of resource protection. There is also the need for further research on ways to fully tap the medicinal benefits of other plant parts in the Lonicera genus.

    Here, we provide a comprehensive review of relevant scientific literature covering the structure, pharmacology, multi-omics analyses, phylogenetic analysis, biosynthesis, and metabolic engineering of the main bioactive constituents of the Lonicera genus. Finally, we proffer suggestions on the prospects of fully exploiting and utilizing plants of the Lonicera genus as useful medicinal plant resources.

    Structure and distribution of main bioactive constituents of Lonicera

    A total of at least 400 secondary metabolites have been reported for the Lonicera genus. These metabolites are categorized into four main groups (Fig. 1a), including not less than 50 organic acids, 80 flavonoids, 80 iridoids, and 80 triterpene saponins[21−23]. Organic acids are mainly derivatives of p-hydroxycinnamic acid and quinic acid. Among the organic acids, chlorogenic acids are reported to be the main bioactive compounds in L. japonica[24−26]. The organic acids are most abundant in the leaves, while the least amounts are found in the stem of L. japonica. The flowers of the plant are known to contain moderately high amounts of organic acids[27]. The basic core structure of the flavonoids is 2-phenylchromogen. Luteolin and its glycoside which are characteristic flavonoids of the Lonicera genus are most abundant in L. japonica[28]. On the whole, the flavonoid contents in L. japonica are also highest in the leaves, available in moderate amounts in the flowers, and in lowest amounts in the stem[21]. The core structures of the iridoids are iridoid alcohols, the chemical properties of which are similar to hemiacetal. The iridoids often exist in the form of iridoid glycosides in plants. Secoiridoids glycosides are predominant in the Lonicera genus[25]. In L. japonica, the contents of the iridoids are most abundant in the flowers, moderate in leaves, and lowest in the stem[21]. The characteristic saponins of the Lonicera genus are mainly pentacyclic triterpenoids, including the hederin-, oleanane-, lupane-, ursulane- and fernane-types, etc[22]. The hederin-type saponins are reported in the highest amounts in L. macranthoides[17] (Fig. 1b).

    Figure 1.  Core structures of main secondary metabolites and their distribution in five species of Lonicera. (a) 1 and 2, the main core structures of organic acids; 3, the main core structures of flavonoids; 4, the main core structures of iridoids; 5, the main core structures of triterpene saponins. (b) Comparison of dry weight of four kinds of substances in five species of Lonicera[17,28].
    DownLoad: Full-Size Img PowerPoint

    Biosynthesis and regulation of the main bioactive constituents of Lonicera

    Biosynthesis of chlorogenic acids and flavonoids

    The similarities between chlorogenic acid (CGA) and flavonoids can be traced back to their biosynthesis since p-coumaroyl CoA serves as the common precursor for these compounds[29]. p-coumaroyl CoA is obtained through sequential catalysis of phenylalanine and its biosynthetic intermediates by phenylalanine-ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H) and 4-coumarate CoA ligase (4CL)[30−33].

    CGA is a phenolic acid composed of caffeic acid and quinic acid and is the most important bioactive compound among the organic acids. Its biosynthesis has been relatively well-established; three main biosynthetic routes have been propounded (Fig. 2a). One route relates to the catalysis of caffeoyl-CoA and quinic acid by hydroxycinnamoyl-CoA quinate transferase (HQT)/hydroxycinnamoyl CoA shikimate/quinate hydroxycinnamoyl transferase (HCT) to produce CGA[34−37]. The HQT-mediated pathway has been deemed the major route for CGA synthesis in in different plant species[38,39]. The second biosynthetic route stems from the biosynthesis of p-coumaroyl quinate through the catalytic effect of HCT/HQT and subsequent hydroxylation of p-coumaroyl quinate under the catalysis of p-coumarate 3'-hydroxylase (C3’H)[34,36,37]. For the third route, caffeoyl glucoside serves as the intermediate to form CGA, a process that is catalyzed by hydroxycinnamyl D-glucose: quinic acid hydroxycinnamyl transferase (HCGQT)[40,41].

    Figure 2.  Biosynthetic pathways of main bioactive constituents of Lonicera. (a) Biosynthetic pathways of chlorogenic acid. (b) Biosynthetic pathways of luteoloside. (c) Biosynthetic pathways of secologanin. (d) Biosynthetic pathways of hederin-type triterpene saponins. PAL, phenylalanine ammonia-lyase; C4H, cinnamate 4-hydroxylase; 4CL, 4-hydroxycinnamoyl CoA ligase; HCT, hydroxycinnamoyl CoA shikimate/quinate hydroxycinnamoyl transferase; C3’H, p-coumaroyl 3-hydroxylase; HQT, hydroxycinnamoyl-CoA quinate transferase; UGCT, UDP glucose: cinnamate glucosyl transferase; CGH, p-coumaroyl-D-glucose hydroxylase; HCGQT, hydroxycinnamoyl D-glucose: quinate hydroxycinnamoyl transferase; CHS, Chalcone synthase; CHI, Chalcone isomerase; FNS, Flavone synthase; F3H, flavonoid 30-monooxygenase/flavonoid 30-hydroxylase; UF7GT, flavone 7-O-β-glucosyltransferase; GPS, Geranyl pyrophosphatase; GES, geraniol synthase; G8O, geraniol 10-hydroxylase/8-oxidase; 8HO, 8-hydroxygeraniol oxidoreductase; IS, iridoid synthase; IO, iridoid oxidase; 7DLGT, 7-deoxyloganetic acid glucosyltransferase; 7DLH, 7-deoxyloganic acid hydroxylase; LAMT, loganic acid O-methyltransferase; SLS, secologanin synthase; FPS, farnesyl pyrophosphate synthase; SS, squalene synthase; SE, squalene epoxidase; β-AS, β-amyrin synthase; OAS, oleanolic acid synthetase.
    DownLoad: Full-Size Img PowerPoint

    The key enzymes in the biosynthesis of p-coumaroyl CoA, and invariably CGA, thus, PAL, C4H, and 4CL have been established in diverse studies such as enzyme gene overexpression/knockdown[42], enzyme activity analysis[33] and transcriptomics[18]. However, the centrality of HQT in the biosynthesis of CGA remains disputable. While some studies have reported a strong correlation between HQT expression level with CGA content and distribution[18,35,39,43,44], others found no such link[45], bringing into question the role of HQT as a key enzyme in CGA biosynthesis.

    Few studies have been conducted on the regulation of CGA biosynthesis in the Lonicera genus. It was found that overexpression of the transcription factor, LmMYB15 in Nicotiana benthamiana can promote CGA accumulation by directly activating 4CL or indirectly binding to MYB3 and MYB4 promoters[46]. LjbZIP8 can specifically bind to PAL2 and act as a transcriptional repressor to reduce PAL2 expression levels and CGA content[47]. Under NaCl stress, increased PAL expression promoted the accumulation of phenolic substances in leaves without oxidative damage, a condition that was conducive to the accumulation of the bioactive compounds in leaves[48].

    Luteolin and its derivative luteolin 7-O- glucoside (luteoloside) are representative flavonoids of the Lonicera genus. Similar to CGA, luteolin is biosynthesized from p-coumaroyl CoA but via a different route. The transition from p-coumaroyl CoA to luteolin is underpinned by sequential catalysis by chalcone synthetase (CHS), chalcone isomerase (CHI), flavonoid synthetase (FNS), and flavonoid 3'-monooxygenase/flavonoid 3'-hydroxylase (F3'H)[45,49,50] (Fig. 2b). Luteoloside is synthesized from luteolin by UDP glucose-flavonoid 7-O-β-glucosyltransferase (UF7GT)[51]. Similar to CGA biosynthesis, the key enzymes of luteolin synthesis include PAL, C4H, and 4CL in addition to FNS[33,45,52]. The content of luteoloside was found to be highly abundant in senescing leaves relative to other tissues such as stem, flowers, and even young leaves[52]. Through transcriptomic analysis, luteoloside biosynthesis-related differentially expressed unigenes (DEGs) such as PAL2, C4H2, flavone 7-O-β-glucosyltransferase (UFGT), 4CL, C4H, chalcone synthase 2 and flavonoid 3'-monooxygenase (F3'H) genes were found to be upregulated in the senescing leaves. Biosynthesis-related transcription factors such as MYB, bHLH, and WD40 were also differentially expressed during leaf senescence[52], while bHLH, ERF, MYB, bZIP, and NAC were differentially expressed during flower growth[53]. Further analysis of the transcription factors revealed that MYB12, MYB44, MYB75, MYB114, MYC12, bHLH113, and TTG1 are crucial in luteoloside biosynthesis[52,53].

    Biosynthesis of iridoids and triterpene saponins

    The biosynthesis of terpenoids mainly involves three stages; formation of intermediates, formation of basic structural skeleton, and modification of basic skeleton[54]. The intermediates of terpenoids are mainly formed through the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways, and eventually converted to the universal isoprenoid precursors, isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP) through a series of enzyme-catalyzed reactions. Under the catalysis of geranyl pyrophosphatase (GPS), IPP is then converted to geranyl pyrophosphate (GPP). Different terpenoids are subsequently derived from GPP as the intermediate product. For instance, in the formation of secoiridoid, GPP first removes the phosphoric acid group to obtain geraniol, second through a series of reactions such as oxidation and cyclization, the skeleton of iridoid, namely iridodial, can be obtained. Finally, through a series of reactions, the basic carbon skeleton of the secoiridoid, namely secologanin, is obtained[55−61] (Fig. 2c). In the formation of triterpene saponins, the key step lies in the formation of the precursor, 2,3-oxidosqualene, a reaction that is catalyzed by squalene epoxidase (SE). There are many pentacyclic triterpenes in the Lonicera genus, the most important type being the hederin-type saponins with hederagenin as aglycones. Hederin-type saponins are produced after the synthesis of oleanolic acid from β-amyrin and catalyzed by β-starch synthetase (β-AS) and Oleanolic acid synthase (OAS)[62,63]. The skeletal modification of the triterpenoid saponins is mainly achieved via the activities of the CYP450 enzymes and UDP-glycosyltransferase (UGT). Hence, the corresponding aglycones are first obtained via oxidation by the CYP450 enzymes (e.g., CYP72A), and further subjected to glycosylation by the appropriate UGT enzyme[63−65] (Fig. 2d). Skeletal formations of the iridoids and triterpene saponins in general have been well researched, but the same cannot be said about the enzymes involved in biosynthesis of these groups of compounds in the Lonicera genus. To fully utilize the iridoids and triterpene saponins in the Lonicera genus, it is necessary to further explore their biosyntheses with the view to enhancing and optimizing the process.

    Metabolic engineering of the main bioactive compounds of the Lonicera genus

    Given the importance of the bioactive compounds in the Lonicera genus, continual isolation of these compounds using the traditional methods are not only tedious and time-consuming, but also unsustainable. With the development and application of microbial metabolic engineering, different strategies have been introduced to produce these bioactive compounds by heterologous synthesis (Table 1).

    Table 1.  Biosynthesis of Lonicera-specialized metabolites using metabolic engineering.
    Engineering bacteriaOperational methodsProductsYieldRefs
    S. cerevisiaeEliminate the tyrosine-induced feedback inhibition, delete genes involved in competing pathways and overexpress rate-limiting enzymesCaffeic acid569.0 mg/L[69]
    S. cerevisiaeEmploye a heterologous tyrosine ammonia lyase and a 4HPA3H complex composed of HpaB and HpaC derived from different speciesCaffeic acid289.4 mg/L[73]
    S. cerevisiaeSupply and recycle of three cofactors: FADH2, S-adenosyl-L-methion, NADPHCaffeic acid
    Ferulic acid    		Caffeic acid: 5.5 g/L;
    Ferulic acid: 3.8 g/L    		[117]
    E. coliKnocking out competing pathwaysCaffeic acid7,922 mg/L[118]
    E. coliArtificial microbial community, a polyculture of three recombinant Escherichia coli strainsChlorogenic acid250 μM[68]
    Cell-free biosynthesisExtract and purify spy-cyclized enzymes (CFBS-mixture)Chlorogenic acid711.26 mg/L[70]
    S. cerevisiaeThree metabolic engineering modules were systematically optimized: shikimate pathway and carbon distribution, branch pathways, CGA pathway genesChlorogenic acidFlask fermentation: 234.8 mg/L;
    Fed-batch fermentation:
    806.8 mg/L    		[119]
    E. coliUsing modular coculture engineering: construction of the defective strain improves the production and utilization of precursor substancesChlorogenic acid131.31 mg/L[122]
    E. coliIntroduce heterologous UDP-glucose biosynthetic genesLuteolin34 mg/L[120]
    Y. lipolyticaOverexpression of the key genes involved in the mevalonate pathway, the gene encoding cytochrome P450 (CYP716A12) to that encoding NADPH-P450 reductaseOleanolic acid129.9 mg/L[85]
    S. cerevisiaeImprove the pairing efficiency between Cytochrome P450 monooxygenase and reductase and the expression level of key genesOleanolic acid606.9 mg/L[121]
    S. cerevisiaeHeterologous expression and optimization of CrAS, CrAO, and AtCPR1, and regulation of ERG1 and NADPH regeneration systemOleanolic acid433.9 mg/L[123]
     | Show Table
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    Metabolic engineering of chlorogenic acid, luteolin and their glycosides

    Due to the demand for CGA in the food, pharmaceutical, chemical, and cosmetic industries, the traditional means of obtaining the same requires a relatively longer period for plant maturation to obtain low yields of the desired product. This therefore brings into question the sustainability and efficiency of this approach. The alternative and sustainable approach has been to produce CGA using synthetic biology and metabolic engineering.

    Current research has sought to utilize Escherichia coli (and its mutant strain) and Saccharomyces cerevisiae to synthetically generate CGA and other flavonoids[66−73]. For instance, Cha et al. employed two strains of E. coli to produce a relatively good yield of CGA (78 mg/L). Their approach was based on the ability of one strain to generate caffeic acid from glucose and the other strain to use the caffeic acid produced and quinic acid as starting materials to synthesize CGA[66]. Using a bioengineered mutant of E. coli (aroD mutant), Kim et al. increased the yield of CGA to as high as 450 mg/L[67]. Others have sought to increase the yield of CGA by employing a polyculture of three E. coli strains that act as specific modules for the de novo biosynthesis of caffeic acid, quinic acid and CGA. This strategy eliminates the competition posed by the precursor of CGA (i.e., caffeic acid and quinic acid) and generally results in improved production of CGA[68]. Saccharomyces cerevisiae is a chassis widely used for the production of natural substances from plants with an intimal structure that can be used for the expression of cytochrome P450 enzymes that cannot be expressed in E. coli. Researchers have used yeast to increase the production of organic acids[69]. A de novo biosynthetic pathway for the construction of CGA in yeast has been reported new cell-free biosynthetic system based on a mixture of chassis cell extracts and purified Spy cyclized enzymes were adopted by Niu et al. to a produce the highest yield of CGA reported so far up to 711.26 ± 15.63 mg/L[70].

    There are many studies on the metabolic engineering for the synthesis of flavonoids, but few on luteolin and its glycosides. Strains of E. coli have been engineered with specific uridine diphosphate (UDP)-dependent glycosyltransferase (UGT) to synthesize three novel flavonoid glycosides. These glycosides were quercetin 3-O-(N-acetyl) quinovosamine (158.3 mg/L), luteolin 7-O-(N-acetyl) glucosaminuronic acid (172.5 mg/L) and quercetin 3-O-(N-acetyl)-xylosamine (160.8 mg/L)[71]. Since most of the flavonoid glycosides synthesized in E. coli are glucosylated, Kim et al. in their bid to synthesize luteolin-7-O-glucuronide, deleted the araA gene that encodes UDP-4-deoxy-4-formamido-L-arabinose formyltransferase/UDP-glucuronic acid C-4'' decarboxylase in E.coli and were able to obtain a yield of 300 mg/L of the desired product[72].

    Metabolic engineering of iridoids and triterpene saponins

    Terpenoidal saponins are mostly derived from slow-growing plants and usually possess multiple chiral centers[74]. Traditional isolation and even chemical synthesis of the terpenoidal saponins are both tedious and uneconomical for large-scale production. Therefore, it is necessary to find other ways to synthesize these compounds known to have diverse pharmacological functions.

    Heterologous synthesis has become an important way to improve the target products. With the development of synthetic biology, heterologous synthesis of triterpene saponins involves chassis of both plant and microbial origin. In this regard, Nicotiana benthamiana is a model plant species for the reconstruction of the biosynthetic pathways of different bioactive compounds including monoterpenes, hemiterpenes, and diterpenes[59,75−77]. Aside from Nicotiana benthamiana, other plants have also been used as heterologous hosts[78]. Heterologous synthesis using microbial hosts mainly involves Saccharomyces cerevisiae and Escherichia coli[79−81], and other microorganisms[82,83]. Comparatively, plants as biosynthetic hosts have the advantages of an established photosynthetic system, abundant supply of relevant enzymes, and presence of cell compartments, etc. They are however not as fast growing as the microorganisms, and it is also difficult to extract and separate the desired synthesized compounds from them as hosts.

    Although heterologous synthesis has many advantages, the premise of successful construction of synthetic pathway in host is to elucidate the unique structure of the compound and the key enzyme reaction mechanism in the biosynthetic pathway. There is little research on metabolic engineering of the hederin-type pentacyclic triterpene saponins in Lonicera, but there are studies on the heterologous synthesis of its aglycone precursor, oleanolic acid[84,85]. There is a dearth of scientific literature on key enzymes in the biosynthesis of pentacyclic triterpenoid saponins in the Lonicera genus.

    Pharmacological activities of the main bioactive compounds of Lonicera

    Scientific evidence by diverse research groups has linked members of the Lonicera genus to a wide range of pharmacological effects (Fig. 3). These pharmacological effects are elicited by different chemical constituents, much of the underlying mechanisms of which have been elucidated by the omics techniques. Here, we summarize the pharmacological effects and pharmacodynamics of the Lonicera genus in the last 6 years.

    Figure 3.  Schematic summary of four main pharmacological effects (anti-inflammatory, antimicrobial, anti-oxidative and hepatoprotective effects) of the Lonicera genus and the underlying mechanisms of actions.
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    Anti-inflammatory effects

    Bioactive compounds of plants in the Lonicera genus have demonstrated varying degrees of anti-inflammatory actions. In a recent study, Lv et al. showed that lonicerin inhibits the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) through regulating EZH2/AtG5-mediated autophagy in bone marrow-derived macrophages of C57BL/6 mice[86]. The polysaccharide extract of L. japonica reduces atopic dermatitis in mice by promoting Nrf2 activation and NLRP3 degradation through p62[87]. Several products of Lonicera have been reported to have ameliorative effects on DSS-induced colitis. Among them, flavonoids of L. rupicola can improve the ulcerative colitis of C57BL/6 mice by inhibiting PI3K/AKT, and pomace of L. japonica can improve the ulcerative colitis of C57BL/6 mice by improving the intestinal barrier and intestinal flora[88,89]. The flavonoids can also ameliorate ulcerative colitis induced by local enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in Wistar rats by inhibiting NF-κB pathway[90]. Ethanol extract from L. Japonica has demonstrated the potential to inhibit the expressions of inflammatory cytokines in serum and macrophages of LPS-induced ICR mice[91]. The water extract of L. japonica and luteolin were found to exhibit their anti-inflammatory effects via the inhibition of the JAK/STAT1/3-dependent NF-κB pathway and induction of HO-1 expression in RAW263.7 cells induced by pseudorabies virus (PRV)[92].

    Antimicrobial effects

    Existing scientific evidence indicates that the extracts of plants in the Lonicera genus exhibit strong inhibition against different pathogenic microorganisms. Phenolic compounds from L. japonica demonstrated a particularly significant inhibitory effect against Staphylococcus aureus and Escherichia coli, in vitro, making these compounds potential food preservatives[93]. Influenza A virus is a serious threat to human health. Recent research has found the ethanol extract of L. japonica to possess a strong inhibitory effect against H1N1 influenza virus-infected MDCK cells and ICR mice[94]. The incidence of the COVID-19 pandemic called to action various scientists in a bid to find safe and efficacious treatment[95]. Traditional Chinese medicines became an attractive alternative in this search. The water extract of the flower bud of L. japonica which has traditionally served as a good antipyretic and antitussive agent attracted the attention of researchers. Scientific evidences have confirmed that the water extract of L. japonica can induce let-7a expression in human rhabdomyosarcoma cells or neuronal cells and blood of lactating mice, inhibiting the entry and replication of the virus in vitro and in vivo[96]. In addition, the water extract of L. japonica also inhibits the fusion of human lung cancer cells Calu-3 expressing ACE2 receptor and BGK-21 cells transfected with SARS-CoV-2 spike protein, and up-regulates the expression of miR-148b and miR-146a[97].

    Anti-oxidative stress effect

    Oxidative stress has been implicated in the pathophysiology of many diseases, hence, amelioration of the same could be a good therapeutic approach[98,99]. In keeping with this therapeutic strategy, various compounds from the Lonicera genus have demonstrated the ability to relieve oxidative stress due to their pronounced antioxidant effects. For instance, the polyphenolic extract of L. caerulea berry was found to activate the expression of AMPK-PGC1α-NRF1-TFAM proteins in the skeletal muscle mitochondria, improve the activity of SOD, CAT and GSH-Px enzymes in blood and skeletal muscle, relieve exercise fatigue in mice by reducing oxidative stress in skeletal muscle, and enhance mitochondrial biosynthesis and cell proliferation[100]. The diverse health benefits of the anthocyanins from L. japonica have been mainly credited to their antioxidant and anti-inflammatory effects. The anthocyanin and cyanidin-3-o-glucoside have been reported to possess the potential to prolong life and delay senescence of Drosophila through the activation of the KEAP1/NRF2 signaling pathway[101].

    Hepatoprotection

    The liver is an essential organ that contributes to food digestion and detoxification of the body. These functions expose the liver to diverse toxins and metabolites. The Lonicera genus is rich in phytochemicals that confer protection on the liver against various toxins. The phenolic compound, 4, 5-di-O-Caffeoylquinic acid methyl ester was shown to be able to improve H2O2-induced liver oxidative damage in HepG2 cells by targeting the Keap1/Nrf2 pathway[102]. Hepatic fibrosis is a complex dynamic process, with the propensity to progress to liver cancer in severe cases. The L. japonicae flos water extract solution increased the cell viability of FL83B cells treated with thioacetamide (TAA), decreased the levels of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP), inhibited the transformation growth factor β1 (TGF-β1) and liver collagen deposition[103]. Sweroside, a secoiridoid glucoside isolate of L. japonica is known to protect the C57BL/6 mice liver from hepatic fibrosis by up-regulating miR-29a and inhibiting COL1 and TIMP1[104].

    Other pharmacological effects

    Aside from the aforementioned, other pharmacological effects have been ascribed to the Lonicera genus. The ethanolic extract of L. caerulea has been reported to inhibit the proliferation of SMMC-7721 and H22 hepatoma cells, while its anthocyanins induced the apoptosis of tumor cells via the release of cytochrome C and activation of caspase[105]. AMPK/PPARα axes play an important role in lipid metabolism. A chlorogenic acid-rich extract of L. Japonica was found to significantly decrease the early onset of high-fat diet-induced diabetes in Sprague-Dawley rats via the CTRPs-AdipoRs-AMPK/PPARα axes[106]. In a high-fat diet-induced non-alcoholic fatty liver disease in C57BL/6 mice, treatment with L. caerulea polyphenol extract decreased serum inflammatory factors and endotoxin levels and the Firmicutes/Bacteroidetes ratio, an indication of its modulatory effect on the gut microbiota[107]. The iridoid-anthocyanin extract from L. caerulea berry contributed to alleviating the symptoms of intestinal infection with spirochaeta in mice[108].

    Chloroplast genomic and phylogenetic relationships of Lonicera species

    The traditional classification of the Lonicera genus based on the morphology of member plants is further categorized into two subgenera, Chamaecerasus and Periclymenum. The Chamaecerasus includes four categories, Coeloxylosteum, Isika, Isoxylosteum and Nintooa. The Periclymenum includes two categories, Subsect. Lonicera and Subsect. Phenianthi (Supplemental Table S1).

    High-throughput chloroplast genome sequencing of L. japonica found its length to be 155078 bp, which is similar to the structure of the typical angiosperm chloroplast genome. It contains a pair of inverted repeat regions (IRa and IRb, 23774 bp), a large single copy region (LSC, 88858 bp) and a small single copy area (SSC, 18672 bp)[109,110]. However, compared with chloroplast genomes of other plants, the chloroplast genome of L. japonica has a unique rearrangement between trnI-CAU and trnN-GUU[110]. Based on the phylogenetic analysis of the plastid genomes of seven plants in the Lonicera genus, 16 diverging hot spots were identified as potential molecular markers for the development of the Lonicera plants[111]. The phylogeny of Lonicera is rarely researched at the molecular level and the pattern of repetitive variation and adaptive evolution of the genome sequence is still unknown. Chloroplast genome sequences are highly conserved, but insertions and deletions, inversions, substitutions, genome rearrangements, and translocations also occur and have become powerful tools for studying plant phylogeny[112,113].

    We present here the phylogenetic tree of the Lonicera genus based on the published complete chloroplast genome sequences downloaded from the National Center for Biotechnology Information (NCBI) database using the Maximum likelihood method (Fig. 4). Based on our chloroplast phylogenies, we propose to merge L. harae into Sect. Isika and L. insularis into Chamaecerasus, but whether L. insularis belongs to Sect. Isika or Sect. Coeloxylosteum is uncertain. Based on protein-coding regions (CDS) of the chloroplast genome or complete chloroplast genomes, Liu et al. and Chen et al. supported the classification of the two subgenera in Lonicera[111,114]. Sun et al. and Srivastav et al. demonstrated a classification between the two subgenera with more species by using sequences of nuclear loci generated, chloroplast genome, and restriction site-associated DNA sequencing (RADSeq)[115,116]. However, our phylogenetic analysis and that of Sun et al. show relations within the subgenus Chamaecerasus are tanglesome in some respects[116]. Plant traits are affected by the environment to varying degrees. Since evidence of plant speciation is implicit in its genome sequence, comparative analysis at the molecular level provides a relatively accurate depiction of inherent changes that might have occurred over time. These findings suggest the need for more species of the Lonicera genus to be sequenced to provide a more accurate theoretical basis for the evolution of the Lonicera plants and a more effective revision in the classification of the Lonicera genus.

    Figure 4.  Phylogenetic tree of 42 species of the Lonicera genus based on complete chloroplast genome sequence data. The phylogenetic tree was constructed by the maximum likelihood method. Coeloxylosteum, Isika, Isoxylosteum, and Nintooa belong to Chamaecerasus and Subsect. Lonicera belongs to the Periclymenum. Chamaecerasus and Periclymenum are the two subgenera of Lonicera. 'Not retrieved' indicates that the species failed to retrieve a subordinate taxon in the Lonicera.
    DownLoad: Full-Size Img PowerPoint

    Conclusions and future perspectives

    The Lonicera genus is rich in diverse bioactive compounds with immeasurable prospects in many fields. Members of this genus have been used for thousands of years in traditional Chinese medicine for heat-clearing and detoxification. These plants generally have a good taste and form part of the ingredients of various fruit juices. In cosmetics, they are known to possess anti-aging and moisturizing functions. Plants of the Lonicera genus are also known for their good ecological adaptability and can be used to improve soil and ecological environment. Based on the value of the Lonicera genus, besides researching their use through molecular biological means, their efficient utilization can also be promoted in the following ways: (1) The stems and leaves of the plants could be developed for consumption and use since the chemical profiles of these parts do not differ significantly from the flowers. This way, the wastage of this scarce resource could be minimized or avoided. (2) Most of the Lonicera plants are vines or shrubs and their natural regeneration speed is slow, so the introduction and domestication of species could be strengthened to avoid overexploitation of wild resources.

    At present, only the research on the biosynthesis and efficacy of chlorogenic acid is quite comprehensive and has been used widely in various fields. There is limited research on various aspects of other bioactive compounds and should therefore be given priority in future research goals. Currently, the multi-omics analytical approach has gradually evolved as a reliable and helpful analytical platform. Hence, multi-omics research on the Lonicera genus could lead to discoveries in drug discovery and human health.

    Author contributions

    The authors confirm contribution to the paper as follows: study conception and design, draft manuscript preparation: Yin X, Chen X, Li W, Tran LSP, Lu X; manuscript revision: Yin X, Chen X, Li W, Tran LSP, Lu X, Chen X, Yin X, Alolga RN; data/literature collection: Chen X, Yin X; figure preparation: Chen X, Yin X; figure revision: Alolga RN, Yin X, Chen X, Li W, Tran LSP, Lu X. All authors reviewed the results and approved the final version of the manuscript.

    Data availability

    All data generated or analyzed during this study are included in this published article and its supplementary information file.

    Acknowledgments

    This work was partially supported by the National Natural Science Foundation of China (NSFC, Nos 82173918 and 82373983).

  • The authors declare that they have no conflict of interest. Xiaojian Yin is the Editorial Board member of Medicinal Plant Biology who was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer-review handled independently of this Editorial Board member and the research groups.

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  • Cite this article

    Liu Z, Feng L, He Y, Yuan S, Xu C. 2022. The Association between Vitamin D and Hashimoto Thyroiditis: An Up-to-date Systematic Review and Meta-analysis. Food Materials Research 2:9 doi: 10.48130/FMR-2022-0009
    Liu Z, Feng L, He Y, Yuan S, Xu C. 2022. The Association between Vitamin D and Hashimoto Thyroiditis: An Up-to-date Systematic Review and Meta-analysis. Food Materials Research 2:9 doi: 10.48130/FMR-2022-0009
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The Association between Vitamin D and Hashimoto Thyroiditis: An Up-to-date Systematic Review and Meta-analysis

  • 1.

    The Out Patient Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • 2.

    Psychology Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • 3.

    The Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • 4.

    Office of The Standardized Residents Training in Hospitals, Graduate School, Southern Medical University, Guangzhou 510515, China

  • Received: 27 May 2022
  • Accepted: 31 May 2022
  • Published online: 28 June 2022
Food Materials Research  2,  Article number: 9  (2022)  |  Cite this article

Abstract: The objective of the surrent study was to summarize the up-to-date studies to investigate the relationship between vitamin D and Hashimoto thyroiditis (HT). An online search of English and Chinese databases was performed. The studies concerned the investigation of the relationship between vitamin D and HT including meta-analysis, meanwhile the heterogeneities were revealed by subgroup analysis. Fourty six elated studies containing 15,336 participants (HT: 6,138 versus control: 9,198) were included. HT patients had lower levels of 25(OH)D3 (standardised mean difference, −1.09; 95%CI: [−1.42, −0.75]; P < 0.01), and were more likely to be deficient in 25(OH)D3 (OR, 2.77; 95%CI, [1.88, 3.91]; P < 0.05). Obvious heterogeneities in the results of meta-analysis were down to the difference of detection methods and criteria of vitamin D insufficiency among studies. Vitamin D deficiency was colncluded to have a significant relation with HT.

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    INTRODUCTION

    • T and B lymphocyte mediated immune tolerance disorder led to abnormal auto-antibodies invasion in thyroid glands, which was the main mechanism of Hashimoto thyroiditis (HT). The increase of HT continued[1], and gradually became the most common cause of thyroid hormone insufficiency. Besides, it was suggested a link to diseases including ischemic heart disease, osteoporosis, diabetes, cardiovascular disease and cancer[2−6]. Papillary thyroid carcinoma was the most common form of cancer associated with HT[7]. Even the health of children was threatened by HT with higher risk of dyslipidemia and cardiovascular disease[8]. Along with the progress of HT, the secretion of thyroid hormone was significantly insufficient, and patients had to replenish with Euthyroxin throughout their life, but still suffered from higher risk of HT related complications. Therefore, effective methods for HT prevention were considered to be urgent research.

      Since Vitamin D receptors were shown to be present in the thyroid[9], Vitamin D was considered as HT prevention in resent studies. Krysiak et al.[10] suggested that Vitamin D combined with atorvastatin could improve thyroid autoimmunity. In addition, supplementation with cholecalciferol for HT patients was indicated to twist the balance of CD4+ T-cell subsets toward ameliorative composition[11]. Although the relationship between Vitamin D and HT seemed clear, it still needed further investigation[12], for there existed study reported they had no evident correlation[13]. These contradictory conclusions maybe due to the small sample size of the local population, but it was very difficult to conduct a high-quality epidemiological study with a large sample size. Therefore, to indicate whether vitamin D deficiency was really correlated to HT, which may affect clinical strategy whether we should use Vitamin D to prevent HT, evidence-based medical research tools such as systematic review and meta-analysis were necessary for a more reliable conclusion.

      We conducted a systematic review and meta-analysis of the domestic and foreign studies that investigated the relationship between Vitamin D and HT. Compatible data were pooled into meta-analysis to provide rigorous evidence-based medical reference for the prevention of HT.

    METHODOLOGY

      Bibliographic search

    • The present systematic review and meta-analysis were performed under PRISMA guidelines[14]. An online bibliographic search was performed in Pubmed (for English), and China National Knowledge Infrastructure (CNKI) and Wanfang Databases (both for Chinese) by two investigators with key words of 'Vitamin D' and 'Hashimoto thyroiditis'. Studies were considered if they were in English or Chinese, and updated to 27 September 2021. If the abstract displayed investigation about the relationship between Vitamin D and HT, the full text was read in detail by at least two authors (Fig. 1).

      Figure 1. 

      Forest plot of 25(OH)D3 level (random model).

      Inclusion criteria

    • Studies were finally included if they fulfilled the following criteria: (1) included the comparison of HT patient group with a healthy control group; (2) serum levels of 25(OH)D3 level and/or the quantity of patients with 25(OH)D3 insufficiency were reported; (3) written in English or Chinese; (4) with a quality score above or equal to 6 according to the coding manual for case-control studies[15] assessed by two authors respectively.

      Data extraction

    • The following information was extracted from each study by two investigators independently: (1) the first author; (2) year of publication; (3) region; (4) sample size; (5) serum levels of 25(OH)D3; (6) cut-off of serum 25(OH)D3 insufficiency; (7) the quantity of patients with 25(OH)D3 insufficiency; and (8) quality score. After that, the extracted information was summarized and checked by another two authors.

      Statistical analysis

    • RevMan 5.3 (the Cochrane Collaboration) was used to perform a meta-analysis on the data obtained. Firstly, Weighted mean differences (WMD) for continuous variable and Odds Ratios (OR) for binary variables were calculated. Subsequently, statistical heterogeneity was assessed with I2 test, and the main source of heterogeneity was revealed by subgroup analysis. Lastly, publication bias was evaluated by funnel plots. For statistical analysis above, 'P < 0.05' was considered a significant difference between groups.

    RESULTS

      Search results

    • Online search obtained 336 studies, in which 280 were excluded by abstract screening. Then, of the 56 remaining, 10 were excluded by full text in-detail evaluation; finally 46 studies with 15,336 individuals in total (6,138 HT patients and 9,198 healthy controls) were included into the present study for the systematic review[16−61]. Characteristics of included studies are summarized in Table 1.

      Table 1.  Characteristics of included studies.

      Study
      (published year)      		RegionSample size (HT:C)25(OH)D3
      Assay method      		Serum 25(OH)D3 level
      (HT vs C)
      (ng/mL)      		Serum 25(OH)D3 insufficiency cut off (ng/mL)Number of 25(OH)D3
      insufficiency (HT:C)      		Quality
      score
      Maciejewski et al. 2015[23]Poland62/32ELISA
      		8.00 ± 5.06 vs
      12.12 ± 7.80      		< 3061/277
      Ucan et al. 2016[27]Turkey
      		75/43RIA
      		9.37 ± 0.69 vs
      11.9 ± 1.01      		< 2075/369
      Bozkurt et al. 2013[12-17]]Turkey
      		360/180CLS12.2 ± 5.6 vs
      15.4 ± 6.8      		< 10150/378
      Kim 2016[20]Korea221/555CLS36.84 ± 22.96 vs
      39.84 ± 21.48      		< 30108/2068
      Sonmezgoz et al. 2016[25]Turkey
      		68/68CLS16.8 ± 9.2 vs
      24.1 ± 9.4      		< 3061/548
      De Pergola et al. 2018[18]Italy
      		45/216CLS−< 2031/1138
      Botelho et al. 2018[16]Brazil
      		88/71CLS26.4 (7.6–48.2) vs
      28.6 (13–51.2)      		< 3061/397
      Ma et al. 2015[22]China70/70ELISA
      		12.40 ± 4.46 vs
      16.53 ± 5.79      		< 3070/677
      Yasmeh et al. 2016[29]America97/88CLS24.5 ± 6.42 vs
      20.6 ± 6.5      		< 3066/747
      Xu et al. 2018[28]China194/200CPBA16.16 (13.72–18.76) vs
      23.32 (20.84–25.92)      		−−7
      Kivity et al. 2011[21]Israel
      		28/98CLS−< 1022/308
      Mansournia et al. 2014[24]Iran
      		41/45SC15.9 ± 1.21 vs
      24.4 ± 1.73      		< 2034/248
      Tamer et al. 2011[26]Turkey
      		161/162RIA
      		16.3 ± 10.4 vs
      29.6 ± 2.55      		< 30148/1028
      Chaudhary et al. 2018[32]India
      		35/50HPLC13.39 ± 6.8 vs
      26.16 ± 12.28      		< 2031/388
      Evliyaoğlu et al. 2015[31]Turkey
      		90/79HPLC16.67 ± 11.65 vs
      20.99 ± 9.86      		< 2080/698
      Unal et al. 2014[30]Turkey
      		254/124CLS17.05 (5.4−80) vs
      19.9 (9−122.7)      		< 20160/-7
      Ke et al. 2017[19]China
      		61/51EBL22.10 ± 1.52 vs
      33.40 ± 1.56      		< 2034/127
      Camurdan et al. 2012[33]Turkey
      		78/74HPLC31.2 ± 11.5 vs
      57.9 ± 19.7      		< 2069/247
      Dellal et al 2013[34]Turkey51/27RIA
      		17.3 ± 8.0 vs
      21.8 ± 15.2      		−−6
      Siklar et al. 2016[35]Turkey32/24HPLC16.02 ± 9.84 vs
      21.91 ± 7.68      		< 2022/107
      Nalbant et al. 2017[36]Turkey253/200CLS33 ± 29.6 vs
      43.7 ± 26.2      		< 20161/1118
      Giovinazzo et al. 2017[37]Italy
      		100/100HPLC21.2 ± 12.9 vs
      35.7 ± 16.7      		< 2070/187
      Guleryuz et al. 2016[38]Turkey
      		136/50HPLC14.88 ± 8.23 vs
      15.52 ± 1.34      		−−6
      Perga et al. 2018[39]Italy
      		55/59CLS−< 2037/42
      Yavuzer et al. 2017Turkey
      		49/34ELISA19.5 ± 15 vs
      23.8 ± 19      		−−6
      Priya et al. 2016India25/27ELISA14.3 (12.65−17.90)
      vs 26.2 (21.00−32.8)      		−−6
      Chao et al. 2020[42]China373/4889RIA
      		16.66 ± 6.51 vs
      15.81 ± 6.42      		< 20363/47389
      Feng et al. 2020[44]China36/30ELISA17.39 ± 8.49 vs
      35.15 ± 14.16      		−−6
      Ahi et al. 2020[43]Iran633/200CLS13.22 (8.1−24.27) vs
      20.4 (11.2−29.6)      		−−7
      Liu and Zhang. 2012[46]China30/20RIA
      		16.48 ± 6.25 vs
      24.31 ± 7.88      		−−7
      Xiang et al. 2017[47]China41/106CLS19.71 ± 8.43 vs
      20.56 ± 11.64      		< 3038/906
      Zhang et al. 2015[48]China31/19HPLC17 ± 6 vs
      24 ± 7      		−−6
      Chen et al. 2015[45]China34/52CLS14.4 ± 5.6 vs
      17.4 ± 5.6      		< 2029/377
      Li et al. 2015[49]China50/56−21.19 (18.40−25.28) vs
      24.06 (18.94−33.90)      		< 3044/376
      Cvek et al. 2021[50]Croatian461/176CLS19.7 (14.4−25.2) vs
      17.3 (13.2−22.7)      		< 20127/657
      Salem et al. 2021[51]Egypt120/120ELISA7.6 ± 4.4 vs 20.6 ± 5.5< 10120/1127
      Hana et al. 2021[52]Egypt112/48HPLC10.1 (8.7−11.7) vs 12.0 (9.3−15.6)< 30101/406
      Olszewska et al. 2020[53]Italy30/20−17.9 ± 7.9 vs 18.5 ± 8.1−−6
      Rezaee et al. 2017[40]Iran51/45CLS– −−6
      Ren et al. 2021[55]China62/80−13.49 ± 4.32 vs 15.75 ± 5.85< 3060/766
      Huang et al. 2018[56]China61/50CLS16.27 ± 6.99 vs 29.01 ± 9.72< 20−6
      Chi et al. 2020[57]China32/30CLS15.27 ± 5.98 vs 28.89 ± 9.58−−6
      Yang et al. 2021[58]China88/60−13.37 ± 3.49 vs 17.58 ± 5.63−−6
      Ke et al. 2021[59]China152/50CLS20.56 ± 1.4 vs 33.4 ± 6.5< 2090/67
      Wang et al. 2015[64]China31/30ELISA10.08 ± 0.44 vs 14.32 ± 3.74−−6
      Fu et al. 2021[61]China334/300−16.84 (11.81, 23.39) vs 16.66 (11.98, 22.13)< 30214/2097
      H: hashimoto thyroiditis group; C: Healthy control group; ELISA: Enzyme Linked Immunosorbent Assay; RIA: Radioimmunoassay; CLS: Chemiluminesent lmmunoassay Assay; CPBA: competitive protein binding assay; SC: Solid Chromatography, HPLC: High Performance Liquid Chromatography, EBL: Euglobulin lysis method, −: Non reported.

      Evaluation of indexes

      Serum 25(OH)D3 level

    • Meta-analysis included 33 studys with 3,161 patients in HT group and 7,488 healthy individuals in the control group for comparison. Random model indicated 25(OH)D3 levels of HT group were significantly lower than the control group (WMD: −7.44, 95%CI [−9.29, −5.60], P < 0.01). I2 test (98%) suggested significant heterogeneity in the meta-analysis (Fig. 1). The subgroup meta-analysis basing on 25(OH)D3 assays in a fixed model revealed similar results (WMDs: −0.55; 95%CI [−0.60, −0.49], P < 0.01), and its significant heterogeneity among subgroups represented by I2 = 98.3% suggested the difference of 25(OH)D3 assays was the main source of heterogeneity (Fig. 2,). Lastly, we separated the Chinese studies with 6,639 individuals (HT: 1,102 vs C: 5537) to perform another particle meta-analysis in random model. Result showed that, in the Chinese population, serum 25(OH)D3 level of HT patients was significantly lower than that of healthy individuals (WMD: −7.04, 95%CI [−10.37, −3.71], P < 0.01 ). Meanwhile, I2 = 98.0% also suggested a significant heterogeneity (Fig. 3).

      Figure 2. 

      Subgroup forest plot of 25(OH)D3 level(fixed model).

      Figure 3. 

      Forest plot of prevalence of Vitamin D insufficiency (random model).

      Prevalence of 25(OH)D3 insufficiency

    • A total of 29 studies comprising 11,795 individuals (HT: 3,709 vs C: 8,086) were pooled for OR of 25(OH)D3 insufficiency. Random model indicated HT patients had higher prevalence of Vitamin D insufficiency compared to healthy individuals (OR: 2.54, 95%CI [1.77, 3.63], P < 0.01). I2 test (86%) suggested significant heterogeneity in meta-analysis (Fig. 4). Subgroup meta-analysis in a fixed model based on different 25(OH)D3 insufficiency cut-off also revealed similar results as above (OR: 1.84; 95%CI [1.64, 2.07], P < 0.01). Meanwhile, I2 equaled to 93% suggested the main source of heterogeneity was from the different cut-off of 25(OH)D3 insufficiency (Fig. 5). Chinese studies with 1,373 individuals (HT: 700 vs C: 673) were separated to perform another particle meta-analysis in random model. Results displayed a trend that the HT population had a higher prevalence of 25(OH)D3 insufficiency compared to healthy individuals, but it was not statistically significant (P > 0.05), and meanwhile significant heterogeneity was indicated by I2 equal to 91% (Fig. 6).

      Figure 4. 

      Subgroup forest plot of prevalence of Vitamin D insufficiency (fixed model).

      Figure 5. 

      Forest plot of 25(OH)D3 level (random model, Chinese studies).

      Figure 6. 

      Forest plot of prevalence of Vitamin D insufficiency (random model, Chinese studies).

      Publication bias

    • A funnel plot of serum 25(OH)D3 level in subgroup analysis exhibited that the included studies accumulated at the top of the funnel, which suggested that publication bias may exert little adverse effect on the confidence in the meta-analysis (Fig. 7). Similarly, results of the funnel plot suggested low risk of publication bias in prevalence of 25(OH)D3 insufficiency comparisons (Fig. 8).

      Figure 7. 

      Funnel plot of 25(OH)D3 level.

      Figure 8. 

      Funnel plot of quantity of individuals with 25(OH)D3 insufficiency.

    DISCUSSION

    • The present study reinforced the close relationship between Vitamin D insufficiency and HT with methods of systematic review and meta-analysis. To our knowledge, the present systematic review summarized the most related studies to date; among them, Chinese studies, which may be ignored by other foreign researchers, were also included. Hence, we believe our conclusion produce more confident evidence for a relationship between Vitamin D insufficiency and HT.

      Although a series of related factors of HT have been revealed, the real etiology has so far not been clearly understood[62]. Vitamin D has been proved to closely relate to HT, for it plays a vital role in regulating inflammatory response and maintaining immune balance[63]. Multiple epidemiological studies suggested a close relationship between Vitamin D and HT; however, differences in quality, region and population may affect the conclusions. Therefore, high quality systematic review or meta-analysis was still needed to acquire more reliable evidence. Wang et al.[64] published a meta-analysis in 2015 to indicate the relationship between Vitamin D insufficiency and HT. Štefanić et al.[65] subsequently included more recent studies for meta-analysis and drew a similar conclusion, but their results seemed to weaken the relationship of Vitamin D insufficiency and HT compared with Wang et al.[64]. However, these two studied did not include enough recent Chinese studies which should not be ignored. This may not only decrease the confidence of the conclusions, but also weaken the reliability for Chinese researchers. To fulfill this deficiency, we included Chinese studies into the present systematic review and meta-analysis. As anticipated, the general results including serum 25(OH)D3 level and quantity of individuals with Vitamin D insufficiency displayed similar results to Wang et al.[64] and Štefanić et al.[65], which meant the relationship of Vitamin D insufficiency and HT also existed in the Chinese population. We next separated the Chinese studies to perform a particle meta-analysis. The particle result of serum 25(OH)D3 levels of Chinese HT patients were significantly lower than healthy individuals generally, but its difference was less (−7.05 vs −7.44). However, concerning the prevalence of Vitamin D insufficiency, Chinese HT patients were not likely to have more Vitamin D insufficiency cases compared to healthy individuals, suggesting the relationship between Vitamin D insufficiency and HT in the Chinese population may not be as strong as in the global population. Note that, the Chinese population in the present study was only a small part of the total, the negative result maybe due to the small sample size. Further studies with larger sample sizes and high quality investigating the prevalence of Vitamin D insufficiency in the HT population are necessary in China in the future.

      With regards to the studies included in the systematic review, most studies reported lower serum 25(OH)D3 levels and higher prevalence of Vitamin D insufficiency in HT patients compared to healthy individuals. The present study had drawn a similar conclusion, but the results contained significant heterogeneity. According to the systematic review, this heterogeneity may be due to the difference of 25(OH)D3 assays, thus we performed an analysis which separated studies with the same assay into several sub-groups. Results similarly indicated lower serum 25(OH)D3 levels in HT patients, and the most significant heterogeneity among sub-groups (I2 = 99.5%), which hinted that the heterogeneity was mainly caused by the difference in 25(OH)D3 assays. In parallel with lower serum 25(OH)D3 levels, HT patients were at higher risk of 25(OH)D3 insufficiency, indicated by our meta-analysis. Meanwhile, significant heterogeneity was indicated owing to the difference of serum 25(OH)D3 insufficiency criteria. With regard to the publication bias, we determined that heterogeneity would bring significant publication bias displayed by the funnel plot, but the results showed that the included studies accumulating at the top of the funnel; this suggested the publication bias exerted little influence on our results. However, our study also had limitations, as 25(OH)D3 level in a population could be affected by many other factors such as sunshine duration, season, area, economy, and education, which was not considered in our study. These factors may affect the conclusions of epidemiological research, and bring bias to the meta-analysis. Therefore, we can only indicate that vitamin D insufficiency was related to HT. Whether vitamin D insufficiency could lead to HT should be further investigated by biological research in the future.

      Until recently, further investigations focussed on the HT mechanism in which vitamin D was involved. As is well understood, T lymphocytes including Th1, Th2 and Th17 cells infiltrate the thyroid gland due to immunological disorders in HT patients. Vitamin D can inhibit the differentiation of Th1 cells, and the production of inflammatory cytokines such as TNF-α, INF-γ. It could also suppress inflammatory Th1, but induce anti-inflammatory Th2 which produced anti-inflammatory cytokines such as IL-4 and IL-5[66]. Furthermore, the Th17 cells with their production of IL-17A could also be inhibited by Vitamin D at the transcriptional level[67]. On the other hand, vitamin D could increase the proportion of Treg cells to exert immune regulation[68]. Taken together, vitamin D may have the potential to prevent HT. However, clinical studies have shown contradictory results: Chahardoli et al.[69] reported activated vitamin D supplementation can decrease TSH and TG-Ab antibodies levels in HT patients, but another study showed that activated vitamin D supplementation had no effect on improving HT[70]. To our knowledge, the studies mentioned above may ignore the vitamin D receptors polymorphism. Vitamin D receptors in the thyroid gland have single nucleotide polymorphism and most typical Apal, Bsml, Fokl and Taql single nucleotide variations have been shown to be closely related to autoimmune diseases[71]. Therefore, more prospective studies are needed to confirm the preventive effect of vitamin D on HT.

    CONCLUSIONS

    • In conclusion, the present systematic review and meta-analysis strengthened the relationship between vitamin D insufficiency and HT. HT patients potentially had higher propensity for having lower serum 25(OH)D3 levels compared to healthy individuals. Clinical staff may have to carefully consider the possibility of vitamin D insufficiency in HT patients.

      Conflict of interest

      • The authors declare that they have no conflict of interest.

      Rights and permissions
      • Copyright: © 2023 by the author(s). Published by Maximum Academic Press on behalf of Nanjing Agricultural University. This article is an open access article distributed under Creative Commons Attribution License (CC BY 4.0), visit https://creativecommons.org/licenses/by/4.0/.
    Figure (8)  Table (1) References (71)
  • About this article
    Cite this article
    Liu Z, Feng L, He Y, Yuan S, Xu C. 2022. The Association between Vitamin D and Hashimoto Thyroiditis: An Up-to-date Systematic Review and Meta-analysis. Food Materials Research 2:9 doi: 10.48130/FMR-2022-0009
    Liu Z, Feng L, He Y, Yuan S, Xu C. 2022. The Association between Vitamin D and Hashimoto Thyroiditis: An Up-to-date Systematic Review and Meta-analysis. Food Materials Research 2:9 doi: 10.48130/FMR-2022-0009
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  • Introduction
  • Methodology

  • Bibliographic search

  • Inclusion criteria

  • Data extraction

  • Statistical analysis

  • Results

  • Search results

  • Evaluation of indexes

  • Serum 25(oh)d3 level
  • Prevalence of 25(oh)d3 insufficiency
  • Publication bias
  • Discussion
  • Conclusions
  • Conflict of interest
  • Rights and permissions
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