Immunomodulatory Effects of Edible and Medicinal Mushrooms and Their Bioactive Immunoregulatory Products

1. Introduction

In clinical practice, immunomodulators are usually classified into three categories: immunosuppressants, immunostimulants, and immunoadjuvants [1]. Their market share has increased rapidly over the past few years due to wide-ranging medical applications for patients that require human immune system modulations. Immune system modulations are also commonly used as prophylactic medicine for an increasing number of healthy people [2,3]. While most immunomodulators are synthetic or semi-synthetic compounds, there has been a growing interest in natural immunomodulators. Many natural compounds have shown significant immunomodulatory and overall health-benefiting effects to humans, with no or minimal toxicity. These natural-based products with potential pharmacological and beneficial effects are increasingly perceived as safer than synthetic compounds by the general public [4,5]. Indeed, many of the currently used chemical drugs have negative side effects and the market share of natural immunomodulators is increasing rapidly with an annual growth rate of 8.6% [1,6].

Medicinal mushrooms (MMs) are an important source of natural immunomodulators. Representing a subset of all mushrooms, MMs are broadly defined as macroscopic fungi that are used in the form of extracts or whole mushroom powder for human health benefits [7]. The health benefits may come in the form of helping to prevent and/or treat diseases in humans, and to create a dietary balance of a healthy diet. Dating back to thousands of years, MMs have been historically used as herbal medicines for human health, such as for the treatment of infectious diseases, gastrointestinal disorders and asthmatic conditions [8]. The biomass or specific extracts from all developmental stages of MMs, including the fruiting body, sclerotium, mycelium, and spores, have been used as health foods or dietary supplements [9,10]. Some of the extracted nutrients from mushrooms known as mushroom nutraceuticals have been made into capsules or tablets as dietary supplements. Regular intake of these nutraceuticals has been associated with enhancement of the human immune response, leading to increased resistance to infectious diseases and faster recovery from a diversity of diseases [11].

At present, thousands of branded MM products are sold all over the world. The health benefits of MM products include anticancer, immune-stimulation, antioxidant, antihyperglycemic, antihypertensive, neuroprotective, hepatoprotective, antidiabetic, antifungal, antibacterial, and antiviral activities [7,12]. Their effects have been attributed to many components, such as minerals, essential amino acids, dietary fiber, proteins, polysaccharides, lipopolysaccharides, glycoproteins, and secondary metabolites. Among these, some of the complex organic compounds have shown immunomodulatory effects [7]. For example, polysaccharides from MMs can activate natural killer cells, macrophages, and neutrophils, as well as induce innate immune cytokines and interleukins. In addition, secondary metabolites from MMs, such as sterols, terpenes, and phenols can enhance the survival of hosts by stabilizing their important metabolic functions [8].

Different MMs contain different functional components that may impact the same or different immunomodulatory pathways at varying efficacies. In the following sections, we first provide a brief description of the known MMs. We then summarize the diversity, structure, function, and molecular mechanism of action of functional ingredients from MMs that have shown to be involved in immunomodulation. We finish by briefly describing how genomics can accelerate research on medicinal mushrooms.

2. Medicinal Mushrooms

As mentioned above, medicinal mushrooms refer to all macroscopic fungi whose extracts or powder form from any stages of the mushroom development have shown documented beneficial effects on health [13]. These beneficial effects may have been shown in the forms of in vitro, ex vivo, or in vivo activities. Their effects may cover different groups of organisms such as antagonistic effects against human pathogens and parasites, and/or beneficial effects for human and animal cell lines, or animal and human individuals [11]. Since many edible mushrooms and their products have shown to be a beneficial component of the human diet, some of these edible mushrooms are also commonly included as medicinal mushrooms [7]. In our literature search, a large number of MMs have been documented. For example, terpenes and terpenoids from Ganoderma lucidum could stimulate the expressions of genes coding for proteins in the nuclear factor (NF)–kB pathway and modulate immune system functions [14]. Heteroglycan and heteroglycan-peptide from the mushroom of Hericium erinaceus can modulate the immuno-effects by inducing nitric oxide production and increasing expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-12 [15]. These mushrooms belong to two fungal phyla, Ascomycota and Basidiomycota. Most of the MMs are in phylum Basidiomycota. Table 1 shows the major medicinal mushrooms, including their taxonomy and geographic/ecological distributions. As can be seen, some of these mushrooms are broadly distributed (e.g., the button mushroom Agaricus bisporus) while others are geographically more restricted (e.g., the Himalayan caterpillar fungus Ophiocordyceps sinensis). Some of the mushrooms included in the table e.g., Amanita phalloides are highly poisonous when consumed by humans. However, the dilutions of an A. phalloides extract that contains the toxin amanitin have shown to be effective as an anti-tumor therapy [16].

Some of these MM species have been used as herbal medicine for centuries, including Ganoderma lucidum, Ganoderma lingzhi, Lentinula edodes, Inonotus obliquus, Fomitopsis officinalis, Piptoporus betulinus, and Fomes fomentarius [7,17]. While these mushrooms have attracted most of the medical attention among the MMs, other species in multiple genera have also shown immunomodulatory and anti-tumor effects, such as those in genera Agaricus, Albatrellus, Antrodia, Calvatia, Clitocybe, Cordyceps, Flammulina, Fomes, Funlia, Ganoderma, Inocybe, Inonotus, Lactarius, Phellinus, Pleurotus, Russula, Schizophyllum, Suillus, Trametes, and Xerocomus [12].