• Lee Carroll

Introducing... Shiitake!



Shiitake! Here is a familiar mushroom that is native to Asia but is now commonly incorporated into Western diets. Little do many of us realise that this attractive and delicious mushroom packs a hugely powerful immunological punch when consumed regularly!

Shiitake is the most universal common name for the mushroom of Lentinula edodes, though it is variously known by names like sawtooth mushroom, black forest mushroom, golden oak mushroom, etc. Shiitake is the Japanese name, which literally describes its preferred host (wood of the shii tree, Castanopsis spp.). More alluringly, the Chinese name, xiang gu, translates as “fragrant mushroom”. Indeed, shiitake has a pleasant smell and taste due to a strong umami principle. It has been revered as a powerful therapeutic agent across East Asia for thousands of years [1].

The first record of Shiitake’s use comes from ancient China, where the line between myth and reality is often obscured. We imagine the original people of Japan also valued this mushroom, due to a record of the Kyusuyu people gifting Shiitake to the Japanese Emperor in the year 199 CE [1].


Demand for shiitake required cultivation methods in a time where fungal species were quite mysterious. The legendary Chinese figure Wu San Kwung is credited with developing the first method of cultivation (during the Sung dynasty, 960-1127 CE) [1,2]. To this day it is common for Chinese villages that produce mushroom crops to have a temple in his honour [1]. By the year 1313, Shiitake cultivation techniques were standardised and recorded by Chinese author Wang Cheng in his Book of Agriculture. The Chinese appear to have introduced these techniques to Japan in the 1500s, where the Shiitake was so treasured that it became tradition to gift cultivated logs to new born boys as a kind of positive omen and insurance for their health and financial status when grown [3].

Tradition ascribes shiitake as an elixir of life, claiming it improves stamina and circulation, cures colds and lowers cholesterol [4]. Still adored, it is the second most cultivated mushroom (after the button) in the world [5].


Medicinal Application

Shiitake contains complex bioactive chemistry but the most researched component is lentinan, which is found in both fruiting body and mycelium. It is a shiitake-specific beta-glucan polysaccharide, recognised as a valuable immunotherapeutic agent in Asia [6,7]. Back in 1969, researchers first found evidence of mouse tumor inhibition with polysaccharide extracts from Shiitake [4]. These have been under examination since then for direct anti-cancer and anti-tumor properties. While lentinan shows direct cytotoxic activity against cancer cells in vitro, in biological systems it appears to exert its anticancer effects via its immunoregulatory activity [7]. The immunosuppressive microenvironment of tumors is understood to be a key reason for chemotherapy failure, hence the immunomodulatory effects of Shiitake improves the efficacy of this therapy [7]. It was found that the overall mean response rate for lung cancer treatment, for example, increased significantly (from 43.3% to 56.9%) when lentinan was included with chemotherapy [6]. Early studies indicate extracts improve the overall quality of life and immunological function of cancer patients using chemotherapy [8,9,10]. In a study of patients with metastatic or recurrent gastric cancer, lentinan not only improved chemotherapy outcomes but resulted in significantly longer median overall survival [11].



Shiitake not only supports compromised immune systems, but we even see immune effects in healthy people! Most stunningly, this is demonstrated in a study of realistic dietary intake Shiitake (5 g dry mushroom), taken once or twice daily [12]. After four weeks, certain white blood cells (gamma-delta T cells and natural killer T cells) had increased and were primed to respond more vigorously to threats, while simultaneously, inflammatory activity was reduced (pro- and anti-inflammatory cytokine modulation apparent). Further, a commonly used marker of acute inflammation, C-reactive protein (CRP), which was already within the healthy range for the participants in this study, was significantly reduced. sIgA concentration and rate of production also increased significantly! Previous trials (double-blind, placebo-controlled) also show evidence of immunomodulation in healthy adults [13], including an elderly population [14].


One of the more unusual lines of Shiitake investigation has been regarding its potential in oral health. There are two double-blind trials that use Shiitake extracts topically in a mouthwash and find anticariogenic potential [15,16]. The extracts were low molecular weight fractions (therefore excluding the large polysaccharide components), and they were used for 10-14 days, and compared with both negative (placebo) and positive controls (commercial mouthwash). This extract reduces the metabolic activity of dental plaque [15] and results in significant improvements in plaque index scores (compared to placebo) and in gingival index scores (against both placebo and Listerine), and reduces numbers of some oral pathogens [16]. The oil extract has the best efficacy for biofilm-inhibition due to carvacrol, an aromatic monoterpene (also found in Thyme and Oregano) that breaks up the outer membrane of Gram-negative bacteria [2]. Importantly, Shiitake appears to selectively lower the numbers of some pathogenic species without affecting those associated with oral health (whereas pharmaceutical mouthwash tends to have more of a non-specific nuke effect [17]. It is likely Shiitake is effective as an antifungal and antiviral agent [2,18,19].



Modulation of the gastrointestinal microbiota has broad health ramifications. In a fascinating mouse study [20], 3 groups were compared: young adult mice, old adult mice, and old adult mice fed Shiitake. Aging is associated with a disordered microbiota. What the researchers observed was that Shiitake protected against this age-related dysbiosis. It enhances both systemic and mucosal immunity via modulation of intestinal gene expression. This has deeper implications for our overall health, hence researchers have begun to explore the anti-aging qualities of Shiitake, which are associated with its antioxidant protection [21].

Much of the antioxidant activity is attributed to the L-ergothioneine content, as it can physically trap reactive oxygen and nitrogen species (ROS, RNS), and inflammatory mediators [2]. A human study found Shiitake improves antioxidant activity after exercise-induced muscle damage [22]. Initial investigations indicate that Lentinan has the potential for preventing the oxidative stress-associated damage to pancreatic β-cells caused by increased glucose with insulin resistance, as seen in vitro [23], and in diabetic rats [24]. Shiitake also appears to be hypoglycaemic in type 1 diabetic rats [25].


So, Shiitake seems to improve sugar metabolism, but what about fat metabolism? Some more rat studies indicate some profound activity. Shiitake provided high-cholesterol animals with significant antioxidant, immunomodulatory and hepatoprotective effects [26]. Interestingly, lipid metabolism improvements occur via different mechanisms in rats, depending on sex. A 10% Shiitake diet reduced total cholesterol, HDL, non-HDL, and serum triglycerides in all rats, however females had reduced serum leptin, while males had increased serum insulin with reduced serum glucose [27]. While we can only speculate regarding the mechanisms behind this phenomenon, we do know that Shiitake alters genes involved in cholesterol metabolism similarly to statin medication [28].


Shiitake may even help manage obesity, as it reduced weight gain, circulating triglycerides and total fat [29], as well as fat accumulation in the liver [30]. Shiitake is protects the liver against toxic assault [31]. Recently it was found that Shiitake reduces ethanol absorption and also accelerates ethanol metabolism in the liver by promoting relevant enzymes [32]. It is likely to be valuable in non-alcoholic fatty liver disease too [33].


The above metabolic management helps protect against cardiovascular disease. Further, Shiitake might lower homocysteine [34], a strong risk factor for its development, and prevent plaque deposition associated with atherosclerosis [30,35,36].



Though there appears to be a myriad of health effects possible from Shiitake, I will end on its affinity for bone metabolism. It seems to inhibit osteoclast, and promote osteoblast, activity (improving bone mineralisation). An animal model of osteoporosis sees Shiitake significantly reduce bone loss (in this case it was combined with Maitake which may have added to the effect) [37]. An older mouse study found reduced severity and incidence of collagen-induced arthritis in mice given Shiitake [38]. It is possible that the syringic acid content of Shiitake plays a role here, as it upregulates bone formation in mice, independently of oestrogen signalling [39]. Shiitake can also be a source of vitamin D, being particularly high in ergosterol content, which becomes vitamin D2 with UV exposure. Vitamin D of course promotes bone health, and it appears to enhance the anti-inflammatory effects of Shiitake as well [33].


Safety, Quality and Dosing

I recommend aiming for 5-10 g dry mushroom daily. If you can incorporate a 5 g serve of shiitake into your diet, even if only every second day, you are likely to experience its health qualities.


Shiitake is safe at these recommended doses. In rare case however, ingestion of raw/undercooked shiitake can cause a painful allergic dermatitis, thought to be due to lentinan [40]. How rare you ask? A 2019 review of lentinan use in 9474 cancer patients in China, demonstrated only 18 patients or 0.02 % experienced adverse reactions [7]. Interestingly, I have seen it in clinic once to-date in a patient eating 2-3 raw shiitake daily. Onset of rash occurred within about 1 week. It was painful, extremely itchy and fully resolved on cessation after 10 days. Use caution if combining with anticoagulant and antiplatelet medication as lenthionine may potentiate this activity [41].



I recommend Shiitake as a key player for anyone seeking enhanced and balanced immune system function, as well as an adjuvant to cancer chemotherapy. I also recommend it as part of a broader regime for hypercholesterolemia, fatty liver and metabolic syndrome, obesity, insulin resistance, and to protect against cardiovascular disease development. It looks like has lots of other special powers and I expect it will be beneficial for the health & integrity of our gastrointestinal and oral membranes, skin, bones, and teeth.


References

[1] Wasser SP. Shiitake (Lentinus edodes). Encyclopedia of dietary supplements. 2005:653-64.

[2] Avinash J, Vinay S, Jha K, et al. The Unexplored Anticaries Potential of Shiitake Mushroom. Pharmacogn Rev. 2016 Jul-Dec;10(20):100-104.

[3] Tilak S. The shiitake mushroom – a history in magic and folklore. The Mycophile. 2019 Jan-Feb;59(1):1-4.

[4] Jong SC, Birmingham JM. Medicinal and therapeutic value of the shiitake mushroom. Adv Appl Microbiol. 1993;39:153-84.

[5] Rahman T, Choudhury MB. Shiitake mushroom: a tool of medicine. Bangladesh Journal of Medical Biochemistry. 2012;5(1):24-32.

[6] Zhang Y, Zhang M, Jiang Y, et al. Lentinan as an immunotherapeutic for treating lung cancer: a review of 12 years clinical studies in China. J Cancer Res Clin Oncol. 2018 Nov;144(11):2177-2186.

[7] Zhang M, Zhang Y, Zhang L, et al. Mushroom polysaccharide lentinan for treating different types of cancers: A review of 12 years clinical studies in China. Prog Mol Biol Transl Sci. 2019;163:297-328.

[8] Okuno K, Uno K. Efficacy of orally administered Lentinula edodes mycelia extract for advanced gastrointestinal cancer patients undergoing cancer chemotherapy: a pilot study. Asian Pac J Cancer Prev. 2011;12(7):1671-4.

[9] Tanigawa K, Itoh Y, Kobayashi Y. Improvement of QOL and Immunological Function With Lentinula Edodes Mycelia in Patients Undergoing Cancer Immunotherapy: An Open Pilot Study. Altern Ther Health Med. 2016 Jul;22(4):36-42.

[10] Yamaguchi Y, Miyahara E, Hihara J. Efficacy and safety of orally administered Lentinula edodes mycelia extract for patients undergoing cancer chemotherapy: a pilot study. Am J Chin Med. 2011;39(3):451-9.

[11] Ina K, Kataoka T, Ando T. The use of lentinan for treating gastric cancer. Anticancer Agents Med Chem. 2013 Jun;13(5):681-8.

[12] Dai X, Stanilka JM, Rowe CA, et al. Consuming Lentinula edodes (Shiitake) Mushrooms Daily Improves Human Immunity: A Randomized Dietary Intervention in Healthy Young Adults. J Am Coll Nutr. 2015;34(6):478-87.

[13] Choi JY, Paik DJ, Kwon DY, et al. Dietary supplementation with rice bran fermented with Lentinus edodes increases interferon-γ activity without causing adverse effects: a randomized, double-blind, placebo-controlled, parallel-group study. Nutr J. 2014 Apr 22;13:35.

[14] Gaullier JM, Sleboda J, Øfjord ES, et al. Supplementation with a soluble β-glucan exported from Shiitake medicinal mushroom, Lentinus edodes (Berk.) singer mycelium: a crossover, placebo-controlled study in healthy elderly. Int J Med Mushrooms. 2011;13(4):319-26.

[15] Lingström P, Zaura E, Hassan H, et al. The anticaries effect of a food extract (shiitake) in a short-term clinical study. J Biomed Biotechnol. 2012;2012:217164.

[16] Signoretto C, Burlacchini G, Marchi A, et al. Testing a low molecular mass fraction of a mushroom (Lentinus edodes) extract formulated as an oral rinse in a cohort of volunteers. J Biomed Biotechnol. 2011;2011:857987.

[17] Ciric L, Tymon A, Zaura E, et al. In vitro assessment of shiitake mushroom (Lentinula edodes) extract for its antigingivitis activity. J Biomed Biotechnol. 2011;2011:507908.

[18] Kupcova K, Stefanova I, Plavcova Z, et al. Antimicrobial, Cytotoxic, Anti-Inflammatory, and Antioxidant Activity of Culinary Processed Shiitake Medicinal Mushroom (Lentinus edodes, Agaricomycetes) and Its Major Sulfur Sensory-Active Compound-Lenthionine. Int J Med Mushrooms. 2018;20(2):165-175.

[19] Bisen PS, Baghel RK, Sanodiya BS, et al. Lentinus edodes: a macrofungus with pharmacological activities. Curr Med Chem. 2010;17(22):2419-30.

[20] Xu X, Yang J, Ning Z, et al. Lentinula edodes-derived polysaccharide rejuvenates mice in terms of immune responses and gut microbiota. Food Funct. 2015 Aug;6(8):2653-63.

[21] Wang L, Wang C, Gao X, et al. Purification, characterization and anti-aging capacity of mycelia zinc polysaccharide by Lentinus edodes SD-08. BMC Complement Altern Med. 2015 Apr 9;15:111.

[22] Zembron-Lacny A, Gajewski M, Naczk M, et al. Effect of shiitake (Lentinus edodes) extract on antioxidant and inflammatory response to prolonged eccentric exercise. J Physiol Pharmacol. 2013 Apr;64(2):249-54.

[23] Cao XY, Liu D, Bi RC, et al. The protective effects of a novel polysaccharide from Lentinus edodes mycelia on islet β (INS-1) cells damaged by glucose and its transportation mechanism with human serum albumin. Int J Biol Macromol. 2019 Aug 1;134:344-353.

[24] Zhang Y, Mei H, Shan W, et al. Lentinan protects pancreatic β cells from STZ-induced damage. J Cell Mol Med. 2016 Oct;20(10):1803-12.

[25] Yang BK, Kim DH, Jeong SC, et al. Hypoglycemic effect of a Lentinus edodes exo-polymer produced from a submerged mycelial culture. Biosci Biotechnol Biochem. 2002 May;66(5):937-42.

[26] Nisar J, Mustafa I, Anwar H, et al. Shiitake Culinary-Medicinal Mushroom, Lentinus edodes (Agaricomycetes): A Species with Antioxidant, Immunomodulatory, and Hepatoprotective Activities in Hypercholesterolemic Rats. Int J Med Mushrooms. 2017;19(11):981-990.

[27] Yu S, Wu X, Ferguson M, et al. Diets Containing Shiitake Mushroom Reduce Serum Lipids and Serum Lipophilic Antioxidant Capacity in Rats. J Nutr. 2016 Dec;146(12):2491-2496.

[28] Gil-Ramírez A, Caz V, Smiderle FR, et al. Water-Soluble Compounds from Lentinula edodes Influencing the HMG-CoA Reductase Activity and the Expression of Genes Involved in the Cholesterol Metabolism. J Agric Food Chem. 2016 Mar 9;64(9):1910-20.

[29] Handayani D, Chen J, Meyer BJ, et al. Dietary Shiitake Mushroom (Lentinus edodes) Prevents Fat Deposition and Lowers Triglyceride in Rats Fed a High-Fat Diet. J Obes. 2011;2011:258051.

[30] Yang H, Hwang I, Kim S, et al. Lentinus edodes promotes fat removal in hypercholesterolemic mice. Exp Ther Med. 2013 Dec;6(6):1409-1413.

[31] Sasidharan S, Aravindran S, Latha LY, et al. In vitro antioxidant activity and hepatoprotective effects of Lentinula edodes against paracetamol-induced hepatotoxicity. Molecules. 2010 Jun 23;15(6):4478-89.

[32] Uto-Kondo H, Sakurai A, Ogawa K, et al. Suppressive Effect of Shiitake Extract on Plasma Ethanol Elevation. Nutrients. 2020 Aug 31;12(9):E2647.

[33] Drori A, Shabat Y, Ben Ya'acov A, et al. Extracts from Lentinula edodes (Shiitake) Edible Mushrooms Enriched with Vitamin D Exert an Anti-Inflammatory Hepatoprotective Effect. J Med Food. 2016 Apr;19(4):383-9.

[34] Yang H, Hwang I, Kim S, et al. Preventive effects of Lentinus edodes on homocysteinemia in mice. Exp Ther Med. 2013 Aug;6(2):465-468.

[35] Rahman MA, Abdullah N, Aminudin N. Lentinula edodes (shiitake mushroom): An assessment of in vitro anti-atherosclerotic bio-functionality. Saudi J Biol Sci. 2018 Dec;25(8):1515-1523.

[36] Yamada T, Oinuma T, Niihashi M, et al. Effects of Lentinus edodes mycelia on dietary-induced atherosclerotic involvement in rabbit aorta. J Atheroscler Thromb. 2002;9(3):149-56.

[37] Erjavec I, Brkljacic J, Vukicevic S, et al. Mushroom Extracts Decrease Bone Resorption and Improve Bone Formation. Int J Med Mushrooms. 2016;18(7):559-69.

[38] Chandra L, Alexander H, Traoré D, et al. White button and shiitake mushrooms reduce the incidence and severity of collagen-induced arthritis in dilute brown non-agouti mice. J Nutr. 2011 Jan;141(1):131-6.

[39] Tanaka T, Kawaguchi N, Zaima N, et al. Antiosteoporotic activity of a syringic acid diet in ovariectomized mice. J Nat Med. 2017 Oct;71(4):632-641.

[40] Grotto D, Bueno DC, Ramos GK, et al. Assessment of the Safety of the Shiitake Culinary-Medicinal Mushroom, Lentinus edodes (Agaricomycetes), in Rats: Biochemical, Hematological, and Antioxidative Parameters. Int J Med Mushrooms. 2016;18(10):861-870.

[41] Shimada S, Komamura K, Kumagai H, et al. Inhibitory activity of shiitake flavor against platelet aggregation. Biofactors. 2004;22(1-4):177-9.

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