THE POTENTIAL THERAPEUTIC ROLE OF HERICIUM ERINACEUS EXTRACT IN PATHOLOGIC CONDITIONS INVOLVING THE UROGENITAL-GUT AXIS: INSIGHTS INTO THE INVOLVED MECHANISMS AND MEDIATORS

Lower urinary tract symptoms (LUTS) refer to different symptoms divided into voiding, storage, or postvoiding including urinary hesitancy, straining, nocturia, increased urination frequency, and dysuria. They are frequent in the general population and approximately a third of individuals experience LUTS during their lifetime with a negative impact on patients’ health-related quality of life. There are several causes of LUTS such as benign prostate enlargement, detrusor muscle weakness or overactivity, prostate inflammation (prostatitis), urinary tract infection, prostate cancer, and neurological disease (1). Several studies highlighted the concept that inflammatory conditions affecting the gastrointestinal tract may at least in part contribute to occurrence of genito-urinary disorders, thus being a putative target of intervention (2-4). Hericium erinaceus (H. erinaceus) is an ancient medicinal mushroom from China whose extract main biologicaly activities are neuroprotective and anti-cancer (5, 6). However, H. erinaceus extracts have also shown to exert beneficial effects in a number of pathological conditions due to its anti-inflammatory properties (7, 8). In particular, an H. erinaceus-derived nutraceutical has been demonstrated to be effective in decreasing intestinal inflammation probably, at least in part, due to its prebiotic activity similar to that of other edible mushrooms (8).

In this review we therefore analyze the mechanisms underlying the pathophysiological connection between the urogenital and the gastrointestinal tract. Also, we review the scientific evidence which supports the beneficial effects of H. erinaceus in the gut highlighting the involved mechanisms and mediators. Finally we discuss the potential role of H. erinaceus in the treatment of genito-urinary tract conditions in which the involvement of intestinal inflammation might play a role.

METHODOLOGY

We conducted a narrative review in the Medline (US National Library of Medicine, Bethesda, MD, USA), Scopus (Elsevier, Amsterdam, The Netherlands), and Web of Science Core Collection (Thomson Reuters, Toronto, ON, Canada) databases up to November 2023. The following terms were combined to capture relevant publications: ‘lower urinary tract symptoms’, OR ‘chronic prostate inflammation’, OR ‘urinary tract infection’ AND ‘microbiota’ OR ‘intestinal microbiota’ OR ‘gut microbiota’ OR Hericium erinaceus. Retrospective and prospective studies, both comparative and non-comparative; narrative reviews; systematic reviews; and meta-analysis were included. Reference lists of included studies were searched for additional relevant articles. Letters, editorial comments, replies from authors, case reports, meeting abstracts, and non-human and non-English language articles were excluded. Data were extracted, and the results were qualitatively described, as reported in primary studies.

LOWER URINARY TRACT SYMPTOMS AND THE GASTROINTESTINAL TRACT

Lower urinary tract symptoms (LUTS), mainly due to recurrent urinary tract infections (rUTI), have a significant epidemiological burden in the general population and may negatively affect patients quality of live. Moreover, they represent a therapeutic challenge and require management with both antibiotic-based and behavioural strategies (9). Gut is a well known reservoir of uropathogenic bacteria and therefore it has been regarded to as a possible source of rUTI. In recent years. In recent years, the concept of the ‘gut-bladder axis’, identified by the complex interactions between the gastrointestinal and genitourinary digestive systems, is increasingly emerging (10). This relationship is often expressed by the co-occurrence of LUTS and intestinal disease (11). Indeed, it is well known, that women who suffer from fecal incontinence also frequently suffer from urinary incontinence and that in patients with irritable bowel syndrome, urinary symptoms such as voiding frequency and urgency coexist (12). In this regard, we have recently evaluated the prevalence of LUTS in a large cohort of 301 patients with inflammatory bowel disease (IBD) through standardised questionnaires (i.e. Bristol female lower urinary tract symptoms (BFLUTS), NIH-chronic prostatitis symptom index (NIH-CPSI), and international prostate symptom score (IPSS)).

Our study demonstrated that women had an increased prevalence of LUTS as determined by BFLUTS total score, high age at diagnosis being a significant predictor of worse filling symptoms and a worse quality of life (13). Similarly, in men 67.1% had mild, 28.5% moderate, and 4.4% severe LUTS as assessed by IPSS with an overall NIH-CPSI prevalence of chronic prostatitis-like symptoms as high as 26.8% (13).

The pathophysiological link between diseases of the urogenital tract and intestinal tract is well explained by the concept of cross-organ sensitization which refers to the ability of a given organ to influence the homeostasis of an adjacent or distant organ by the transmission of noxious stimuli. In particular, the pathophysiology of a number of chronic urogenital conditions such as interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome has been attributed to a cross-organ sensitization between the genito-urinary tract and the gut (14). Pelvic cross-organ sensitization has also been demonstrated between experimentally-induced colitis and bladder overactivity and painful sensation in a murine experimental model (15). Indeed, in animal models of experimental colitis, increased neuronal activity with amplification of bladder sodium ion current in the intestinal microenvironment was demonstrated when urinary bladder distension occurred (15).

Intestinal microbiome and its ability to modulate intestinal permeability may represent a putative link between genito-urinay tract and gastrointestinal tract since these two microenvironments share a wide range of bacterial and fungal species (e.g., Firmicutes, Bacteroidetes, Proteobacteriae, Actinobacteria) (10, 16-18). In particular, short chain fatty acids produced by gut bacteria, are capable of affecting gut permeability by strengthening tight junctions, stimulating mucus production and IgA synthesis (16). Short chain fatty acids, in particular acetic acid and propionic acid, have also been found in higher concentrations in the saliva of patients with gastro-esophageal reflux disease compared witth control subjects (19). Also, E. coli-derived indole stimulates the synthesis of proteins present in tight and adherence junctional complexes of intestinal epithelial cells (16). It has therefore been hypothesized that a quali-quantitative modification of gut microbiota may induce a leaky gut syndrome (i.e., a syndrome associated to increased intestinal permeability) which may then favour the transmission of noxious agents, such as bacteria or bacterial products, to the genito-urinary tract (18). Other mechanisms of cross-organ -sensitization in the pelvis may also occur through shared sensory neural pahways at different prespinal, spinal and supraspinal levels (20), thus causing an impairment of sensory pathways of the bladder (17). Another mechanism underlying cross-organ sensitization may be represented by glutamate and glutamate receptors, as well as capsaicin and its receptor, TRPV1 (21). To support the relevance of intestinal microbiota in the occurrence of urinary-tract disorders, Worby et al. in a study conducted in women with and without rUTI, found that women with a history of rUTI had significantly decreased microbial richness and depleted butyrate-producing bacteria compared to controls (22). Interestingly in a recent study, Thanert et al. analyzed whole genome sequences of uropathogenic E. coli (UPEC) in the stool and urine of a large cohort of men and women and found 119 lineages of antibiotic-resistant UPEC. Some of these were found only in urine, some only in the stools some in both. Interestingly dual colonizers (i.e., present in both urine an stools) UPEC had higher genetic diversity due to the presence of genetic adaptations favouring successful establishment in both niches (23). Altogether, experimental and clinical evidence strengthen the concept of the role of the urinary-intestinal axis in a number of genito-urinary pathologic conditions with a direct impact of gut microbiota composition (18, 24).

HERICIUM ERINACEUS AND ITS BENEFICIAL EFFECTS IN THE GUT

Mounting evidence accumulated over the past decades strongly supports the concept that products isolated or purified by foods (in our case an edible mushroom) may exert a biologically activity with a physiological benefit and/or protection against chronic diseases (25). When these products are in a medicinal form such as a pill, a powder or a suppository, they are named nutraceuticals (i.e. naturally bioactive products which cover the gap between nutrition and pharmaceutical) (26). In other words a nutraceutical gives the opportunity to deliver, under a medicinal form, the biologically active component of a given food in a concentration higher than that you might deliver by simply eating that particular food. In this respect, H. erinaceus, also known in Japan as Yamabushitake and in China as Houtou, is an edible mushroom belonging to the class Basidiomycota, subclass Holobasidiomycetidae, order Hericiales, and family Hericiaceae (27). H. erinaceus has a number of bioactive metabolites and the main biologically active constituents are erinacines, steroids, alkaloids, and lactones such as vitamin B12-c-lactone (7, 8). Moreover, H. erinaceus contains numerous endopolysaccharides such as the β-glucans and chitin, in the fungal cell wall, which exert a marked anti-inflammatory and anti-cancer effect being also able to positively modify the gut microbiota (28). Wang et al. have demonstrated that H. erinaceus-derived polysaccharides inhibit the secretion of a number pro-inflammatory cytokines and promote the secretion of interleukin-10 (IL-10) thus favouring an anti-inflammatory cytokine pattern in an in vitro model consisting of a co-culture of cancer colon 2 (CaCo-2) cells and Caco-2/RAW264.7 cells under bacterial lipopolysaccharide stimulation (29). Because of its potent anti-inflammatory effects, H. erinaceus has been studied as a potential therapeutic agent in inflammatory conditions involving the gut, such as inflammatory bowel disease (i.e ulcerative colitis (UC) and Crohn’s disease (CD)). Diling et al. (8) in a model of trinitrobenzene-sulfonic acid (TNBS)-induced colitis showed that treatment with mixed extracts of H. erinaceus (polysaccharide, ethanol extracts, and cumulative fractions) for 14 days led to a significant clinical and histological improvement with a reduced neutrophil infiltration and a recovery of the pro-inflammatory/anti-inflammatory cytokine balance. This beneficial effect was also confirmed in a different experimental colitis model (i.e. dextran sulphate sodium-induced colitis) and, in this case, was associated to a significant anti-oxidant activity (30). More recently, in an ex-vivo model consisting of biopsy specimens obtained from the intestine of patients with IBD, we evaluated the anti-inflammatory potential of a nutraceutical compound consisting of H. erinaceus, berberine, and quercetin (i.e., HBQ-Complex®). Incubation for up to 180 minutes with HBQ-Complex® of biopsies obtained from inflamed intestinal areas resulted in a progressive decrease in the gene and protein expression of the proinflammatory cyclo-oxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-α) compared to base-line, control values. On the other hand, the anti-inflammatory IL-10 showed an opposite trend, with a progressive increase of mRNA and protein expression compared with base-line values (31). The anti-inflammatory effect of H. erinaceus might be contributed to by its potent anti-oxidant effect (32).

Another mechanism whereby H. erinaceus extracts from fruiting bodies or mycelia may promote beneficial effects in the gut might be through the modulation of gut microbiota, which seems to play a crucial role in the development and progression of IBD, as well as in the treatment of several gastrointestinal pathological conditions, including IBD (33) Mounting evidence suggests that H. erinaceus extract is capable of favouring a healthy phenotype of the gut microbiota, both quantitatively and qualitatively by selecting certain beneficial bacterial strains at the expense of pathogenic strains (8, 34-36). Xie et al. (36) studied the effect of fourteen days administration of 1 g of H. erinaceus powder containing polysaccharides, peptides, crude fat, and trace elements in 13 healthy young volunteers and showed an increase in the alpha diversity of the gut microbiota with an increase in Bifidobacterium and Bacteroides, an increase in short-chain fatty acid (SCFAs) production, and a reduction in the relative abundance of pathogenic bacteria (Streptococcus thermophilus, Roseburia intestinalis, Bacteroides caccae, and Anaerostipes hadrus). SCFA-producing bacteria are known to be able to regulate lymphocyte chemotaxis and phagocytosis and to possess anti-inflammatory and anti-tumourigenic properties (37) and are associated with a reduced risk of IBD and IBD-associated dysbiosis (38) Also, Yang et al. (39) studied the impact of a polysaccharide from H. erinaceus on the quality of murine gut microbiota and found a change in the relative abundance of different bacteria depending on the age of the mice used for the microbiota analysis. In particular, they demonstrated an increase in the relative abundance of Lachnospiraceae, Ruminococcaceae, which, among other bacteria, are the most important butyrate-producing bacteria. Butyrate is an SCFA used as an energy source by the intestinal mucosa to promote gut health and protect against colorectal cancer (40-43). Fig. 1 shows H. erinaceus contituents, their effects and putative mechanisms of action.

Fig. 1. Hericium erinaceus constituents, their effects, and putative mechanisms of action. HECP, H. erinaceus crude polysaccharide; HERP, H. erinaceus refined polysaccharide; EP-1, purified unique polysaccharide isolated from H. erinaceus mycelium 1; HEP25, purified polysaccharides from H. erinaceus, ethanol 25%; HEP75, purified polysaccharides from H. erinaceus, ethanol 75%; ROS, reactive oxygen species; MMP-9, matrix metalloproteinase-9; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; HO-1, heme oxygenase-1; γ-GCLC, gamma-glutamylcysteine synthetase.

HERICIUM ERINACEUS AS A POTENTIAL THERAPEUTIC AGENT IN EXTRAINTESTINAL PATHOLOGIC CONDITIONS AND IN DISORDERS OF THE LOWER URINARY TRACT

H. erinaceus has shown beneficial effects in a number of clinical conditions, besides IBD, due to its anti-inflammatory and anti-tumorigenic effect. In particular, extracts from H. erinaceus have proven efficacy as anti-depressant agent and this is mainly due to the modulation of monoamine neurotransmitters as well as pro-inflammatory cytokines (44) and to stimulation of nerve growth factor release (45). H. erinaceus extract from mycelia has also been demonstrated to inhibit TNF-α-induced angiogenesis and generation of reactive oxygen species through the suppression of matrix metalloproteinase-9- and nuclear factor-κB signalling pathways (46). Moreover H. erinaceus up-regulated gene expressions of heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GCLC), and glutathione levels, thus contributing to inhibition of reactive oxygen species (ROS) (46). Also, H. erinaceus was found to exert chrondroprotective activities both in in vitro and in vivo models thus showing a potential in the treatment of osteo-arthritis conditions (47). Interestingly, Hetland et al. outlined the potential anti-infectious activity of H. erinaceus which showed antimicrobial activity against viral agents, Gram negative and Gram positive bacteria and parasites. Because this effect is not accounted for by an antibiotic-like effect but is rather due to its immunomodulatory capabilities, H. erinaceus should be effective also against multi-resistant agents (48). In this regard, H. erinaceus has proven effective against faecal Gram negative bacteria (49) and enterovirus 71 (50), which might be responsible of rUTI. The immunomodulation exerted by H. erinaceus is mainly due to the β-glucans which are the main constituent of the cell wall in fungi (28). Finally, erinacine A from H. erinaceus mycelia has proven to be neuroprotective against neurodegenerative diseases (51). Table 1 summarizes the studies which show positive outcomes of H. erinaceus in the intestine.

Table 1. Summary of studies showing positive outcome of Hericium erinaceus in the intestinal tract.

Because of its anti-inflammatory and anti-oxidant effects, well documented in the gastrointestinal tract, due to its ability to positively affect the gut microbiota, because of its immunomodulatory action, and also due to its ability of modulating neurotransmission, we hypothesize that H. erinaceus extract might represent a novel therapeutic agent capable of ameliorating symptoms and or inflammation in the lower urinary tract, mainly in those cases arising from an altered gut microbiota, intestinal inflammation and/or increased intestinal permeability (52, 53). In partial support of this hypothesis we tested the efficacy of an H. erinaceus-derived nutraceutical (i.e. HBQ complex) in a small pilot study involving 20 patients suffering from chronic prostatitis. Int his proof-of concept pilot study, we found a significant decrease in the IPSS after 1 month of treatment, thus supporting the concept of a possible therapeutic role of H. erinaceus in the treatments of LUTS (M. Romano, unpublished observation). Should this be confirmed in a prospective study with a larger series of patients, one might envision the use of this nutraceutical, alone or in combination with conventional therapies or other nutraceuticals, such as those containing lycopene (54) to efficiently treat chronic prostatitis, which is a condition predisposing to prostate cancer (55). A schematic diagram on the putative targets of intervention of H. erinaceus in urogenital conditions linked to inflammation of the gut is presented in Fig. 2.

Fig. 2. Schematic representation of cross-organ sensitization between the colon and lower urinary tract and the mechanisms of potential beneficial effects of Hericium erinaceus. The colon and bladder interact with each other through several mechanisms that emerged during fundamental preclinical studies in mouse models. In detail, the central nervous system mediates the transmission of visceral sensory signals between these two organs. Inflammatory phenomena in one organ (e.g., colitis) can affect the other organ and vice versa. This is the case, for example, of inflammatory colitis, which can result in afferent neuroinflammation, potentially affecting bladder function. In addition, the leaky gut syndrome can also indirectly result in hyperpermeability of the bladder urothelium and positively or negatively regulate bladder motility. In addition, through its motility, the bladder may increase the transmission of sodium currents into the colon and modulate its function. Finally, the colon and bladder share several bacterial species in their microbiota, which may be an additional point of contact between these two organs. H. erinaceus is a fungus with known anti-inflammatory, neuromodulatory and prebiotic properties and may, as a proof-of-concept, be a potential beneficial agent in such pathophysiological phenomena. This figure was created using the BioRender program (© 2023 BioRender).

In this narrative review we have provided evidence that a pathophysiological link exists between the low urinary tract and the gastrointestinal tract. Cross-organ sensitization seems to play a major role and, in this respect, data from the literature suggest that an altered gut microbiota is crucial in driving increased gut inflammation and permeability which may favor the transmission of noxious stimuly/agents to pelvic organs. We have also shown that H. erinaceus, a chinese traditional medicinal mushroom, has proven efficacy in a number of clinical conditions, including those affecting the gastrointestinal tract. In details, it has been shown to exert anti-inflammatory, immunomodulatory, anti-oxidant and anti-angiogenetic effects also being able to positively modulate intestinal microbiota serving as a prebiotic. In a small pilot study preliminar to a prospective study in a larger cohort of patients, we have shown that an H. erinaceus-derived nutraceutical containing H. erinaceus polysaccharides was effective in ameliorating LUTS in subjects with chronic prostatitis. Based on these premises, we hypothesize that H. erinaceus-derived nutraceuticals, in combination with conventional drugs or other nutraceuticals, might be considered a putative therapeutic agent to be used in chronic inflammatory conditions of the low urinary tract to ameliorate inflammation, decrease symptoms and eventually prevent cancer.

Contribution information: two senior authors (L. Romano and l. Napolitano) selected the most relevant studies for design, sample size and level of evidence, according to their knowledge and experience. Other authors reviewed and approved the study selection.

Conflict of interests: None declared.

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