The immunomodulatory or antitumor activity associated with mushroom intake has been suggested to be due to a number of isolated fractions from mushrooms including the β-D-glucans, and other polysaccharides [10
]. The standard approach has been to purify the components and then to test them for efficacy. It is likely that mushrooms possess multiple immunoregulatory components including the selenium, B vitamins and polysaccharides that when ingested together or mixed in vitro
together would have effects that differed from the isolated components. In vitro
WB, crimini, shiitaki, and oyster extracts reduced IL-10 production and increased IL-1β, and TNF-α production by macrophage. The activation of the macrophage with the mushroom extracts preferentially stimulated T cell production of TNF-α and IFN-γ and very little IL-10. This pattern of immuno-regulation by mushrooms is consistent with a model whereby whole mushroom consumption would induce a modest but important boost in immune responses that would improve anti-cancer immunity (Fig. ). In macrophage, the inhibition of IL-10 and activation of IFN-γ, IL-1β, and TNF-α would result in an activated phenotype for the macrophage that would induce production of T cell and macrophage cytokines like IFN-γ and TNF-α that are important in clearance of tumorogenic cells, pro-inflammatory signaling, and killing of infectious organisms (Fig. ). In RAW 264.7 cells the induction of TNF-α production was highest in LPS and WB stimulated rather than the crimini, maitake, oyster, or shitake stimulated cells. The differences might be a result of differences in the quantity of the immunomodulatory substance or substances and or differences in solubility of mushrooms in the DMSO used to produce the extracts. However, the direction of the changes (increase versus
decrease) were not different among the mushroom treatments. The lack of differential effects on cytokine secretion by the mushroom extracts suggests that the whole mushrooms must share a common component(s) that act to regulate immune function.
Figure 7 Model of the effects of whole mushrooms on anti-cancer immunity. Whole mushrooms contain active components that can induce TNF-α, and IL-1β in vitro while inhibiting IL-10 production. Consuming mushrooms in the diet also had an effect (more ...)
Feeding mice diets that included up to 2% WB mushrooms over 4 weeks had no effect on a number of immune parameters including percentage of T and B cells, Con A and LPS stimulated cytokine production and colonic expression of a panel of cytokines including IL-1β, IL-10, TNF-α and IFN-γ. This is consistent with data by Wu et al. that showed that WB mushroom feeding at much higher doses (2–10%) and for 10 weeks did not affect T cell, B cell, NK cell, and macrophage cell numbers or affect Con A and LPS induced cytokine production [14
]. This is not completely unexpected since it would certainly be harmful to have a commonly present dietary component induce or suppress normal immune function.
DSS is normally used to cause transient colonic injury and as a model of acute colitis. WB feeding was protective for some parameters of DSS colitis; early weight loss and colonic shortening. It is unclear by what mechanism the WB feeding would protect from colonic injury. When challenged with DSS the WB mushroom fed animals transiently produced more TNF-α in the colon but showed no other changes in immune function. TNF-α production is negatively associated with colitis symptoms in the DSS model. Therefore the increased local production of TNF-α and decreased colitis injury following WB intake are paradoxical. The improvement in colitis symptoms is unlikely to be related to the increased production of TNF-α but instead might reflect a change in the composition of the bacterial microflora that has been shown to impact disease symptoms in the DSS model [15
]. The data show that WB mushrooms are protective against colonic injury and the mechanisms underlying the protective effects would be an area worthy of future investigation.
Agaritine, a natural compound found in the Agaricus
species of mushrooms, has been implicated as a carcinogen [16
]. Even though animal studies do not show agaritine to be a carcinogen at physiological doses there is still a possible concern regarding toxicity at high intake levels of mushrooms [16
]. WB mushrooms are Agaricus
mushrooms and are the most commonly consumed mushrooms in the US. Toxicity might be expected in tissues that come into contact with the agaritine like the stomach or intestines and those tissues that might break down or excrete absorbed agaratine like the liver or kidney. Based on the normal growth curves of mice fed 2% WB mushrooms for 4 weeks and data by Wu et al. showing that intake as high as 10% WB mushrooms for 10 weeks did not affect body weight we can conclude that there are no gross effects of feeding mice agaritine containing mushrooms [14
]. In addition, histopathology sections of the stomach, small intestine, large intestine, liver and kidney from mice fed WB mushrooms showed no changes that might indicate an affect of increased agaritine intakes over the 4 weeks of the study. While it still might be possible that longer term intake of agaritine containing mushrooms might prove toxic, the present data using moderate doses of mushrooms does not support the claim.
Mushrooms contain a significant amount of protein, vitamins and minerals in addition to a large amount of carbohydrate much of which are polysaccharides that are indigestible by humans and therefore are considered dietary fiber [19
]. It is possible that differences in the cultivation of mushrooms in different regions and by different growers may affect the composition of an important immunomodulatory factor. One of the limitations of the present study is that the results presented may only reflect results of mushrooms grown in Pennsylvania and more specifically by the manufacturers of those mushrooms in Pennsylvania. Future research should sample mushrooms from different suppliers of the same species for comparison of immunomodulatory functions.
Several major substances have been isolated from mushrooms and shown to be immunomodulatory. What has not been considered is that mushrooms have a number of bacteria, yeasts and molds associated with them. In fact microorganisms are required for initiation of fruit body formation. Normal healthy mushrooms have high bacterial populations associated with them with the numbers ranging from 6.3–7.2 log CFU/g of fresh mushrooms [19
]. The bacteria associated with mushrooms are predominately the pseudomonads [19
]. The pseudomonads have been shown to activate the innate immune response by interactions with the Toll like receptors (TLR), especially TLR-5 [23
]. It is likely that the microbiota ingested with the mushrooms are triggering the mucosal innate immune response through the TLR. More research is required to determine the relative contributions of bacteria, versus
nutrient and other components of mushrooms as immune system regulators.