Intractable Enteritis: How Lingzhi Can “Tune” It—The Polysaccharide Perspective

If it hadn't been for Japanese Prime Minister Shinzo Abe’s sudden announcement of his resignation on August 28, many people would never have noticed this lifelong autoimmune disease—ulcerative colitis (also known as ulcerative colitis).

In fact, just over a year after Abe first took office as Japan’s prime minister in 2007, he was forced to abandon his ambitious plans due to a recurrence of ulcerative colitis. This chronic illness, which had been with Abe since he was 17, first brought down Japan’s youngest-ever prime minister (at age 53) and then went on to topple Japan’s longest-serving prime minister (at age 66), underscoring how stubborn and difficult this disease is to treat.

On the afternoon of August 28, 2020, Japanese Prime Minister Shinzo Abe held a press conference and announced his resignation from the post of prime minister. (Photo/Wikimedia Commons)

Because of immune dysregulation, the inflammation persists.

For most people, a few days of stomach upset or bacterial infection causing abdominal pain and diarrhea is already unbearable. How much more so for ulcerative colitis—a condition that, once it flares up, forces sufferers to run to the bathroom over ten times a day, and may even be accompanied by symptoms such as bloody stools, fever, vomiting, dehydration, and dramatic weight loss? In the former case, since there’s a clear cause, the illness can usually be cured with appropriate medication. But in the latter case, the underlying cause remains unknown: it’s an inflammation and damage of the intestinal mucosa whose root cause cannot be eliminated by medication alone. All we can do is try to suppress the inflammation and alleviate the associated symptoms.

To put it bluntly, the problem with ulcerative colitis lies in “inflammation that shouldn’t occur but just won’t stop.” When the immune system—responsible for initiating the inflammatory response—loses its regulatory control, it’s as if one keeps stepping on the accelerator without ever hitting the brake, or mistakenly identifies a good guy or even one’s own body as an enemy and starts attacking it. As a result, what should be a protective and healing inflammatory response turns into a devastating health killer that can break your heart—and over the long term, repeated episodes of inflammation may even trigger cellular cancerous transformation.

Figure 1: Schematic diagram of the colon and endoscopic image of ulcerative colitis

The large intestine is divided into three segments: the cecum, the colon, and the rectum (left diagram). The cecum is connected to the small intestine and prevents food that has entered the large intestine from flowing backward. The colon is responsible for the digestive and absorptive functions of the large intestine, and it transforms residual waste into feces, temporarily storing them in the rectum until they are expelled. Ulcerative colitis primarily affects the mucosal tissues of the colon and rectum; endoscopic examination (right diagram) reveals inflammation and ulceration of the colonic mucosa. (Image/Wikimedia Commons)

Anti-inflammation only treats the symptoms; regulating the immune system is what addresses the root cause.

Regarding immune dysregulation, current medications can only address the “symptoms” triggered by the immune dysfunction. Although there’s a chance to turn an active volcano into a dormant one (just as Abe managed to keep things under control for a while), it’s difficult to guarantee that the volcano won’t suddenly erupt again one day—and this time, the eruption could be even more uncontrollable.

If we can not only alleviate symptoms but also correct the imbalanced immune response—effectively cleaning up the mess while addressing the root cause—we may be able to turn a major volcano into a smaller one, extend the dormant period of a dormant volcano, thereby reducing both the severity of flare-ups and the frequency of recurrences, and even push the risk of cancer development farther away.

“Regulating immunity and strengthening the body’s vital essence” has always been Lingzhi’s signature strength in the world of herbal medicine. According to currently published scientific literature, both polysaccharides and triterpenes derived from Lingzhi can play a significant role in improving ulcerative colitis by targeting immune regulation.

Ganoderma lucidum polysaccharides reduce the severity of intestinal inflammation flare-ups.

A report published in 2018 by the Department of Immunology at China Medical University in the Journal of Immunology Research, as well as a study published in 2019 by the Department of Food Science and Engineering at Jinan University in Food & Nutrition Research, independently demonstrated that prophylactic oral administration of Ganoderma lucidum polysaccharides for 2 to 3 weeks can significantly reduce the severity of acute exacerbations of ulcerative colitis (Figure 2).

 

 

 

 

Figure 2: Ganoderma polysaccharides alleviate symptoms of ulcerative colitis.

Mice supplemented with ganoderma polysaccharides for two weeks prior to induction (100 mg/kg daily) exhibited less weight loss and lower disease activity when subjected to an acute exacerbation of ulcerative colitis. Specifically, they showed milder degrees of weight loss, diarrhea, and rectal bleeding. Moreover, their colon lengths were longer—indicating a lesser degree of inflammatory damage—and the extent of tissue injury—including mucosal damage and leukocyte infiltration—was also reduced. (Source/Reference 1)

Why can ganoderma polysaccharides improve ulcerative colitis? Two research studies analyzed this phenomenon from two different perspectives: “modulating immune responses” and “regulating gut microbiota.”

Mechanism 1: Ganoderma lucidum polysaccharides regulate the inflammatory response, and inhibiting Th17 cells is crucial.

A study conducted by China Medical University found that mice supplemented with Ganoderma lucidum polysaccharide GLP beforehand exhibited fewer inflammation-associated cytokines in the colonic mucosal tissue when induced into an acute flare-up of ulcerative colitis (Figure 3). Moreover, there were fewer natural killer cells and Th17 cells—both of which promote inflammation—and conversely, B cells, which secrete IgA—the primary antibody in the mucosal tissue—showed increased activity.

These immunological changes not only help to dampen inflammatory responses and enable the gut to resist potential infections, but also offer an opportunity to correct the imbalance between Th17 cells and regulatory T cells (Tregs), thereby addressing the autoimmune issues underlying ulcerative colitis at their root.

Every autoimmune disease has key factors that trigger its onset and exacerbate its progression. In the case of ulcerative colitis, one such key factor is a specific subtype of T cells known as “Th17 cells.” The cytokine they secrete—IL-17 (with IL-17A being the most prominent)—plays a crucial role in the intestinal immune barrier by mediating inflammatory responses to combat various bacterial and fungal infections.

However, both excess and deficiency in anything can be harmful. Th17 cells and another subset of T cells known as “regulatory T cells” maintain a delicate balance: when one population is abundant, the other tends to be scarce. The function of regulatory T cells is to preserve autoimmune tolerance—that is, to prevent the immune system from launching an immune response against the body’s own tissues—and to promptly put the brakes on inflammatory responses when necessary. Therefore, if Th17 cells become overly active, regulatory T cells will be put at a disadvantage, leading to persistent inflammation.

The imbalance between these two cell populations is considered to be the key trigger of ulcerative colitis. In the aforementioned study conducted by China Medical University, although the number of regulatory T cells in the colonic mucosal tissue of mice did not increase following the intervention with ganoderma polysaccharides, the levels of Th17 cells and IL-17A secretion were significantly reduced (Figure 3). This represents a promising start toward restoring the balance between Th17 cells and regulatory T cells.

 

Figure 3: Ganoderma polysaccharides regulate immunity and ameliorate colitis.

Mice supplemented with Ganoderma lucidum polysaccharide GLP at 100 mg/kg daily for two weeks showed a significant reduction in the levels of inflammation-associated cytokines—including tumor necrosis factor (TNF-α), IL-1β, IL-6, IL-4, and IL-17A—in the colonic mucosal tissue when subjected to an induced acute exacerbation of ulcerative colitis. The levels of Th17 cells were also markedly decreased; however, there was no statistically significant difference in the levels of regulatory T cells compared to those in mice with colitis that had not been given Ganoderma lucidum polysaccharide. (Source/Reference 1)

Mechanism 2: Ganoderma polysaccharides regulate the gut microbiota, helping to restore immune balance.

Research from Jinan University has found that ganoderic polysaccharide GLP can regulate the balance among gut microbiota in experimental rats—for example, by reducing populations of bacteria that are prone to causing disease and increasing populations of bacteria that promote anti-inflammation and short-chain fatty acid production. This, in turn, stimulates the gut microbiota to secrete more short-chain fatty acids (Figure 4), thereby modulating the immune response of the intestinal mucosa and alleviating the severity of ulcerative colitis flare-ups.

A significant portion of the substances absorbed by the large intestine are produced by the bacteria that live there. When polysaccharides—such as dietary fiber and ganoderma polysaccharides—that cannot be digested by the small intestine reach the large intestine, they are broken down by a specific group of bacteria that thrive on these compounds into various short-chain fatty acids. These short-chain fatty acids—acetic acid, propionic acid, and butyric acid—not only nourish intestinal cells but also help protect the mucosal barrier and regulate immune responses. In contrast to these beneficial bacteria, some gut microbes act as promoters of inflammation. When the balance among these microbial populations is disrupted, it often marks the onset of disease.

Existing research has confirmed that an imbalance in the gut microbiota and insufficient secretion of short-chain fatty acids can lead to immune dysfunction, which in turn triggers ulcerative colitis. However, Ganoderma lucidum polysaccharides can work in reverse: by modulating the gut ecosystem, they can regulate the immune system and further alleviate ulcerative colitis. Isn't that cool? (To be continued—on Ganoderma triterpenes!)

 

Figure 4: Ganoderma lucidum polysaccharides regulate the gut microbiota and ameliorate colitis.

Rats were fed a diet supplemented with Ganoderma lucidum polysaccharide (GLP) at a dose of 393.75 mg/kg per day for three weeks, after which they were induced to experience an acute flare-up of ulcerative colitis. In inflamed intestines, it is typically observed that the abundance of Proteobacteria increases, while the abundance of Firmicutes decreases and the production of short-chain fatty acids is reduced. However, in the colon protected by Ganoderma lucidum polysaccharide, these two microbial groups showed significant changes: the abundance of Firmicutes increased markedly, whereas the abundance of Proteobacteria decreased significantly. Moreover, the levels of short-chain fatty acids rose substantially. (Source/Reference 2)

[References]

1. Wei B, et al. Suppression of Th17 Cell Response in the Alleviation of Dextran Sulfate Sodium-Induced Colitis by Ganoderma lucidum Polysaccharides. J Immunol Res. 2018 May 20;2018:2906494. doi: 10.1155/2018/2906494. eCollection 2018.

2. Xie J, et al. Ganoderma lucidum Polysaccharide ameliorates DSS-induced colitis in rats by modulating the cecal microbiota and gene expression in colonic epithelial cells. Food Nutr Res. 2019 Feb 12;63. doi: 10.29219/fnr.v63.1559. eCollection 2019.

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