A critical review on the health promoting effects of mushrooms nutraceuticals

Goxing M,Wenjin Yng,Liyn Zho,Fei Pei,Donglu Fng,Qiuhui Hu,,*

a College of Food Science and Technology,Nanjing Agricultural University,Nanjing,Jiangsu,210095,China

b College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing,Nanjing University of Finance&Economics,Nanjing,Jiangsu 210023,China

ABSTRACT Extensive elucidations focusing on the efficient health promoting properties and high nutritional values of mushrooms have been expanded dynamically from the past few decades.Due to its high quality of proteins,polysaccharides,unsaturated fatty acids,mineral substances,triterpenes sterols and secondary metabolites,mushrooms have always been appreciated for their vital role in protecting and curing various health problems,such as immunodeficiency,cancer,inflammation,hypertension,hyperlipidemia,hypercholesterolemia and obesity.Moreover,investigations in recent years have revealed the correlations between the health-promoting benefits and gut microbiota regulating effects induced by the mushrooms intake.Researches on the immense role in the nutritional and health benefits displayed by mushrooms have become an emergent task to study.The present article overviewed and compiled the latest information correlated to the health benefits and underlying functional mechanisms of mushroom nutraceuticals,and concluded that the supplementation of mushrooms as a dietary composition could become a natural adjuvant for the prevention and treatment of several health diseases.

Keywords:Mushrooms Bioactive nutraceuticals Health benefits Functional mechanisms Gut microbiota regulation

1.Introduction

As a kind of macro fungi,mushrooms have been cultivated and consumed by mankind for dozens centuries because of the attractive sensory characteristics[1],abundant nutritional compositions[2],multiple functional activities [3]and manageable cultivate conditions [4].According to different usages by the consumers,the most cultivated mushroom species were divided into edible mushrooms with the representatives ofPleurotus ostreatus,Lentinula edodes,Agaricus bisporus,Flammulina velutipesandAuricularia auricular,and medicinal mushrooms mainly includeGanoderma lucidum,Cordyceps sinensisandPoria Cocos.China was documented as the earliest country to cultivate mushrooms all around the world,as well as one of the countries with the highest mushrooms production along with the United States,Italy,The Netherlands,and Poland.Particularly,civilizations from China,Early Greek,Egypt,Roman and Mexico were treated and appreciated mushrooms as functional culinary delicacies and even as medicine for a long history[5].

Knowledges about the bioactive compositions and nutritional values of different mushrooms have been increased massively significant in the past several years,from which the mushrooms were defined as a potential functional food with the high content of dietary fiber and low level of fat.Moreover,the high quality of proteins including most of the essential amino acids were also found in mushrooms,as well as the numerous vitamins and mineral substances [6].Specifically,the bioactive nutraceuticals detected in mushrooms were polysaccharides[7,8],proteins[9],glycoproteins[10],unsaturated fatty acids[11],phenolic compounds[12],tocopherols[13],ergosterols[14],lectins[15]etc.Multitudinousstudies focusing on the health and therapeutic benefits of mushrooms specific bioactive nutraceuticals have been carried out in recent years,including the immune function enhancement,antitumor,antiinflammation,antioxidant,antifungal,antibacterial and antiviral activities [16].Moreover,mushroom have also been proved owes the abilities of attenuating the health hazards induced by obesity,hypotensive,hypolipedemic,hypertension and the impaired functions caused by aging[17-21].

According to the descriptions above,knowledges concerning the health benefits and functioning mechanisms of mushrooms supplementation have become an intriguing interest in the food nutrition area,and contributed to the formulation of the more balanced diet pattern by all human,which will exploit a new way for the prevention even cure some major diseases,such as cancer,heart and nervous problems.In this context,we aimed at giving an overview and summarization of the nutritional and therapeutic benefits of mushrooms in the present review,including the bioactive nutraceuticals in mushrooms and their functioning mechanisms,which could be conducive to the better understanding of the correlations between the mushroom consumption and health improvement,and evaluate the advantages of the insertion of mushrooms into human diet,consequently.

2.Molecules obtained from mushrooms with bioactive functions

The molecules obtained from mushrooms with bioactivities,including their preparation methods and structure characterizations,have been investigated by numerous scientists all around the world,which were mainly belonged to polysaccharides,proteins,terpenes,phenolic compounds and unsaturated fatty acids,and could be used during the biotechnological processes,even for the exploitation of newly intelligent drugs[22].The representative achievements were dietary fibers,proteases and protease inhibitors,ribosome-inactivating proteins and hydrophobins,respectively[23].Moreover,researches focusing on the origin bioactive nutraceuticals,such as the polysaccharides and proteins,could also contributed to the development of potential functional foods with high qualities and nutritional values.The present review will summarize and discuss the preparation methods and structure characterizations of such active compounds in detail.2.1.Polysaccharides

Polysaccharides were known as one of the most potent and common compounds derived from mushrooms,and exhibit numerous health benefits activities.Some of the mushrooms polysaccharides have been developed and exploited as functional food substances,including the lentinan fromLentinus edodes,schizophyllan fromSchizophyllumcommune,pleuran fromPleurotus species,calocyban fromCalocybe indicaand ganoderan fromGanoderma lucidium,most of which were proved and considered as the outstanding representatives of D-glucans with the common(1→3)or(1→6)βlinked glucose backbones and distinguished by different patterns and degrees of branches [24,25].The most common monosaccharides detected in mushrooms polysaccharides were glucose,galactose,fructose,xylose,mannose,fucose,rhamnose,arabinose,trehalose and mannitol [22].A large amount of studies have investigated and revealed the potential abilities of mushrooms polysaccharides on such biological activities as Table1 shows.Overall,antitumor,immunomodulatory and anti-inflammatory activities of mushrooms polysaccharides were the top 3 health benefits investigated by researchers,from which we could confirmed that the activation of dendritic cells,monocytes,neutrophil,natural killer cells,cytotoxic macrophages and cytokines(interleukins,interferons,and colony stimulating factors) were the common functioning mechanisms of different mushrooms polysaccharides which involved in these three activities[26].

Moreover,studies focusing on the health benefits of mushrooms polysaccharides through the regulation of gut microbiota,as well as the gastrointestinal function,have generated considerable interest by the scientists all around the world[27].Basically,most of the mushrooms polysaccharides have been proved as dietary fibers and displayed an interaction process with the colonized microbiota in gastrointestinal tracts,which could altered different variations of gut microbiota and impacted the host health level,consequently[28].Specifically,polysaccharides obtained from mushrooms could be degraded by the gut microbiota and absorbed as energy source for some specific bacterial groups,which displayed stimulation effects on their propagation and production of beneficial compounds,mainly including the short chain fatty acids(SCFAs),such as acetate,propionate,butyrate and valerate acid [29,30].Specifically,study has revealed thatG.lucidumextracts,which were mainly composed of polysaccharide,owed the ability of raising the abundance ofBifidobacteriaduring the fermentation process[31].Moreover,the abundances of the bacteria with health benefits to host,such aslactobacillus,roseburiaandlachnospiraceaewere increased significantly by the daily supplementation ofG.lucidumpolysaccharide strain S3[32].

On the other side,such health problems as the autoimmune diseases,allergic disorders,inflammatory bowel disease,irritable bowel syndrome,ulcers,colorectal cancer,necrotizingenterocolitis and obesity,have been testified related to the gut microbiota during the past few years [33].From which the alterations of mushrooms polysaccharides on gut microbiota might be the new direction to reveal its function mechanisms.Since 2005,Wong et al found that β-glucans obtained from mushrooms can be utilized by the colonized bacteria of human colon,which displayed the potential to improve human gut health by selectively changing the abundances of bacteria includingbifidobacteriaand lactic acid bacteria [34].Studies have revealed that polysaccharide ofL.edodesrejuvenates mice in terms of gut microbiota community structure,such as the ratio reduction ofFirmicutes/Bacteroidetes,the reducedBacteroidiaabundance and the decreasedBacilliandBetaproteobacteria[35].Chih-Jung Chang et al proved that high molecular weight polysaccharides (＞300 kDa) isolated from the water extracts ofG.lucidummycelium produce antiobesity and microbiota-modulating effects,such as reduced body weight,inflammation and insulin resistance in mice fed a high-fat diet,and decreasedFirmicutes/Bacteroidetesratios and endotoxinbearingProteobacterialevels [36].Researches have reported that administration ofInonotus obliquuspolysaccharide could regulate gut microbiota composition and diversity to a healthy profile in mice with chronic pancreatitis [37].In our previous studies,the in vivo fermentation ofP.eryngiipolysaccharide and its effects on fecal microbiota composition and immune response were investigated and thePorphyromonadaceae,Rikenellaceae,BacteroidaceaeandLactobacillaceaeabundances were all increased in associated with the immune response alteration[29].Throughout most of the published reports,more studies are needed in the future to reveal more relationships between the health benefits alteration and gut microbiota regulation induced by mushrooms polysaccharides supplementation.2.2.Proteins and peptides

Studies have revealed that the protein content in dry mushrooms was 228 and 249 g/kg dry matter(Dry Weight),which was much higher than other protein sources [38].Proteins and peptides are significant bioactive nutraceuticals in mushrooms with multiple health benefits,such as the enhancement of the digestion and absorption of exogenous nutritional ingredient,the modulation of the immune function to help the host defending the invasion of pathogens,and the activities inhibition of some enzymes [22].Overall,the proteins and peptides in mushrooms with pharmaceutical potential have been found and named as lectins,fungalimmunomodulatory proteins(FIPs),ribosome inactivating proteins(RIPs),ribonucleases and laccases [39],moreover,the bioactive proteins and peptides from the common mushrooms have been identified since last century by the researchers [40-42].Specifically,lectins have been demonstrated as the nonimmune proteins or glycoproteins binding to the carbohydrates of cell surface,which possess the significant activities ofimmunomodulatory properties,antitumor,antiviral,antibacterial,and antifungal [15].FIPs are a novel family of bioactive proteins obtained from mushrooms with the potential of be utilized as adjuvants for tumor treatment due to their significant activity in suppressing the invasion and metastasis of tumor cells [43].The RIPs are a category of enzymes that could inactivate ribosomes by eliminating one or more adenosine residues from rRNA.Studies focusing on the biological activities of RIPs have found that RIPs owes the ability ofinhibiting the HIV-1 reverse transcriptase activity and fungal proliferation [44].Ribonucleases extracted from mushrooms have been proved an significant inhibition on the proliferation of Staphylococcus aureus,Pseudomonas aeruginosaandPseudomonas fluorescensat the RNA level [45].Laccases are a widespread class of enzymes,and have been certified relating to the pathogenesis,immune genesis and morphogenesis of organisms.Moreover,Laccases have also been found the turnover ability of complex organic substances metabolic[39].

Table1 The discovered mushroom polysaccharides with health benefits.

The research findings of the bioactive proteins and peptides obtained in mushrooms in the past few years were listed in Table2,from which we could found that lectins and FIPs were the two major category proteins and most of the bioactive proteins and peptides were isolated from the medical and rare mushrooms in the past two years.Among the list literatures,we could confirm that most of the bioactive proteins and peptides were related to the anti-tumor,antiviral,anti-inflammation and immunomodulation activities and owes the ability being potential candidates for the treatment in suppressing tumor invasion and metastases [43,46].Particularly,function studies,mainly the anti-tumor and immunomodulation activities,were focusing on most of the identified proteins and peptides were carried out utilizing the hepatoma HepG2 cells,human leukemic T cells,and breast cancer MCF7 cells;on the other side,the anti-viral activity studies were the inhibition effects on the reverse transcriptase activity of the immunodeficiency virus(HIV-1).

In addition,along with the interests of researchers focusing on the relationship between gut microbiota and health situation increasing during the past years,the health effects of gut microbiota regulation induced by the functional proteins and peptides have been investigated and illustrated.For example,the effects of the quantity and source of dietary protein on microbiota composition,bacterial metabolite production,and consequences for the large intestinal mucosa in humans were evaluated by Martin Beaumont et al,from which they concluded that high protein diets induced a shift in bacterial metabolism towards amino acid degradation with different metabolite profiles according to the protein source[47].Yingying Zhu et al collected colonic contents from the growing rats fed with casein,beef,chicken or soy proteins for 90 days,and revealed that meat protein intake may maintain a more balanced composition of gut bacteria and reduce the antigen load and inflammatory response from gut bacteria to the host [48].However,the correlations between proteins and peptides isolated from mushrooms and gut microbiota were lacking studies in the recent years.A single-band protein(HEP3)exhibited immunomodulatory activity in lipopolysaccharide-activated RAW 264.7 macrophages by decreasing the overproduction of cytokines was isolated from Hericium erinaceus and further studies revealed that HEP3 could improve the immune functions via regulating the composition and metabolism of gut microbiota in mice[49].Researches on the aspect required in-depth and further study in the future,which will reveal the novel mechanisms of the mushrooms proteins and peptides on human health modulation.

2.3.Terpenes

The terpenes obtained from mushrooms are considered as a cluster of volatile unsaturated hydrocarbons,which are classified as monoterpenoids,sesquiterpenoids,diterpenoids and triterpenoids [50].Researchers have investigated numerous types of sesquiterpenoids obtained from mushrooms,including aristolane,bisabolane,cuparene,drimane,fomannosane,lactarane,nordasinane,spiro,sterpurane.The mushroom diterpenoids was mainly detected as cyathane type,whereas most of the triterpenoid compounds isolated from mushrooms were lanostane type [50].Moreover,the mushroom terpenes have been proved associating with multiple health benefits,including antioxidant[51],antiviral[52],anticancer[53,54],anti-inflammatory[55,9],antimalarial[56]and anticholinesterase[57]activities.

Specifically,the terpenes isolated from mushroom species and their health benefits are showed in Table3.As shown in Table3,few researches were focusing on the isolation and functional activities of mushroom monoterpenoids,whereas multiple sesquiterpenoids,diterpenoids and triterpenoids were obtained from many mushrooms species,mainly includingF.velutipes,PleurotusandGanodermaspecies.Specifically,flammulinol and flammulinolides were the two main terpenes isolated fromF.velutipeswith the cytotoxicity against three tumor cell lines namely; HepG2,HeLa and KB,whereas terpenes fromPleurotusspecies were revealed significant bioactivities to the host,such as the five monoterpenoids and two sesquiterpenoids with anti-inflammatory activities isolated from Pleurotus cornucopiae.Particularly,methyl ganoderate A acetonide and n-butyl ganoderate H fromG.lucidumwere found owes the ability of anti-acetylcholinesterase activity,from which the pharmaceutical companies developed possible drugs for the treatment of Alzheimer’s and related neurodegenerative diseases[58].

2.4.Phenolic compounds

Overall,the mushroom phenolic compounds,mainly including the phenolic acids,flavonoids,hydroxybenzoic acids,hydroxycinnamic acids,lignans,tannins,stilbenes,and oxidized polyphenols[59],were considered as aromatic hydroxylated compounds with one or more aromatic rings and one or more hydroxyl groups.Literatures have reported that the most significant bioactivity of phenolic compounds was antioxidant activity in biological systems,acting as free radical inhibitors,peroxide decomposers,metal inactivators,or oxygen scavengers [60,61].Specifically,phenolic compounds provide protection against several degenerative disorders,including brain dysfunction,aging,and cardiovascular diseases.These health benefits were mainly related to their capacity of scavenging free radicals and reactive oxygen species,which is essential for the biological processes and molecular functions ofliving organisms [62].The phenolic compounds in mushrooms displayed excellent antioxidant capacity.The phenolic compounds and their antioxidant capacity of eight mushrooms includingA.bisporus,Boletus edulis,Calocybe gambosa,Cantharellus cibarius,Craterellus cornucopioides,Hygrophorus marzuolus,Lactarius deliciosusandPleurotus ostreatuswere evaluated,from which 1-6 mg phenolics were extracted from 1 g of dried matter mushrooms and all of the obtained phenolics were displayed an significant inhibition effect against the lipid oxidation [63].Elhadi M.Yahia et al analyzed the phenolic compounds of seventeen species of wild mushrooms and detected their antioxidant activities by FRAP and DPPH assays,suggesting an effective nutritional and health value of different mushroom species[64].Accounting for the phenolic compounds contents and their antioxidant activities of mushrooms,researchers have turn their attentions on the brain protecting activities of mushrooms.Qiuhui Hu et al investigated the neuroprotection of six components fromF.velutipes,which were mainly phenolic compounds,on H2O2-induced oxidative damage in PC12 cells,and demonstrated that most of the components displayed an neuroprotective effects,along with their antioxidant activities[65].Darija Cor et al evaluated the anti-acetylcholinesterase activity of Ganoderma Lucidum extracts,which were mainly composed of phenolic compounds[66].

On the other hand,numerous studies have revealed the bioactivities of mushroom phenolic compounds,such as the antiinflammatory,antimicrobial,anticancer,and antiviral effects over the past few years.Three phenolic compounds were obtained from the edible mushroomPhellinus baumii Pilat(Hymenochaetaceae),and owed the ability ofinhibiting LPS-stimulated nitric oxide(NO) production in RAW264.7 cells [67].Kun Liu et al characterized the polyphenolic compounds inInonotus sanghuangand proved their antiproliferative and antimicrobial activities,including the strongest antiproliferative effect against tumor cell PC3 and gram-positive bacteria[68].Hispidin,a phenolic compoundderived from the mushroom Phellinus species,has been found possessing distinct anti-inflammatory activities through suppressing ROSmediated NF-κB pathway in mouse macrophage cells[69].Another phenolic compound named hispolon was isolated from the mushroomPhellinus linteus,with the anti-inflammatory mechanisms of decreasing in the level of MDA in the edema paw through increasing the activities of SOD,GPx and GRx in the liver,as well as the suppression of TNF-α and NO [70].Moreover,hispolon extracted fromPhellinusspecies induce epidermoid and gastric cancer-cell apoptosis and regardless of p53 status,hispolon inhibited breastand bladder-cancer cell growth[71].The dichloromethane extract of G.lucidum composed with flavonoids,terpenoids,phenolics,and alkaloids displayed anti-human papillomavirus 16(HPV 16)E6 oncoprotein activity.Epidermoid cervical carcinoma (CaSki) cells when treated with the crude dichloromethane extracts HPV 16 E6 production was suppressed[72].

Table2 The present research findings of bioactive proteins and peptides obtained from mushrooms.

2.5.Polyunsaturated fatty acids

As the most common lipid in mushroom,polyunsaturated fatty acids have been proved contributing to the reduction of serum cholesterol [22].Interestingly,trans isomers of unsaturated fatty acids have not been detected in mushrooms.The major sterol produced by mushrooms was detected as ergosterol,which displayed the significant antioxidant properties [73].Moreover,researches have demonstrated the critical role of a sterols rich diet in the prevention of cardiovascular diseases [74].Another polyunsaturated fatty acid was detected as tocopherols,which were considered as novel and effective natural antioxidants because their free radical scavenging peroxyl components produced from different reactions.These antioxidants have high biological activity for protection against degenerative malfunctions,microbial,and cardiovascular diseases [61,75,76].Linoleic acid,also displayed as an important fatty acid fraction to humans,was also isolated from mushrooms,and participating in multiple physiological functions,especially the reduction ofinflammatory level through inhibiting the NO production and suppressing the expression of pro-inflammatory cytokines including TNF-α,IL-6,IL-1β,and NOS2 in RAW 264.7 cells [77],and the decreasing impact on the Alzheimer’s disease risk correlating with its inhibition effects against on the acetylcholinesterase(AChE)and butyrylcholinesterase(BChE)[78].

3.The use of mushrooms as functional foods

The mushrooms were not being consumed as dietary food but also considered as an important and valuable resource for the development of functional food,even the life threaten diseases preventing products by scientists and the pharmaceutical companies according to the revealed pharmacological medical properties,which was helpful in the early intervention of the sub-healthy states in host.Researches focusing on the novel functional foods or health protecting drugs production by the utilization of fruit bodies,mycelia and the extracts obtained through different preparation methods of mushrooms have become a common and effective direction.The addition of mushroom speciesA.bisporuscombined with dried dates were found displayed an increasing impact on the nutrients quality of white bread,including the improvement of protein,iron and all the other nutrients contents[79].Moreover,another published literature investigated the quality characteristics ofA.bisporuspowder enrichment in sponge cake,and found an better nutritional value with more acceptable sensory in theA.bisporuspowder enrichment cake [80].The milk mixed with residue from a hydroalcoholic extract ofAgaricus blazeidisplayed an stronger antioxidantactivityafter in vitro digestion process[81].Lei Zhong et al mixed cereal grains withCordyceps militarisand developed an extruded product.By the utilization of exercise-induced fatigue animal model,the new extruded product was detected a significant enhancement of anti-fatigue property compared to the product of cereal grains[82].

In addition to the participation in the production of functional food,the mushroom bioactive nutraceuticals were majoring studied and developed as dietary supplements,which could inhibit the high risking of some threaten disease and protect the body from the damage of some disadvantageous environment.The proteoglycan constituents detected inTrametes versicolor,such as the Krestin and polysaccharide peptide,were all utilized in the production for drugs with anticancer activities[83].A significant mushroom species for the development of functional dietary supplements wasG.lucidum,a typical medical mushroom of the world.Specifically,G.lucidumand its bioactive polysaccharides were proved owes multiple health benefits,including the repression for the injury of ethanolinduced steatohepatitis via anti-inflammation,anti-oxidation and reducing hepatic lipid in mice [84],immunomodulatory activity purified T Lymphocytes through Ca2+/CaN and mitogen-activated protein kinase pathway[85],inducing the activation and maturation of murine myeloid-derived dendritic cells[86],and inhibiting prostate cancer cell migration via the protein arginine methyltransferase 6 signaling pathway [87].Moreover,with the increasing knowledge of the relationship between host health level and gut microbiota,theG.lucidumpolysaccharides were detected as an ideal and efficient prebiotic for the colonized microbiota in host gastrointestinal tracts (GITs).For example,polysaccharide from mycelia ofG.lucidumwere found increasing the richness of gut microbiota and modulating gut bacterial composition,as well as regulating the intestinal immunological barrier functions of rats[88].S Xu et al revealed that theG.lucidumpolysaccharides owes the ability ofimproving insulin sensitivity by regulating inflammatory cytokines and gut microbiota composition in mice [89].Not only theG.lucidum,theP.eryngiipolysaccharide was also investigated with the significant fecal microbiota composition and immune response regulation activities[29].

Beside the description above,the mushroom species such asI.obliquus,Hericium erinaceus,Antrodia Camphorata,Grifola frondosaandF.velutipeswere all studied and considered as the raw material for the development of potential functional foods.Extract fromI.obliquus was approved as an antitumor components,which was owing to its capability in curing certain cancers like breast,lung,and stomach cancers [90].Functional foods developed fromH.erinaceushave been extensively utilized in the treatment of neurological pathological changes,such as the Alzheimer diseases.Hericenones obtained from the fruit bodies and erinancines isolated from the mycelium ofH.erinaceusdisplayed an significant reduction of the expression of neurotrophic factors such as nerve growth factor(NGF)[83].Since countless researches were focusing on the investigation of novel and efficient products based on the bioactivities of mushroom,deeper research is still needed for the demonstration of the correlation between the functional activities and mechanisms,as well as their safety evaluation and safe range ofintake.

4.Conclusion

The present review described the main bioactive nutraceuticals obtained from mushrooms,as well as the represent host health benefits,suggesting the mushrooms could considered as a valuable,complete and suitable health dietary food,which could be consumed by all age groups depending on its richness in polysaccharides,proteins and other functional ingredients with multiple bioactivities.Moreover,the mushrooms,along with the numerous bioactive nutraceuticals,could also be utilized as the efficient material for the development of functional foods based on the immense nutritional supremacy.Such bioactive molecules like polysaccharides,terpenoids,proteins and polyphenols,which displayed a critical role in enhancing the immune strength,lowering and preventing risks of cancers,inhibiting the proliferation of tumor cells growth,protecting the nervous system from the damage of aging etc.Moreover,the prebiotic effects estimated by mushrooms were attracting the main attentions of the researchers all around the world,especially the correlations between the gut microbiota structure regulation and host health problems,including the gut immune function,obesity,gut inflammation,colonic cancer and neurological diseases.Overall,we could confirm that the spectrum of various health benefits activities generated by the mushrooms were heterogeneous and it is anticipated that with the current knowledges and advancements in nutrigenomics and molecular nutrition,mushrooms could consume as one of the best acceptable nutraceutical food for the daily supplementation.However,more information and new aspects focusing on its physiological properties,which could gain a better perceive in the functional foods development process,are still needed in the future.

Conflict ofinterest statement

The authors report no conflict ofinterest.

Acknowledgements

This work was supported by China Agriculture Research System(CARS-20).