Date Published: September 6, 2011
Publisher: Hindawi Publishing Corporation
Author(s): Geir Hetland, Egil Johnson, Torstein Lyberg, Gunnar Kvalheim.
The medicinal mushroom Agaricus blazei Murill from the Brazilian rain forest has been used in traditional medicine and as health food for the prevention of a range of diseases, including infection, allergy, and cancer. Other scientists and we have examined whether there is scientific evidence behind such postulations. Agaricus blazei M is rich in the immunomodulating polysaccharides, β-glucans, and has been shown to have antitumor, anti-infection, and antiallergic/-asthmatic properties in mouse models, in addition to anti-inflammatory effects in inflammatory bowel disease patients. These effects are mediated through the mushroom’s stimulation of innate immune cells, such as monocytes, NK cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation.
The edible Basidiomycetes mushroom Agaricus blazei Murill (AbM), a.k.a. Agaricus subrufescens Peck (already described in 1893), and Agaricus brasiliensis Wasser  (Figure 1), of Brazilian rain forest origin is used in traditional medicine against cancer and various diseases [2, 3]. It is related to the champignon (Agaricus bisporus) and is shown to be rich in immunomodulating substances such as highly branched β-1,3-/1,6-glucans  and proteoglycans . These are known ligands for CD11b/18 (complement receptor 3, CR3) , dectin-1 , and toll-like receptor 2 (TLR2)  on monocytes, dendritic cells (DC), granulocytes, and NK cells  of the innate immune system. AbM is also shown to contain agaritine and ergosterol (provitamin D2) that is found to induce apoptosis in leukemic cells  and inhibit tumor-induced angiogenesis , respectively, as well as isoflavonoids with potent hypoglycemic action that could be useful against diabetes mellitus . AbM is reported to have antitumor properties in mouse models of fibrosarcoma, myeloma, ovarian, lung, and prostate cancer, and in human studies against gynecological cancer (increased NK cell activity and quality of life) and leukemia .
We found that an AbM-based extract (AndoSan, http://www.immunopharma.net/), also containing the medicinal Basidiomycetes mushrooms Hericium erinaceum (15%) and Grifola frondosa (3%), given orally increased survival from bacterial sepsis in mice inoculated i.p. a day afterward with pneumococci (Figure 2)  or fecal bacteria . The mixed mushroom extract also protected against IgE-mediated allergy in a mouse model when given p.o. either before or after ovalbumin s.c. sensitization of the animals (Figure 3) . In supernatants of cultured spleen cells from the sacrificed AbM-treated mice, there was an increased T-helper cell 1 response relative to the allergy-inducing Th2 response. The observation fits with the reduced specific serum IgE levels in these animals and shows that also adaptive immunity is engaged by the mushroom. Since the original Th1/Th2 dichotomy  says that the antitumor and anti-infection Th1 response is inversely related to the Th2 response, the spleen cell finding above also helps explain the concomitant antiallergic, antitumor, and antiinfection effects of AbM. Moreover, this agrees with the very interesting report finding that AbM extract ameliorated a skewed Th1/Th2 balance both in asthma-induced and in tumor-bearing mice . It is previously known that patients with advanced cancer have malfunctional Th1 cells and a Th2-skewed immune system . However, it is not known whether AbM contributed to rectify a possibly induced Th1/Th2 imbalance in the above-mentioned sepsis models in mice [14, 15].
In a human phase I study in 15 healthy volunteers, we recently found no side effects after intake of the AbM-based AndoSan extract [23, 24]. In particular, there were no significant changes in general blood parameters and no negative effects on kidney, liver, or pancreas function. This agrees with a toxicity study over two years in rats , which rather found that animals ingesting the highest AbM concentration lived the longest, presumably due to reduced cancer development. In the mentioned phase I study, AbM extract had an anti-inflammatory effect as shown by significantly reduced levels of proinflammatory cytokines. Although this is contrary to our in vitro findings of increased production of proinflammatory cytokines by monocytes, monocyte-derived DC (MDDC), and human umbilical vein endothelial cells (HUVEC), we did, as a consequence of the phase I trial, conduct a clinical pilot study at our hospital on patients with the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease. The result was a significant decrease in plasma levels of proinflammatory cytokines after 12 days of AndoSan intake orally and also decreased levels of the inflammatory marker calprotectin in feces of ulcerative colitis patients . Figure 4 shows that MIP-1β, IL-6, IL-8, MCP-1, IL-1β, G-CSF, and GM-CSF levels were reduced in the blood of ulcerative colitis patients and MIP-1β, MCP-1, IL-8, IL-1β, G-CSF, IL-17, GM-CSF, and IL-2 levels in blood of Crohn’s patients, respectively. This anti-inflammatory property of AbM may also be of importance for the mushroom’s therapeutic effect on allergy and asthma in mouse models [18, 21], both of which are inflammatory conditions, and it may bear promise for use against autoimmune diseases. In addition, it may explain some of AbM’s antitumor effects discussed below.
The reason for the forceful and swift engagement of innate immunity when encountering an edible and harmless mushroom, such as AbM, is its sharing of pathogen-associated molecular patterns (PAMP) with other highly poisonous species. Such mushrooms and fungi are usually a health threat due to the action of their toxins, for example, muscimol from Amanita muscaria and the vasoconstrictor ergotamine from Claviceps purpurea, or invasion in immunodeficient patients (e.g., Aspergillus fumigatus) or normal individuals (e.g., Stachybotrys chartarum).
As mentioned, the Agaricus mushroom is reported to inhibit various tumors , including hematological cancers such as myeloma in a recent mouse model  and leukemia in a human study . One proposed mechanism behind the antitumor effects of AbM is the induction of apoptosis in tumor cells, which is demonstrated in vitro . This is confirmed by the microarray finding of increased expression of genes inducing apoptosis as well as inhibition of cell division  in PBMC from patients with hepatitis C virus infection who drank AbM extract for 1 week. Other contributing mechanisms are (i) the known antitumor action of ergosterol [11, 54] contained in AbM extract, (ii) the anti-inflammatory effect of AbM [23, 24], which may reduce levels of the “tumor-friendly” neoangiogenic and granulocyte-chemoattractant factor IL-8 and thus may also decrease intratumor formation of reactive nitrogen and oxygen species that may hamper the infiltration of cytotoxic T cells , and (iv) the amelioration of the proposed skewed Th1/Th2 balance in advanced cancer . There is a well-established connection between inflammation and tumorigenesis , and it is known that organs with chronic inflammation are prone to cancer, for example, the colon in inflammatory bowel diseases, the pancreas after chronic pancreatitis, and the liver secondary to chronic viral hepatitis. Since up to 1/4 of all cancers are estimated to be caused by underlying infections and inflammation , there has lately been a novel interest for the use of anti-inflammatory treatment in cancer therapy . Hence, both the anti-inflammatory [23, 24] and anti-infection [14, 15] properties of AbM that we have disclosed may contribute to the mushroom’s antitumor activity. Interestingly, whereas there was a little, nonsignificant reduction in HCV load in serum in the mentioned clinical pilot trial in 4 patients with chronic IFNα-resistant HCV infection, the gene for IFNαβ receptor was significantly upregulated by the 7 days AbM treatment .
The medicinal mushroom Agaricus bM has been shown to have beneficial effects on a range of diseases including cancer, infections, allergy/asthma, and inflammatory disorders. The explanation is the mushroom’s engagement of innate immunity, which is “broad-spectered.” When adaptive immunity then is engaged through the stimulation of DC, it results in an enhanced Th1 antitumor and anti-infection response relative to the proallergic Th2 response. Thus, AbM ameliorates the Th2-skewed balance found in advanced cancer, mycobacterial infections and allergy and asthma. In addition, there may be a general anti-inflammatory effect of AbM, which may be therapeutical for inflammatory bowel diseases and augment the mushroom’s antitumor and antiallergy/antiasthma properties. Hence, AbM extract may show promise as a prophylacticum and as an additive treatment for quite different and some serious diseases.