Effects of fungal based bioactive compounds on human health: Review paper

Abstract

Since the first years of history, microbial fermentation products such as bread, wine, yogurt and vinegar have always been noteworthy regarding their nutritional and health effects. Similarly, mushrooms have been a valuable food product in point of both nutrition and medicine due to their rich chemical components. Alternatively, filamentous fungi, which can be easier to produce, play an active role in the synthesis of some bioactive compounds, which are also important for health, as well as being rich in protein content. Therefore, this review presents some important bioactive compounds (bioactive peptides, chitin/chitosan, β-glucan, gamma-aminobutyric acid, L-carnitine, ergosterol and fructooligosaccharides) synthesized by fungal strains and their health benefits. In addition, potential probiotic- and prebiotic fungi were researched to determine their effects on gut microbiota. The current uses of fungal based bioactive compounds for cancer treatment were also discussed. The use of fungal strains in the food industry, especially to develop innovative food production, has been seen as promising microorganisms in obtaining healthy and nutritious food.

Graphical Abstract

Highlights

1. Fungal-based bioactive compounds have various health benefits.

2. Prebiotic fungi play an active role in the regulation of gut microbiota.

3. Anti-tumor effective fungal components will contribute to alternative medicine.

4. Beta-glucan and chitin are the most promising fungal metabolites for cancer treatment.

Keywords:

• Bioactive compounds
• health benefits
• fungal biomass
• functional food
• gut microbiata
• anti-cancer

Introduction

Mushrooms are one of the foods that have been widely consumed as food since the first periods of history, used for health, and even considered sacred by some cultures (Bernart, Chang and, and Miles 2005). Even in the oldest civilizations of history, mushrooms have a special place; The Greeks believed that it gave strength to the soldiers, and in wars, the soldiers were fed mushrooms. The Romans, on the other hand, sanctified the mushroom even more and saw it as the ‘food of the gods’ and therefore consumed it on special days and holidays. In Chinese culture, mushrooms have been seen as a healthy food for centuries and have even been called the ‘elixir of life’ (Ogidi, Oyetayo, and Akinyele 2020). Mushrooms which have taken their place in health studies for centuries, have recently; it is preferred more in scientific studies for reasons such as easier production and increased efficiency and storage conditions (Bernart, Chang and, and Miles 2005).

Filamentous fungi such as mushrooms have been used traditionally for many years to obtain high-protein food products by the fermentation of agricultural products such as rice and soybeans, especially in Indonesia, Japan, China and Korea. Zygomycete Rhizopus oryzae, R. delemar, R. oligosporus species have been used in the preparation of fermented foods such as tempeh. Ascomycetes Aspergillus oryzae (it’s fermented products are shoyu, miso, and hamanatto), Neurospora intermedia (it’s fermented product is oncom) and Monascus purpureus (it’s fermented product is red rice) are also fungal species used to produce traditional fermented products (Denny, Aisbitt, and Lunn 2008; Filho, Andersson, et al. 2019; Moore and Chiu 2001; Sar, Ferreira, et al. 2020). Alternatively, the biomass produced by Fusarium venenatum currently provides an alternative protein source as Quorn^TM containing 50% protein in the market (Gmoser et al. 2020; Wiebe 2002). Single-cell protein obtained from these fungal species (mycoprotein) is known as generally recognized as safe (GRAS) (Sar, Larsson, et al. 2022).

Filamentous fungi can be grown not only in cereal products but also in various food by-products (Table 1) since they can secrete many different enzymes (amylase, invertase, cellulase, xylanase, lipase, and protease) (Awasthi, Harirchi, et al. 2022; Ferreira et al. 2016). It is possible to obtain biomass abundantly after a short incubation period using these wastes from laboratory-scale shake-flasks to industrial-scale fermenters (Rousta, Hellwig, et al. 2021; Sar, Larsson, et al. 2022). Moreover, different cultivation strategies such as submerged or solid-state fermentation can be utilized for fungal biomass production (Awasthi et al. 2023). In addition, the obtained fungal biomass can be evaluated as a food and/or animal feed source according to its composition (protein, fatty acid, mineral, etc.) and the type of substrate used (Sar, Larsson, et al. 2022; Strong et al. 2022; Uwineza et al. 2021). Moreover, the biomass obtained from oat flour and bread left over from the market has become an alternative food product such as hamburger (Hellwig et al. 2020; Rousta, Hellwig, et al. 2021; Rousta et al. 2022).

Table 1. Potential food industry based substrates for fungal biomass production.

Food industry wastes/by-products	Filamentous fungi	Finding results	References
Potato-based starch water	Aspergillus oryzae Rhizopus oryzae	12 g/L of dry biomass with 35% of protein content	(Filho, Zamani, et al. 2019)
Potato Protein Liquor	R. oryzae	65 g of fungal biomass per liter of PPL with 70 g/kg total Kjeldahl nitrogen content	(Filho, Zamani, and Taherzadeh 2017)
Potato Protein Liquor	R. delemar	Fungal biomass (containing 53% protein, 41% essential amino acids and 33% polyunsaturated fatty acids) was produced in demo-scale reactor.	(Sar, Larsson, et al. 2022)
Bread leftover	Neurospora intermedia R. oryzae R. oligosporus R. delemar	Evaluation of surplus food to nutritious food Improvement of protein content (from 13% to up to 36%) of the leftover bread	(Gmoser et al. 2020; Hellwig et al. 2022; Svensson et al. 2021; Wang et al. 2021)
Oat husk	A. oryzae	4.62 g/L biomass containing 10.27% protein	(Sar, Arifa, et al. 2022)
Pea by-product	A. oryzae Fusarium venenatum Monascus purpureus N. intermedia R. oryzae	A. oryzae had the best regarding protein contents of fungal biomass	(Souza Filho et al. 2018)
Brewers’ spent grain (BSG)	A. oryzae N. intermedia R. delemar	The protein content of BSG was increased from 22.6% to 34.6%.	(Parchami, Ferreira, and Taherzadeh 2021)
Thin Stillage	N. intermedia A. oryzae N. intermedia	A. oryzae had highest biomass 19 g/L containing 48% (w/w) crude protein.	(Ferreira, Lennartsson, and Taherzadeh 2014, 2015)
Vinasse	A. oryzae N. intermedia R. oryzae	Protein contents between 44.7% to 57.6% The fungal biomass potentially used for aquaculture feed applications.	(Karimi et al. 2019; Nair and Taherzadeh 2016)
Olive oil mill water	A. oryzae N. intermedia R. delemar	A.oryzae had best productivity of fungal biomass The protein content was between 15% to 45%	(Sar, Ozturk, et al. 2020)
Fish industry side streams	A. oryzae R. oryzae	220-480 kg of biomass containing 33–62% protein was produced per ton of COD.	(Sar, Ferreira, et al. 2020; Sar, Ferreira, and Taherzadeh 2021)
Dairy industry (expired milk, fat-rich substrate, and dairy waste)	A. oryzae N. intermedia	Protein-rich biomass was produced. COD levels were reduced	(Mahboubi et al. 2017a, 2017b; Thunuguntla et al. 2018)

Fungi are very rich in easily digestible protein content, polyunsaturated fatty acids antioxidants, dietary fiber, vitamins, and minerals (Alberti, Foster, and Bailey 2017; Grangeia et al. 2011). The bioactive compounds produced by fungi can be divided into two groups: high molecular weight compounds (e.g., polysaccharides and enzymes) and low molecular compounds (e.g., phenolic compounds). As the common feature of these two groups that we have separated; thanks to the immunomodulator ability of these components show some biological activities such as antiallergic, antibacterial, antiviral, antioxidant, anticancer, neuroprotective, anti-inflammatory or hypoglycemic effects (Gargano et al. 2017; Madhu et al. 2022; Varsha et al. 2022).

This study aimed to investigate the production and potential benefits of bioactive compounds (bioactive peptides, chitin/chitosan, β-glucan, gamma-aminobutyric acid, L-carnitine, ergosterol and fructooligosaccharides) synthesized by fungal species. In addition, potential probiotic and prebiotic fungi on gut microbiota were also mentioned. Moreover, the effects of bioactive compounds derived from fungi on health benefits were discussed in detail.

Bioactive compounds in fungi and their health benefits

Mushrooms and filamentous fungi are rich in protein, fibers, lipids, minerals and vitamins which are essential for human diet (Awasthi et al. 2023; Gmoser et al. 2020; Heleno et al. 2013; Sar, Larsson, et al. 2022). In addition, filamentous fungi can synthesize some important metabolites and components such as bioactive peptides, chitin/chitosan, β-glucan, gamma-aminobutyric acid, L-carnitine, ergosterol and fructooligosaccharides. These bioactive compounds synthesized by fungal strains are important in human nutrition and can play a critical role in the prevention of different diseases (Tables 2 and 3).

Table 2. Fungal based bioactive peptides and their potential health effects.

Fungi	Bioactive peptides*	Bioactivity(Health effect)	Source	References
Aspergillus oryzae	H-F-N-I-G-N-R-C-L-C at the N. terminus	Anticancer	Shellfish	(Cheong et al. 2013)
A. oryzae, S. cerevisiae	VPP, IPP	Anti-hypertensive	Fermented casein derived miso paste	(Inoue et al. 2009)
Aspergillus sp.	QYP	Antioxidant	Pork, koji; rice with. and salt, fermented meat source	(Ohata et al. 2016)
A. sojae	AW, GW, AY, SY, GY, AF, VP, AI, VG	ACE inhibitory	Fermented soybean seasoning	(Nakahara et al. 2010)
R. oligosporus	AV, GL, GF, PL, AP, DM, PAP, DY, IAK, ALEP, VIKP, RIY	Antihypertensive	Tempeh	(Tamam et al. 2019)
	KP, MY	Antioxidant
	PS, SV, AE, SI, EP, HV, VH, PF, RN, NR, DY and HF	Antidiabetic
	EF	Antitumor
Aspergillus oryzae	Peptides with inhibitory effect on alpha amylase and amyloglucosidase	Antidiabetic	Lentil flour	(Magro et al. 2019)
A. egyptiacus	FIG	Antihypertensive	Douchi	(Zhang et al. 2006)
R. microspores	The sequence is not identified	Antioxidant Antimicrobial	Tempeh	(Gibbs et al. 2004),
Monascus pilosus	–	ACE inhibitory	Fermented soybean	(Pyo and Lee 2007)
A. oryzae	–	Antimicrobial	Meju
A. oryzae, R. chinensis	–	Antithrombic	Rice	(Shirasaka et al. 2012; Xiao-Lan et al. 2005)
Rhizopus sp. and Fusarium sp.	–	Antithrombic	Soybean	(Sugimoto et al. 2007)
Rhizopus microsporus	–	–	Soy (1%), Peptone (1%) and dextrin (2%)	(Zhang et al. 2015)
N. sitophila, M. subtilissimus	–	–	Soybeans and Wheat Bran	(Lan Liu et al. 2016; Clementino et al. 2019)

* A: Alanine, R: Arginine, N: Asparagine, D: Aspartic acid, C: Cysteine, E: Glutamic acid, Q: Glutamine, G: Glycine, H: Histidine, I: Isoleucine, L:Leucine, K: Lysine, M:Methionine, F: Phenylalanine, P: Proline, S: Serine, T: Threonine, W: Tryptophan, Y:Tyrosine, V: Valine

Table 3. Fungal based bioactive compounds and their potential health effects.

Bioactive compound in fungi	Bioactivity(Health Effects)	References
Gamma-aminobutyric acid	Regulate pain and anxiety sensation Improving memory and learning capacity Treating depression and insomnia Blood pressure modulation Anti-diabetic (stimulate the insulin secretion from pancreas) Anti-cancer	(Nuss 2015; Tabassum et al. 2017; Singh and Zhao 2017; Dupont and Légat 2020; Q. Wang, Ren, et al. 2019; H. Lee, Lin, et al. 2015)
L-carnitine	Promoting physical performance Helping to weight loss Antioxidant Anti-inflammatory Anti-diabetic (improving insulin sensitivity)	(Fielding et al. 2018; Talenezhad et al. 2020; Ribas, Vargas, and Wajner 2014; B.-J. Lee, Lin, et al. 2015; Xu et al. 2017)
Ergosterol	Antioxidant Anti-inflammatory Anti-cancer Anti-hypercholesteremic Anti-obesity Precursor of vitamin D2	(Corrêa et al. 2018; Al-Rabia et al. 2021; Chen et al. 2017; He et al. 2020; Jeong and Park 2020; Nowak et al. 2022)
Chitin, chitosan	Anti-hypercholesteremic Anti-hypertensive Antidiabetic Anti-microbial Anti-tumor Immune modulator Reduce the risk of colorectal condition	(Zhai et al. 2021; Naveed et al. 2019; Jean et al. 2012; Guarnieri et al. 2022; Liu et al. 2019; Mudgal et al. 2019; Debnath et al. 2019)
β-glucan	Anti-diabetic Anti-hypertriglyceridemia Anti-hypercholesterolemic Anti-cancer Anti-infection Anti-inflammatory Promoting skin health Lowering the risk of metabolic syndrome and obesity	(Andrade et al. 2015; Pino, Mujica, and Arredondo 2021; Afiati et al. 2019; Richter et al. 2016; Vetvicka and Vetvickova 2020; Bacha et al. 2017; Du, Bian, and Xu 2014; Rahmani et al. 2019)
Fructooligosaccharides	Anti-hypercholesteremic Anti-hypertriglyceridemia low sweetness intensity prevent dental caries Helping minerals absorption Reduce the risk of colorectal cancer	(Moharib et al. 2014; Yuanita, Wikandari, and Sabtiawan 2017; de Morais, Cruz, and Bolini 2013; de la Rosa et al. 2017; Bryk et al. 2015; O’Keefe 2016)

Bioactive peptides

Proteins are one of the fundamental macronutrients in the diet and their consumption is essential throughout one’s life. They have an important role in the organism’s growth and maintenance, and they act as enzymes, membrane transporters, metabolic process regulators, and oxygen transporters. Furthermore, proteins have also been shown to have health benefits whether intact or hydrolyzed (World Health Organization 2007). Hydrolyzed protein fragment, also known as bioactive peptides (Bp), have a positive impact on physiological functions and may eventually influence health in addition to their nutritional significance (Daliri, Oh, and Lee 2017; Korhonen and Pihlanto 2006; Sánchez and Vázquez 2017). Bioactive peptides have low molecular weight (<6000 D) and usually contain between 2 and 20 amino acids residues, and they may have an inherent resistance to digestion in the gastrointestinal tract. The peptides are inactive, when they are encrypted in the structure of proteins, once released due to proteolytic activity they may operate as physiological modulators with hormone-like activity (Lafarga and Hayes 2014; López-Barrios, Gutiérrez-Uribe, and Serna-Saldívar 2014; Montoya-Rodríguez et al. 2015; Mora and Hayes 2015; Sánchez and Vázquez 2017). The most studied bioactive peptides are present in meat, fish, dairy products, and legumes fermented using lactic acid bacteria, yeasts and Bacillus species (Cipolari, de Oliveira Neto, and Conceição 2020; Venegas-Ortega et al. 2019; Xing et al. 2019). Moreover, for filamentous fungi, legumes, particularly soybean, and some cereals such as quinoa, oat and lentil, are the most studied substrates for bioactive peptides (Magro et al. 2019; Nascimento et al. 2020; Tamam et al. 2019).

Producing bioactive peptide by fungal protease activity attract great attention from biotechnologists due to the ability of fungi to produce variety of protease which are active over a wide pH range as well as growing on low-cost substrate (Soukup, Keller, and Wiemann 2016). In addition using filamentous fungi as an starter culture for producing fermented food and beverages eliminates the need for extra enzymatic recovery processes, as well as the inconvenient extraction and exogenous treatment of enzymes (Chávez et al. 2015). Filamentous fungi are able to produce Bp through both solid-state fermentation (SSF) and submerged fermentation (SmF). The fungal based Bp composition may vary depending on the specificity of the fungal protease and the protein composition of the substrate. In addition to microbial species participating in fermentation, some physical characteristics such as temperature, pH, moisture content, salt extent, and cultivation time have a significant impact on the degree of proteolysis and synthesis of Bp (Martínez-Medina et al. 2019; Verardo, Gómez-Caravaca, and Tabanelli 2020). Bioactive peptides, depending on the length and sequence of their amino acids, hydrophobicity and charge, exhibit different functional properties such as antioxidant (Lorenzo et al. 2018; D. P. Mohanty, Jena, et al. 2016), antimicrobial (Agyei and Danquah 2012; D. Mohanty, Jena, et al. 2016; Tan, Fu, and Ma 2021; Tan et al. 2022), immunomodulatory (Agyei and Danquah 2012; Santiago-López et al. 2016), antithrombic (Rojas-Ronquillo et al. 2012; Rutherfurd-Markwick and Moughan 2005), hypocholesterolemic (González-Ortega et al. 2015; Karami and Akbari-Adergani 2019; Peighambardoust et al. 2021) and antihypertensive activities (Aluko 2015; Kim, Ngo, and Vo 2012; Li et al. 2022).

Dipeptidyl peptidase (DPP) IV inhibitor peptides, Lys-Leu and Leu-Arg, derived from soybean fermented by A. oryzae, had previously been identified as antidiabetic agent (Sato et al. 2018). DPP-IV inactivates two hormones which promote insulin production. As a result DPP-IV inhibition is a molecular target for treating diabetes (Yan et al. 2019). Different studies showed the potent DPP-IV inhibitory peptides, composed of a branched chain amino acid such as leucine, isoleucine, or valine at their N-terminal position, or an aromatic residue with a polar group in the side chain mainly tryptophan (Nongonierma and FitzGerald 2019; Tulipano et al. 2015). Bioactive peptides also act as an antidiabetic agent by inhibitory effect on α-amylase and amyloglucosidase (glucoamylase). The inhibition of α-amylase up to 75% has been reported after fermentation of lentil flour by A. oryzae (Magro et al. 2019).

The antihypertensive impact of different peptides has been linked to the inhibition of the angiotensin-converting enzyme (ACE) resulted in lower of blood pressure. Aromatic amino acids as well as leucine, valine, lysine, arginine, and isoleucine have also been demonstrated to have a major impact on ACE inhibition (García-Mora et al. 2017; Pan et al. 2012). In addition, Gly-Tyr, Ala-Phe, Val-Pro, Ala-Ile, and Val-Gly are antihypertensive peptides generated by A. sojae after fermentation of soy sauce. The antihypertensive peptides Val-Pro-Pro and Ile-Pro-Pro were generated by fermenting miso with A. oryzae (Tamam et al. 2019).

The bioactive peptides with hydrophobic amino acids (proline, histidine, tyrosine or tryptophan), phenolics (tyrosine, tryptophan or phenylalanine) and reductive amino acids (methionine or cysteine) are well known with their antioxidant activities (Elias, Kellerby, and Decker 2008; He et al. 2012; Roblet et al. 2012). Antioxidative peptides were defined after fermentation of okara (known as soy pulp) by A. oryzae, R. oligosporus, and Actinomucor elegans. Moreover, antioxidant activities increased due to the significant accumulation of protein hydrolysis end products (peptides and amino acids) after fermentation of colored quinoa fermentation using by R. oligosporus, A. oryzae and N. intermedia (Starzyńska-Janiszewska et al. 2019). The tripeptide of Gln-Tyr-Pro in fermented meat sauce (FMS) by Aspergillus sp. showed extremely high antioxidant activity against OH radical (Ohata et al. 2016).

Anticancer peptides (ACPs) have a cationic charge (Chen et al. 2016). They are amphipathic and usually abundant in arginine and lysine. Anticancer activity of bioactive peptide has been reported after enzymatic hydrolyze of shellfish by A. oryzae. The sequence was partially purified as His-Phe-Asn-Ile-Gly-Asn-Arg-Cys-Leu-Cys at the N-terminus. This peptide effectively induced the death of prostate, breast, and lung cancer cells but not the normal liver cells (Cheong et al. 2013; Yang et al. 2012).

The antithrombotic bioactivity of filamentous fungi is referred to their ability to secret fibrinolytic protease. This enzyme specifically degrade fibrin, which is the main component of thrombus (Verardo, Gómez-Caravaca, and Tabanelli 2020). This bioactivity has significant role on preventing and managing cardiovascular disease with removing blood clots. Many studies have been shown the anti-thrombotic activities of different types of filamentous fungi such as Neurospora sitophila, N. crassa (Duan et al. 2022), Mucor subtilissimus (Nascimento et al. 2017), A. oryzae (Shirasaka et al. 2012), Rhizopus sp. (Polanowska et al. 2020), R. chinensis (Xiao-Lan et al. 2005) and Fusarium sp. (Wu and Xu 2012). The bioactivities of Bp produced by filamentous fungi are shown in Table 2.

Chitin-chitosan

Chitin and chitosan are the major structural biopolymer in exoskeletons of invertebrates, insects, and crustaceans as well as in fungi (Hamed, Özogul, and Regenstein 2016). The molecule is classified as chitin or chitosan, based on the frequency of the latter monosaccharides and chitin can be converted to chitosan by partial deacetylation of the monomer N-acetyl-D-glucosamine to D-glucosamine (Stevens 2019). Chitin and chitosan provides important structural stability to fungal cell walls and their biosynthesis are catalyzed by chitin synthases (CHSs), a family of integral membrane proteins, by transferring N-acetylglucosamine from uridine diphosphate (UDP)-N-acetylglucosamine to a growing chitin chain (M. Li, Jiang, et al. 2016).

Among the fungal phyla, the cell wall of the Ascomycetes, Zygomycetes, Basidiomycetes, and Deuteromycetes have mostly chitin and chitosan (George et al. 2011). However, the chitin and chitosan contents of fungal cell walls vary between different fungal species (e.g., 2% in dry yeast cells and 60% in Mucor rouxii) (Abo Elsoud and El Kady 2019; Knezevic-Jugovic, Petronijevic, and Smelcerovic 2011). It appears that the chitin, chitosan content of the cell wall is higher in Zygomycetes, notably M. rouxii, M. mucedo, M. circinelloides, Rhizomucor miehei, Rhizopus oryzae, Phycomyces blakesleeanus, and Cunninghamella elegans (Knezevic-Jugovic, Petronijevic, and Smelcerovic 2011; Zamani et al. 2007). In addition to fungal strain, the age of the producing microbial cells, cultivation medium, and fermentation type influence the chitinous composition of the fungal cell wall. Li et al. (2021) found that reducing the pH and supplementing extra nitrogen sources increased the chitinous content of A.oryzae.

Chitin and chitosan are well-studied bioactive compounds with numerous biological activities on human health. Chitin is an insoluble dietary fiber and its structure is analogous to indigestible cellulose in plants (Kostag and El Seoud 2021). It prevents and treats constipation as well as reduce the risk of colorectal condition such as hemorrhoids and diverticulitis (Debnath et al. 2019).

Several studies have found that chitin and chitosan are excellent cholesterol-lowering and fat-blocking substances (Chiu et al. 2019; Z. Wang, Ren, et al. 2019). In a randomized, double-blind, and placebo-controlled clinical study, oral chitosan ingestion significantly reduces low-density lipoprotein (LDL), cholesterol, and plasma cholesterol while improving the high-density lipoprotein (HDL) cholesterol/total cholesterol ratio. These investigations suggested that it was caused by increased bile acid excretion and/or impaired cholesterol absorption (Moraru et al. 2018). Today, chitosan is sold in the market as a dietary supplement for reducing cholesterol and body weight.

The antidiabetic effects of chitosan has been reported in animal models of type 1 and type 2 diabetes. Hayashi and Ito (2002) designed to clarify the effects of low molecular weight (LMW) chitosan on hyperglycemia, and hyperinsulinemia, in genetically obese diabetic male KK-Ay mice. The result showed that LMW chitosan lowered the serum glucose levels and improved overdrinking and polyuria observed in these diabetic mice. The study by Jean et al. (2012) revealed that chitosan nanoparticles can be applied for the gene therapy of diabetes in living organisms since they successfully transfected the human insulin gene in vivo and in vitro. Furthermore, several studies have pointed out and reviewed the other biological activities of chitosan and its derivatives such as antimicrobial, immune modulator, antitumor, anti-inflammatory, and anti-hypertensive agent (Naveed et al. 2019; Zhai et al. 2021). It has also been proven that the chitin and chitosan monomer units are essential to repair and maintain healthy cartilage and joint function (Jung and Park 2014). Chitin and chitosan have a wide range of applications in food, health, and pharmaceutical regarding their high biological activities.

However, due to their higher solubility and bioavailability, LMW and chitooligosaccharides (COS) have received the most attention (Gonçalves, Ferreira, and Lourenço 2021).

β-glucans

The non-starch polysaccharide β-glucans is a component of cell walls in yeast, filamentous fungi, and mushrooms. It is also found in the cell wall of some bacteria, and diversity of grains such as rye, barley, and oat (Barsanti et al. 2011). The synthesis of β-glucan in fungi is made up of β-1,3 chains with a variable degree of β-1,6 branching (Papaspyridi, Zerva, and Topakas 2018). This process is catalyzed by glucosyltransferase which utilizes urine diphosphate glucose (UDPG) as a sugar donor (Papaspyridi, Zerva, and Topakas 2018). β-glucan helps to strengthen fungal cell structure and serves as a food reserve (Yoshimi, Miyazawa, and Abe 2017). Properties of β-glucan syntheses are extremely variable depending on the fungal species, condition of growth media (especially pH and glucose content), and their developmental stage. Several studies have shown that the addition of various types and concentrations of carbon sources to the fermentation media significantly influenced the increase in β-glucan contents of S. cerevisiae, R. oligosporus and A. oryzae cells (Kusmiati et al. 2007; Rizal et al. 2020; Utama et al. 2021).

The molecular weight, concentration and conformation of β-glucan structure can define their biological activities (Liu et al. 2016; Özcan and Ertan 2018). The high molecular weight (MW) and high viscosity of β-glucan showed better hypocholesterolemic and hypoglycemic properties (Du et al. 2019). However, low molecular weight of β-glucan showed better immunostimulatory and anti-allergic activity (Jippo et al. 2015; Suárez et al. 2006).

The hypocholestromic and hypoglycemic effect of β-glucan have been well proven and documented in different in vitro and in vivo studies in animals and humans (Afiati et al. 2019; Kim et al. 2005; Pino, Mujica, and Arredondo 2021; Sima, Vannucci, and Vetvicka 2018). In a systematic review by Andrade et al. (2015) concluded that intake of β-glucan is effective in decreasing glucose levels in diabetic patients, with higher or smaller doses for longer periods presenting better results. In addition, ingestion of β-glucan by diabetic rats showed anti-hyperglycemic, anti-hypertriglyceridemia, and anti-hypercholesterolemic activities (Afiati et al. 2019; Kim et al. 2005). Several mechanisms could account for hypocholesterolemic and hypoglycemic effect of β-glucan.

First, β-glucan, as a kind of viscose-soluble dietary fiber, both reduces the absorption rate of the digested nutrients such as glucose, monoglycerides, free fatty acids, and cholesterol. Second, β-glucan increases the fecal excretion through an increase in the viscosity of the contents of the stomach and small intestine. Third, β-glucan undergo fermentation in the intestinal microbiota generates short-chain fatty acids (SCFAs). These compounds, can inhibit the rate-limiting enzyme of cholesterol β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase to inhibit cholesterol synthesis and also, stimulate the release of the peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and ghrelin in entero-endocrine L cells, which boosts insulin secretion and satiety perception (Pino, Mujica, and Arredondo 2021; Vitaglione et al. 2009; Zaremba et al. 2018). Regarding mentioned health properties of β-glucan, the US Food and Drug Administration (FDA) and European Food Safety Authority (EFSA) have authorized health claims for β-glucan (EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) 2011; Nishantha et al. 2018).

β-glucan possess other health promotion effects on human health including anti-tumor (Richter et al. 2016), anti-infection (Vetvicka and Vetvickova 2020), anti-inflammatory (Bacha et al. 2017) and antioxidant (Song and Moon 2006) properties. Furthermore, Du, Bian, and Xu (2014) found that β-glucan plays an important function in skin health promotion as an active ingredient in anti-wrinkle activity, wound healing, antioxidant activity, and moisturizing effect. β-glucan is widely applied in the food, medical, and cosmetic industries regarding its positive health impacts.

Gamma-aminobutyric acid

Gamma-aminobutyric acid (GABA), a four carbon non-protein amino acid with molecular formula of C₄H₉NO₂, is naturally found in plants, animals and microorganisms (Diana, Quílez, and Rafecas 2014). GABA is found in very low concentrations in biological tissues, making it difficult to adequately extract from wild species. Different attempts have been made to synthesize GABA chemically (Nikmaram et al. 2017). However, due to the various disadvantages of corrosive reactants required for chemical synthesis, biological GABA extraction has gained popularity (Rashmi et al. 2018a). Microbial fermentation is recognized as one of the most efficient methods of bioprocessing because of simple reaction procedure and high catalytic efficiency (Sarasa et al. 2020). The most studied GABA producer microorganisms are from genera of bacteria specifically lactic acid bacteria (Cui et al. 2020; Sang, Uyen, and Hung 2018). In addition to bacteria, filamentous fungi have also been found to produce GABA due to the presence of glutamic acid decarboxylase (GAD) in their cell (Cai et al. 2014; Kumar et al. 2000; Masuo et al. 2010). Producing and accumulating of GABA by filamentous fungi improve the tolerance to environmental acid stress (Krulwich, Sachs, and Padan 2011). The main pathway of GABA production by the conversion of alpha-ketoglutarate to succinate in TCA cycle, GABA and succinic semialdehyde via glutamate (Rowley et al. 2012).

Various studies have reported that the GABA content of the fungal product has been increased after cultivation of cereals by different types of filamentous fungi. Cai et al. (2014) suggested that oats fermented by filamentous fungi (Aspergillus oryzae, A. oryzae var. effuses and Rhizopus oryzae) contained higher GABA (125-435 µg/g oat) compared to native oat (57 μg/g), and the resulting fungal product were functional foods. Similarly, GABA content of Thai rice grains is improved through Monascus purpureus cultivations (Jannoey et al. 2010). Under anaerobic conditions, high yield of GABA was achieved through fermentation of soybean by Rhizopus microsporus var. oligosporus to 15-17.4 g/kg (H. Aoki, Furuya, et al. 2003). Different parameters such as pH, temperature, cultivation time and media additives affect the GABA production rate of filamentous fungi (Dhakal, Bajpai, and Baek 2012). For example, the addition of sodium nitrate to the media increased GABA production by M. purpureus (Su et al. 2003).

GABA exerts a great influence on a wide range of health issues. One of the most known effects of GABA is blood pressure modulation. Many studies have shown the effect of GABA on reducing elevated blood pressure in humans and animals. Different studies showed that adding GABA-enriched fermented soybean to the diet of hypertensive rat significantly decreased blood pressure (Hideyuki Aoki, Furuya, et al. 2003; Dupont and Légat 2020; Shizuka et al. 2004). In addition, GABA effectively prevented diabetes by acting as a potent secretagogue of insulin from the pancreas (Q. Wang, Ren, et al. 2019). There is some evidence that GABA has anticancer properties and could slow or inhibit the invasion and metastasis of cancer cells, including mammary gland, colon, hepatic and lung cancer cells (H. Lee, Lin, et al. 2015; Minuk 2000; Oh and Oh 2004; Opolski et al. 2000).

GABA is involved in inhibitory neurotransmission in various pathways of the central nervous system as well as peripheral tissues (Watanabe et al. 2002). According to different researches, GABAergic neuron changes have been linked to Huntington’s disease, Parkinson’s disease, senile dementia, seizures, Alzheimer’s disease, stiff person syndrome, and schizophrenia (Iwakura and Nawa 2013; Sesack and Carr 2002; Shetty and Bates 2016).

GABA increases the levels of growth hormone and the rate of protein synthesis in the brain (Rashmi et al. 2018b). GABA ingestion can regulate pain and anxiety sensations, as well as improving memory and learning capacities. GABA has been used to treat a variety of physiological functions including relaxation, insomnia (Singh and Zhao 2017), and depression. Möhler (2012) reported that normal GABA levels are beneficial in antidepressant medications and mood-stabilizing treatment.

L-carnitine

L-carnitine (β-hydroxy-γ-N-trimethylaminobutyric acid) is a quaternary ammonium compound that plays a crucial role in energy metabolism (Longo, Frigeni, and Pasquali 2016). The chemical and biotechnological processes are used for L-carnitine production. However, biological production has become more prominent due to less organic waste, less waste to incineration and less wastewater than to chemical process (Naidu et al. 2000). Biotechnologically, production of L-carnitine is achieved through the action of microorganisms (fungi and bacteria) on racemic mixture of D,L carnitine and achiral precursor such as crotonobetaine, γ-butyrobetaine, and dehydrocarnitine as substrates (Bernal et al. 2007; Evans and Fornasini 2003). Different ascomycetes and zygomycetes fungi such as Mucor, Rhizopus, Aspergillus, Neurospora, and Fusarium are used in the conversion DL-carnitine derivatives to L-carnitine through stereospecifically hydrolyzing (Naidu et al. 2000). Rhizomucor, Rhizopus and Neurospora are able to convert crotonobetaine to L-carnitine by hydrating step (Tian, Wang, and Zhang 2009). Some fungal strain such as Saccharomyces cerevisiae, Penicillium, Actinomucor, Mucor, Neurospora, Rhizopus and Aspergillus produce L-carnitine from γ-butyrobetaine via hydroxylation (Leung et al. 2010). The biotransformation of achiral compound to L-carnitine are much more productive method rather than racemic mixture (Meyer and Robins 2005). Lonza, commercially produce L-carnitine from γ-butyrobetaine as a starting material (Wutzke and Lorenz 2004).

Fermentative production of L-carnitine is the other biotechnological method using conventional medium with neither achiral nor racemic precursor. Aspergillus, Rhizopus, Neurospora, Mucor and Penicillium are the most fungi used for L-carnitine production through fermentation process (Naidu et al. 2000). These fungi are able to convert trimethyllysine which is synthesized from two essential amino acids, Lysine and methionine or comes from degradation of proteins to L-carnitine, through four enzymatic steps (Rousta, Ferreira, et al. 2021). Different studies have been reported L-carnitine production through solid state and submerged fermentation process by filamentous fungi. Rhizopus oligosporus strain has been used for L-carnitine production on range of substrates such as buckwheat (680.9 μg/kg, (Park et al. 2017)), quinoa (3.14 mg/kg (Hur et al. 2018)), wild ginseng (630 mg/kg (Lee et al. 2020)) via solid state fermentation. Lee et al. (2018) reported that L-carnitine enriched (201.2 mg/kg) oyster mushroom (Pleurotus ostreatus) was produced using solid state fermentation of buckwheat by Rhizopus oligosporus. Rousta, Ferreira, et al. (2021) reported the production of L-carnitine from filamentous fungi (A. oryzae 3 mg/g dried biomass; R. oligosporus 1.3 mg/g dried biomass, R. oryzae 1 mg/g dried biomass, and N. intermedia 0.4 mg/g dried biomass) grown in semi-synthetic medium, and this study showed much higher L-carnitine production rather than solid-state fermentation mentioned above.

L-carnitine has been postulated to have a variety of biological activities, but its principal purpose is to enhance the transfer of fatty acids, making them accessible for mitochondrial β-oxidation (Virmani and Cirulli 2022). Mitochondrial fatty acid oxidation is an important source of cellular energy, especially in cardiac and skeletal muscle (Shimada et al. 2004). L-carnitine is also thought to be necessary for serving as an acyl group acceptor in order to maintain enough levels of free coenzyme A (CoA) in the cell, and it may operate as an osmoprotectant in sensitive organs such as the kidney (Longo, Frigeni, and Pasquali 2016). Based on its functionality, L-carnitine has different effects on human health. Different studies have been shown the effect of L-carnitine on weight loss and promoting physical performance during intensive exercise (Fielding et al. 2018; Pooyandjoo et al. 2016; Talenezhad et al. 2020). L-carnitine enhances bone microstructural properties by decreasing bone turnover (Cao et al. 2011; Hooshmand et al. 2008; Manoli et al. 2004). It acts as an antioxidant and protect three mainly enzymes contribute to antioxidant defense system in the body from further peroxidative damage and it is effective in regulating age-related changes (Cao et al. 2011; Li et al. 2012; Ribas, Vargas, and Wajner 2014). Xu et al. (2017) reported that the role of L-carnitine infusion and oral supplementation in diabetic patients to improve insulin sensitivity as well as increase non-oxidative glucose excretion and glycogen storage in skeletal muscle. In humans, L-carnitine deficiency in human causes skeletal myopathy, hyperlipoproteinemia, ketonemia, cardiac infarction and chronic kidney insufficiency (Magoulas and El-Hattab 2012). As a result of the biofunctionality of carnitine, there has also been an increasing demand for the potential uses of L-carnitine as a therapeutic agent and as a nutritional supplement.

Ergosterol

Ergosterol, a 5,7-diene oxysterol, the primary sterol in fungal membrane cells (yeast, filamentous fungi and mushroom) plays a variety of biological roles including permeability, fluidity, regulation, and cell cycle control (Nowak et al. 2022). Since ergosterol is essential for cell membrane integrity, its production pathway is critical for fungal growth and is a key target for many of the currently available antifungal drugs used to treat serious human fungal infections (Jamzivar et al. 2019). Furthermore, it is a good indicator for measuring fungal growth in solid substrate because of the significant relationship between ergosterol level and hyphae length, as well as the existence of ergosterol exclusively in fungi (Gessner 2020). Ergosterol synthesis is a complex and energy-intensive process that takes place in the endoplasmic reticulum through the sequential activity of 25 distinct enzymes (Jordá and Puig 2020). Squalene epoxidase and lanosterol synthase are two significant and necessary enzymes in the ergosterol production pathway (Hu et al. 2017). The concentration of ergosterol in fungal biomass is related to fungal species, culture age, developmental stage (growth phase, hyphae formation, and sporulation), and environmental conditions (pH and temperature). The average ergosterol content of fungal species ranges from 2.6 to 42 µg/ml of dry mass. Ergosterol concentrations in Aspergillus, Penicillium, Fusarium, and Rhizopus have ranged between 0.4 and 14.3 g/mg dry mass. (Pasanen et al. 1999).

Ergosterol possesses a wide spectrum of biological properties with promoting health effect, such as antioxidant (Corrêa et al. 2018), anti-inflammatory (Al-Rabia et al. 2021; Kobori et al. 2007; Nowak et al. 2022) anticancer (Chen et al. 2017; He et al. 2018; Kang et al. 2015; X. Li, Jiang, et al. 2016; Li et al. 2015; Yongxia et al. 2020) and anti-hypercholesteremic activities which reduced the incidence of cardiovascular disease. Hu et al. (2006) found that two ergosterol-containing extracts of Pleurotus citrinopileatus significantly reduced the serum level of total cholesterol (TC) and triglycerides (TG) in rats. Likewise, the in vitro digestion study conducted by Gil-Ramírez et al. (2014) demonstrated that ergosterol-enriched extracts from Agaricus bisporus could displace the cholesterol by 67%. The addition of 1-1.5% ergosterol to the high cholesterol diet in rats significantly decreased blood levels of TC and LDL (He et al. 2019). Some studies demonstrated that anti-hypercholesteremic effect of ergosterol by suppressing intestine cholesterol absorption and promoting fecal cholesterol excretion (He et al. 2020; He et al. 2019). Anti-hypercholestrolemic health claim for ergosterol has been fully approved by European Food Safety Authority (EFSA). In addition to the above-mentioned health effects of ergosterol, Jeong and Park (2020) revealed the anti-obesity effect of ergosterol peroxide derived from an ethanolic extract of Ganoderma lucidum by inhibition the synthesis of triglycerides.

The other important role of ergosterol on health is related to synthesis of vitamin D2 (ergocalciferol) (Nowak et al. 2022). Ergosterol is known as a precursor of vitamin D2 that can be converted to vitamin D2 by exposure to natural or artificial UV irradiation (wavelengths in the range of 280-320 nm) (Jiang, Zhang, and Mujumdar 2020; Nölle et al. 2017). In the blood circulation, ergocalciferol convert to the biologically active form of vitamin D (calcitriol) after enzymatic processes in the liver and kidney (Cardwell et al. 2018; Charoenngam, Shirvani, and Holick 2019). A low plasma vitamin D level has been linked to the advancement of numerous metabolic diseases, including diabetes, hypertension, autoimmune and inflammatory diseases, cancer, immunological disorders, and infectious diseases (H. Wang, Chen, et al. 2017). Recently, some studies have been reported the correlation between vitamin D deficiency and mortality rate in COVID-19 (Annweiler, Cao, and Sabatier 2020; Giménez et al. 2020; Razdan, Singh, and Singh 2020). Since the rich diet source of vitamin D are animal products, the fungi as the only vegetarian source of vitamin D are highly considered.

Fructooligosaccharides

Fructooligosaccharides (FOSs) are non-digestible carbohydrates which represent a main classes of bifidogenic oligosaccharides (Gropper and Smith 2012; Monsan and Ouarné 2009). FOSs are a common name only for fructose oligomers that are mainly composed of 1-kestose (GF2), nystose (GF3), and lF-fructofuranosyl nystose (GF4) in which fructosyl units (F) are bound at the B-2,1 position of sucrose (GF) respectively (Zhang et al. 2017). They are present in trace amount in higher plants such as Chicory root, bananas, onions, agave, garlic, asparagus, jicama, and leeks (Nobre et al. 2015). However, they are produced commercially through enzymatic process from sucrose by microbial enzyme (Roupar et al. 2022). Two enzymes, namely fructosyltransferases, and β-fructofuranosidases are responsible for the production of fructooligosaccharides (Muñiz-Márquez et al. 2016) that can be found in wide variety of fungi including Aureobasidium sp. (Dominguez et al. 2012; Jung et al. 2011; Zhang et al. 2019), Aspergillus sp. (Choukade and Kango 2022; Nascimento et al. 2019; Ojwach et al. 2020) Fusarium sp. (Ganaie, Rawat, et al. 2014; Maiorano et al. 2020; Michel et al. 2016) Penicillium sp. (Rawat, Ganaie, and Kango 2015; Sánchez Martínez, Soto Jover, and López Gómez 2018) Scopulariopsis brevicaulis (Antosova and Polakovic 2002; Belorkar 2020; Yadav, Singh, and Shukla 2016), Rhizopus stolonifera (Flores-Maltos et al. 2016; Lateef and Gueguim-Kana 2012) and yeasts (Roupar et al. 2022; Yoshikawa et al. 2022). However, Aspergillus niger, Aspergillus japonicus, and Aureobasidium pullulans have a great potential for industrial production of FOSs. In addition to fungal species, optimization the nutritional and culture parameters are the main approaches to increase enzyme yield and productivity (Zhang et al. 2017). For example, improved media conditions containing 24% sucrose and 2.75% yeast extract boosted enzyme and, as a result, FOSs synthesis by Aspergillus japonicus by 180% (Mussatto and Teixeira 2010)

There has been a lot of research on the use of submerged fermentation for the synthesis of FOSs by various fungi (Ademakinwa, Ayinla, and Agboola 2017; Cunha et al. 2019; Flores-Maltos et al. 2016; Hayashi et al. 2000; L’Hocine et al. 2000; Lateef, Oloke, and Prapulla 2007; Muñiz-Márquez et al. 2019; Nascimento et al. 2019; Ottoni et al. 2012; Shin et al. 2004; Vandáková et al. 2004; Yang et al. 2016). Most of these studies used chemically formulated media for microbial fermentation. Fewer studies of the use of SSF in the production of FOSs have been published to that of submerged fermentation (Mussatto et al. 2013; Mussatto and Teixeira 2010; Sangeetha, Ramesh, and Prapulla 2004a, 2004b). However, more research has focused on SSF as a cost-effective alternative technique for FOSs production, using agricultural residual waste or by-product (Batista et al. 2020; de la Rosa et al. 2019; Ganaie et al. 2017; Mussatto et al. 2015). In a study by Mussatto et al. (2015) investigated the economic and environmental effects of different fermentation processes for FOSs production. SSF has become more attractive due to its ability to produce FOSs with higher annual productivity and purity than the other process.

FOSs have various effects on human health due to its prebiotic properties. Short chain fatty acids (SCFAs) produced through the fermentation of FOSs can suppress inflammation and cancer, promote local immune response, and increase ammonia excretion (Liu et al. 2021; Vinolo et al. 2011). Several studies have shown that FOSs are therapeutic agent against ovarian (Oliveira-Ferrer et al. 2014), breast (Luo et al. 2003), prostate (Zhang et al. 2007) and colorectal cancer (Ding et al. 2020). Yu et al. (2014) reported that the anti-tumor and immunostimulatory functions of FOSs produced by fermentation of wheat bran through Aureobasidium pullulans. In addition, FOS has been shown to lower serum lipid levels, have a hypotriglyceridemic and hypocholestrolemic effect therefore, reducing the risk of diabetes, obesity and atherosclerosis (Giacco et al. 2004; Ooi and Liong 2010; Rodríguez-Berdini and Caputto 2019). Different mechanisms have been proposed to explain these effects. One mechanism involves adjusting the concentrations of glucose or insulin. FOSs, as indigestible soluble prebiotic, decrease blood glucose peaks that occur after eating, and as a result, the production of glucose and insulin-induced lipidic enzymes is reduced significantly (Sabater-Molina et al. 2009). The other is related to SCFAs production in the colon. Propionate inhibits lipogenesis and cholesterogenesis pathways while acetate stimulates them, so the ratio of acetate to propionate reaching the liver may be one of the potential lipid-lowering properties of FOSs (Thandapilly et al. 2018). Moreover, FOS positively improves the absorption of minerals. It has been demonstrated that high SCFAs concentration resulting from the fermentation of FOS increases the water content and decreases the pH of the colon, which are two important factors for solubility/availability of minerals particularly, Ca and Mg, in several animal experimental studies (Scholz-Ahrens et al. 2007; Scholz-Ahrens and Schrezenmeir 2007).,

Another health benefits of FOSs relate to its anti-diabetic effect, which is achieved through several mechanisms, including increased glucose absorption in peripheral tissues, decreased gluconeogenesis, improved insulin tolerance, and increased insulin secretion. (Bharti et al. 2013; Erejuwa, Sulaiman, and Wahab 2011; Paul and Kumar 2020). Bharti et al. (2013) reported that antidiabetic activity of FOSs produced by Aureobasidium pullulans using poloxamer-407 induced type 2 diabetes mellitus in rat. Since FOSs are not hydrolyzed by digestive enzymes, they cannot be used as a source of energy (calorie free) and are safe for diabetics and people on slimming diet.

Due to their wide variety of physiological functions and health effects, FOSs have attracted great interest in the market and many biotechnological and pharmacological companies have been developed for their production (Ganaie, Lateef, et al. 2014).

Fungal probiotic and prebiotic properties and their effects on gut microbiota

The role of gut microbiota in health and disease is one of the most debated topics in human nutrition. This is especially true of interactions between resident microbiota and dietary ingredients that support their operations. It has been approved that the gut microbiome contains pathogenic and beneficial components, and the diet affects the gut microbiome composition (Steer et al. 2000). The use of probiotic (use of live microorganisms in food) and prebiotic (carbohydrates that are selectively metabolized by desirable flora moieties) improves the beneficial microbiota in the gut with a wide range of health effects (Kechagia et al. 2013). In this section, the fungi’s probiotic and prebiotic potentials have been discussed.

Probiotic fungi

Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungal kingdom. Saccharomyces, a member of the Ascomycota, is the most well-known yeast in foods as baker’s yeast or brewer’s yeast (Levetin et al. 2016). Saccharomyces cerevisiae and Saccharomyces boulardii are used as human probiotics exerting many beneficial properties on human health (reviewed in Szajewska, Konarska, and Kołodziej (2016), Wang et al. (2015), and Tadesse et al. (2021)). The strain S. cerevisiae IFST 062013 was found to have probiotic properties like tolerance to a wide pH and temperature ranges, gastric fluids, production of organic acids, assimilation of cholesterol, production of vitamins, siderophore, biofilm formation and enzymes. This strain was also showed antimicrobial and antioxidant activities (Fakruddin, Hossain, and Ahmed 2017). S. boulardii isolated form fruits in early 20th century is the only probiotic yeast investigated clinically and extensively studied for its beneficial effects on gastrointestinal system (Czerucka and Rampal 2002; Hossain et al. 2020; Pothoulakis 2009). Many studies have been performed using this strain in the treatment of diarrhea, Crohn’s disease, irritable bowel syndrome (ibs), inactivation of bacterial toxins, inhibition of toxin binding to receptors (Anoop et al. 2015; Offei et al. 2019). Using S. boulardii as a prophylactic supplement in the healthy intestine induced a mucosal immune response (Hudson et al. 2016). Moreover, the strains of S. boulardii isolated from different supplements showed antibacterial and antifungal activities on Salmonella Typhimurium and Aspergillus niger strains (Goktas, Dertli, and Sagdic 2021).

Many of other yeast strains are used in food fermentations or found in gastrointestinal system. Some yeast species other than Saccharomyces sp. were isolated from fermented dairy products such as Candida sp., Debaryomyces sp., Yarrowia sp., Kluyveromyces marxianus, Pichia fermentans, Candida guilliermondii with probiotic properties including specific enzyme productions, antioxidant, antimicrobial and antitumor activities and resistance to adverse environmental conditions like low pH or osmotic stress (Fredlund et al. 2002; Kumura et al. 2004; Mahasneh and Abbas 2010; Moslehi-Jenabian, Lindegaard, and Jespersen 2010; Qvirist et al. 2016; Tadesse et al. 2021; Utama et al. 2019). Candida tropicalis, Pichia sp., Aureobasidium pullulans have also beneficial properties like antimicrobial activities on pathogenic bacteria or enzymatic activities that can be used as promising probiotics in food and feed supplements (Syal and Vohra 2013; Wu et al. 2022).

Foods enriched with yeast probiotics as new functional products are of interest in recent years (Amorim, Piccoli, and Duarte 2018; Di Cagno et al. 2020). Senkarcinova et al. (2019) showed the inclusion of strain S. boulardii for production of alcohol-free probiotic beer additional health benefits. Karaolis et al. (2013) showed that S. boulardii stimulated the growth of lactic acid bacteria in yogurt without affecting organoleptic quality. Swieca et al. (2019) used to lentil and bean sprouts as a carriers for S. cerevisiae var. boulardii and improved microbiological quality of the final sprouts without affecting the their nutritional properties.

It has been suggested that many filamentous fungi (Aspergillus awamori, A. niger, Rhizopus oligosporus, Acremonium charticola, Chrysonilia crassa, Scytalidium acidophilum) can be used as a probiotic (reviewed in Sugiharto (2019)). Studies with the potential probiotic effects of filamentous fungi relate to broiler chicks, poultry and fish production (Poirier et al. 2022). In poultry, fungal-based probiotics could improve growth performance, muscle vitamin E content, skeletal muscle fatty acid profile, and reduce lipid peroxidation in the muscles (Saleh et al. 2011). In fish, some fungal probiotics can stimulate the antioxidant response and immune system, and also stimulate the production of various digestive enzymes (amylases, cellulases, β-glucanases, xylanases, proteases and lipases) (Melo-Bolívar et al. 2020).

Future research should focus on exploring new fungal probiotic strains that can be used in industrial, medical and agricultural applications. More in-depth research into genetic engineering on fungal probiotic strains will also help enhance their probiotic properties.

Prebiotic fungi

Innovative new trend foods have become popular today due to their various benefits on health. The most important functional group for consumers to prefer these foods is prebiotics (Belorkar 2020). Fungal polysaccharides (chitin, chitosan, and β-glucan) act as prebiotics as an alternative to prebiotics, which are usually provided by bacteria. In addition, some fungal species are widely used in the production of oligosaccharides with prebiotic effects (Awasthi, Tarafdar, et al. 2022). Fructooligosacharides (FOS) as explained above and xylooligosaccharides (XOS) are the other prebiotic compounds produced by fungi (Manisha and Yadav 2017). As fungal cultures, Trichoderma viride, Aspergillus foetidus, A. fumigatus, A. brasiliensis and recombinant A. nidulans are potential XOS producers (Carvalho et al. 2015; Chapla, Pandit, and Shah 2012; da Silva Menezes, Rossi, and Ayub 2017; da Silva Menezes et al. 2018; Manisha and Yadav 2017). In addition, Jiang et al. (2021) reported that glycosylceramides, one of the glycosphingolipids abundantly found in Aspergillus, contribute to a prebiotic effects with prevention intestinal deterioration.

Prebiotics are considered as regulators of gut microbiota. These fungal based prebiotics can improve gut health and improve resistance to microbial infection (Strong et al. 2022). They are selectively fermented ingredients that particularly promote the growth of probiotics (Bifidobacteria and Lactobacillus sp.), especially increasing the microflora in the large intestine, as well as decreasing the population of pathogenic bacteria (Clostridium sp.) and reducing gas production (Flores-Maltos et al. 2016; Mussatto et al. 2015). Fermentation of prebiotics by bacteria in large intestine is led to liberation of some metabolites including short chain fatty acids (acetate, propionate, butyrate, lactate, etc.) with specific local physiological functions (Pascale et al. 2018).

Current use potentials of fungi on cancer treatment

While cells divide more rapidly in the first years of life, this rate of division slows down in adulthood. Nevertheless, these capacities of cells are limited, they cannot divide indefinitely. Each cell has the ability to divide a certain number of times during its lifetime (Shammas 2011). A healthy cell knows how much to divide, when to divide and how to die when necessary. The process of conscious death of the cell is called apoptosis or programmed death of the cell. Normally, the body needs to grow, divide, and produce more cells to function properly. But sometimes this process goes wrong, and cells continue to divide excessively and prematurely without the need for new cells. These unconsciously dividing cells are called cancer cells. Unconscious cancer cells begin to divide and multiply uncontrollably (Wong 2011). These excess clumps of cells form a huge size or tumor. Cancer cells that involve this irregular cell growth can be a subversive disease that can extended to more distant parts of the body via the lymphatic system or bloodstream, with some types of which overgrow in the area where they are found and form cancerous tissues (Cooper and Hausman 2000). Research on finding drugs and treatments for cancer, which is the second most common cause of death worldwide after heart diseases, is very important for scientists (Patel and Goyal 2012). For this reason, various ways have been tried for treatment and drug production for years, and different ways are still being tried. For example, mushrooms that were considered sacred in the first years of history and used in health research; since it is thought to be effective against cancer, alternative medicine and traditional medicine have also been used. As an example, various studies from Asian countries show that edible and medicinal mushrooms play an important role in the prevention and treatment of cancer. It is also known that the fruiting bodies of Inonotus obliquus are used as a medicine in the therapy of cancer in Eastern Europe due to the ergosterol peroxide and triterpenes they contain (Kang et al. 2015; Lindequist, Niedermeyer, and Jülich 2005; Molitoris 1994). Nevertheless, while plants and bacteria are given priority in drug preparation and research in modern medicine, these studies have focused on fungi in the light of recent studies (Ogidi, Oyetayo, and Akinyele 2020). Because there are problems with the use of natural products of plant origin although successful drug discoveries in general are from plant sources. Chief among these problems is the generally low production of bioactive compounds obtained using plant sources. Re-isolation of a compound to be produced is problematic because the metabolite composition is also affected by the environment. In addition, drug production time and research cost are also problematic (Newman and Cragg 2012). Considering these problems, other organisms have been sought for the production of bioactive compounds and have tried different microorganisms such as fungi as a resource to fight cancer. As a result of these studies, it was seen that; the use of mushrooms in the fight against cancer has many advantages. Fungi that respond well to routine cultures are relatively easier to amplify productivity than other organisms. Fungi can be produced in large quantities using large reactors, and this overproduction can be conveniently stored regardless of time, providing long-term availability of the resource organism and easier supply of the desired bioactive compounds. Being able to easily supply, for example, antibacterial penicillin, antifungal echinocandin B, immunosuppressive cyclosporine A, cholesterol-lowering lovastatin has been a good tool to demonstrate the importance of searching for fungal sources for new drugs (Cole, Jarvis, and Schweikert 2003; Dewick 1997; Turner and Aldridge 1983). Fungi produce metabolites belonging to a wide variety of structural classes. Examples of these are aromatic compounds, antacenones, butanolides, amino acids, butenolides, cytochalasans, macrolides, naphthalenes, pyrons, terpenes.

In recent studies, surprisingly, although there is no approved anti-cancer drug for fungi yet, but the active compounds of certain fungi with proven anti-cancer properties are of great interest as an area of research. Many clinical studies have been and continue to be conducted to evaluate the benefits of medicinal mushroom extracts used in cancer treatment. As a result of these studies, additional potential uses of mushrooms in the treatment of cancer have emerged individually. For example, mushrooms are known to supplement chemotherapy and radiation therapy by resisting the side effects of cancer such as bone marrow suppression, nausea, anemia and low resistance. As a result of these studies, a number of bioactive molecules, including anti-tumor agents of fungi, which have been known to have in traditional medicine effects for a long time, have been identified (Table 4) (Bains et al. 2021; Lindequist, Niedermeyer, and Jülich 2005; Patel and Goyal 2012).

Table 4. The use of different fungal metabolites for cancer treatment.

Fungi	Components	Outcome	References
Saccharomyces cerevisiae	Yeast Cell Wall	Induce pro-inflammatory cytokine expression in M2 macrophages Reduce tumor weight without toxicity at 6 mg/kg in BALB/c mice Promote controlled drug release and high stability in simulated gastrointestinal environment	(Ren et al. 2018; Zhou et al. 2019; Seif et al. 2017)
Saccharomyces cerevisiae	β-glucan	Activate macrophages via upregulation of IL-1β, TNF-α, IFN-γ expression Increase cellular uptake	(Chen and Seviour 2007; Huang et al. 2020)
Auricularia auricular	Water-soluble polysaccharides	Inhibit tumor growth in BALB/c nude mice	(Qiu et al. 2018)
Cunninghamella elegans	Chitosan Oligosaccharides	Changed IC50 value	(Sathiyaseelan et al. 2020; Y. Wang, Chen, et al. 2017)
Monascus pilosus	Monascin Ankaflavin	Changed IC50 value and induce apoptosis Inhibit mouse skin carcinogenesis by UVB and TPA	(Akihisa et al. 2005; Su et al. 2005)
Xylaria psidii	5-methylmellein	Changed IC50 value and induce apoptosis and ROS	(Arora et al. 2016; Arora et al. 2017)
Flammulina velutipes	Sterols (ergosterol and 2223-dihydroergosterol)	Changed IC50 value	(Yi et al. 2013)
Xyralia primorskensis	Xylaranic acid	Changed IC50 value Induced apoptosis via upregulation of p53 and caspase-3 and downregulation of BCL-2 genes	(Adnan et al. 2018)
Inonotus obliquus	Chaga extract	Reduce cell viability	(Gil et al. 2018)
Aspergillus molds	gliotoxin	Inhibit angiogenesis and suppress tumor growth	(Reece et al. 2014)
Trichoderma atroviride	Fungal metabolites - TM2	Reduce cell viability Induce apoptosis via activation of caspase-3 and inhibition of BCL-2	(Saravanakumar et al. 2021)

Fungal gut microbiota dysbiosis and its role in carcinogenesis

The gut microbiota is a variety community consisting of bacteria, fungi and archaea. This complex ecosystem plays a veritably important part in the balance of body and health. These resident microorganisms in our gut can produce abundant bioproducts and metabolites that maintain homeostasis of the host and gut. The quantitative and qualitative changes in the composition of the gut microbiota are also defined as gut dysbiosis. Although this gut dysbiosis is known to play a role in the development of certain types of cancer, some bacterial and fungal components may also exert anti-tumor effects on the contrary (Kaźmierczak-Siedlecka et al. 2020). For example, as a result of a study about relationship cancer and gut microbiota by taking samples from patients with oral cancer and people with non-oral cancer, it is seen that Candida, which produces high ethanol derivative Acetaldehyde (ACH), isolated from patients with oral cancer, is more common than patients with non-oral cancer (Alnuaimi et al. 2016). In addition, Candida isolated from patients with oral cancer indicates hydrolytic enzyme activity along with huge biofilm mass and biofilm metabolic activity. As a result of this research, Candida promotes the development of oral cancers due to its ability to produce hydrolytic enzymes and metabolize alcohol to the carcinogenic ACH (Alnuaimi et al. 2016; Kaźmierczak-Siedlecka et al. 2020).

Fungal β-glucans used as adjuvants to treat cancer patients

Some components (lectin, krestin, lentinan, hispolon, calcaelin, illudin S, psilocybin, ganoderic acid, schizophilan, laccase; Table 4) found in mushrooms/fungi may be promising in cancer treatment. Polysaccharides are best known as immunomodulatory and anti-tumor agents. β-glucan, which is polysaccharide, is the most versatile metabolite owing to its broad-spectrum biological activity. These β-glucans consist of a backbone of glucose residues linked by β (1-3)-glycosidic bonds, usually side chain glucose residues joined by β (1-6) bonds (Chen and Seviour 2007). Their mechanism of effect includes their recognition as non-self-molecules, so the immune system is induced by their entity. In fact, β-glucans purified from the cell walls of S. cerevisiae, as it is known, have been introduced as a healthy supplement that helps cancer treatment and prevention, weight loss, lowers cholesterol and increases vulnerable responses to infection (Volman, Ramakers, and Plat 2008). For some time, injectable soluble β-glucans, which are claimed in some studies, have been investigated as immune-enhancing agents with antibodies or chemotherapy in the treatment of cancer, and the results support this claim (Chen and Seviour 2007). What we see from the results of these studies seems to work primarily through the complementary intake of the tumor and the activation/renewal of neutrophils (Chen and Seviour 2007). After oral administration of particulate glucans, which mimics some of the benefits of injectable soluble β-glucans in animal models, orally administered particulate glucans are taken up by intestinal phagocytes, trafficked to the bone marrow and lymphoid organs, resulting in circulating soluble β-glucans, which can kill neutrophils and activate tumor cells (Hong et al. 2004). It is uncertain whether endogenous commensal fungi are converted to circulating β-glucan fractions, which are also undefended in "normal" situations or during fungal eruptions. Clinically, β-glucan blood assays are often used to identify invasive fungal complaint (Chen and Seviour 2007), and fungal colonization of the gut (without invasive complaint) may conduce to the changeable delivery status of circulating β-glucans detected. In addition, hispolon, that is a vigorous polyphenol component, additionally contained in mushrooms; it’s celebrated to own doubtless anti-neoplastic properties and doubtless the toxicity of chemotherapeutical agents. research to support the claims has accelerated in recent years (Arun et al. 2022). Although the findings show that some fungi add concert with commercial antitumor medicine as a good tool to treat drug-resistant cancers, there is not enough provability as it is still a new area of research. This shows us that mushrooms/fungi will take part in much more cancer research in the coming years (Patel and Goyal 2012).

Conclusion and future perspectives

In recent years, researches on both the production of valuable industrial metabolites (enzymes, organic acids, protein, pigment, etc.) and waste treatment through filamentous fungi have progressed exponentially, but their effects on the food industry need to be determined. In fact, the important bioactive compounds of mushrooms and their prevention on diseases (such as diabetes, hypertension, cancer, hypercholesterolemia and cardiovascular diseases) have been extensively studied and suggested to be used as a therapeutic supplement. Similarly, filamentous fungi with their high protein contents are important bioactive compounds producers. Studies on the antioxidant, antimicrobial and anticancer effects of these fungi-based bioactive compounds and secondary metabolites are promising in human health. Pharmacological investigation of existing bioactive compounds and secondary metabolites of fungi, which are easier to produce compared to mushrooms, and determination of their in vitro and in vivo health effects will make new generation food production more important.

Author contributions

Conceptualization: Taner Sar, Mohammad J. Taherzadeh; Visualization: Neda Rousta, Melissa Aslan, Taner Sar; Writing - original draft: Neda Rousta, Melissa Aslan, Meltem Yesilcimen Akbas, Taner Sar; Writing - review & editing: Neda Rousta, Meltem Yesilcimen Akbas, Ferruh Ozcan, Taner Sar, Mohammad J. Taherzadeh; Project administration: Mohammad J. Taherzadeh.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by the Swedish Agency for Economic and Regional Growth through a European Regional Development Fund. Open access funding was provided by University of Borås, Sweden