Introduction

Hericium erinaceus (H. erinaceus), berberine and quercetin showed anti-inflammatory potential in mouse models of experimental colitis. H. erinaceus (class Agaricomycetes, phylum Basidiomycota) is a mushroom belonging to traditional Chinese medicine that has been demonstrated in experimental colitis to be able to control pathways induced by Nuclear Factor kappa-light-chain-enhancer of activated B cells in an anti-inflammatory direction by suppressing the production of Tumor Necrosis Factor (TNF) and increasing the expression of Interleukin-10 (IL-10).

Aims & Methods

This ex vivo study aimed to evaluate the anti-inflammatory potential of a nutraceutical compound of H. erinaceus, berberine, quercetin, biotin and niacin (HBQ-Complex®) in Inflammatory bowel diseases (IBD) tissues obtained from both Normal-Appearing Mucosa (NAM) and Inflamed Mucosa (IM) tracts of patients with Crohn's Disease (CD) and patients with Ulcerative Colitis (CD). NAM tracts were identified from colic segments with Simple Endoscopic Score for CD = 0 or Mayo Endoscopic subscore = 0 (for CD and UC, respectively). NAM and one IM samples were frozen at -70° and then evaluated at T0. Two other IM samples were grown in DMEM medium in a temperature-controlled incubator and exposed to HBQ-Complex® for 120 minutes (T1) and 180 minutes (T2). RT-PCR and Western blot evaluations were performed for TNF, IL-10 and cyclooxygenase 2 (COX-2) at T0, T1, and T2. The HBQ-Complex® consisted of 525 mg of H. erinaceus powder (5 % polysaccharides from sporophorum) and 225 mg of H. erinaceus as an extract (30 % polysaccharides from sporophorum), 75 mg of quercetin titled to 98 %, 225 μg of biotin, 27 mg of niacin and, finally, 75 mg of Berberis vulgaris titled to 97 %.

Results

20 IBD treatment-naïve patients (50% CD, 50% UC) were enrolled. None of them had other comorbidities or was taking drug therapies within six months of the start of the study. According to the Harvey-Bradshaw index and partial Mayo score, four patients had mild CD and six moderate CD. The same was for UC patients. At T0, both CD and UC samples showed TNF and COX-2 genic expressions higher in IM than NAM (p < 0.0001). In IM samples, Incubation with HBQ-Complex® resulted in a progressive decrease in gene and protein COX-2 and TNF expression at T1/T2 in CD (p=0.002) and UC (p=0.003) samples. However, IL-10 showed an opposite trend, with a progressive genic expression increase from T0 to T1 (p=0.054) and T1 to T2 (p=0.002). The same was for UC samples (p < 0.01). These variations in PCR expressions of mRNAs were also recalculated from the same protein variations at Western blot analysis.

Conclusion

HBQ-Complex® might possess nutraceutical therapeutic potential in IBD. This could be explored in translational studies evaluating whether HBQ-Complex® can impact IBD's already validated clinical, endoscopic, and histological parameters.

References

- Diling C, Chaoqun Z, Jian Y, Jian L, Jiyan S, Yizhen X, et al. Immunomodulatory Activities of a Fungal Protein Extracted from Hericium erinaceus through Regulating the Gut Microbiota. Front Immunol. 2017;8:666.
- Ren Y, Geng Y, Du Y, Li W, Lu ZM, Xu HY, et al. Polysaccharide of Hericium erinaceus attenuates colitis in C57BL/6 mice via regulation of oxidative stress, inflammation-related signaling pathways and modulating the composition of the gut microbiota. J Nutr Biochem. luglio 2018;57:67–76.
- Qin M, Geng Y, Lu Z, Xu H, Shi JS, Xu X, et al. Anti-Inflammatory Effects of Ethanol Extract of Lion’s Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), in Mice with Ulcerative Colitis. Int J Med Mushrooms. 2016;18(3):227–34.

Introduction

Inflammatory bowel disease (IBD), comprising of Crohn’s disease and Ulcerative Colitis (UC), is a debilitating inflammatory disease of the gastrointestinal tract with no known cause. Although extensive work has linked numerous genetic loci to IBD, most of these associations remain poorly understood. In addition, some studies have associated IBD to metabolic diseases such as diabetes and non-alcoholic fatty liver disease (NAFLD), although the precise molecular and pathophysiological mechanisms underlying these associations are unknown.

Aims & Methods

The central objective of this study was to understand the molecular mechanisms underlying the associations between IBD and obesity related metabolic diseases. To address this research question, we used multiple mouse models of colitis (dextran sodium sulfate or DSS), DSS and Azoxymethane induced colitis associated colon cancer and Helicobacter hepaticus infection induced colitis in Il-10-/- mice) and high fat diet (HFD) and genetic models of obesity and obesity associated metabolic diseases. In addition, for mechanistic studies, we used chimeric mice generated through bone marrow transplantation as well as conditional knockout mouse models. Lastly, we employed CRISPR/Cas9 edited cells in vitro to understand the molecular mechanism.

Results

Employing multiple murine models of colitis, colitis-associated colon cancer (CAC) and obesity associated metabolic diseases, we have identified DUPD1, a phosphatase of unknown function, that links IBD with metabolic diseases. Specifically, Dupd1^-/-mice are protected from dextran sodium sulfate (DSS) and Helicobacter hepaticus induced colitis, and DSS/azoxymethane (AOM) induced CAC. Dupd1^-/- mice also exhibited protection against high fat diet (HFD) induced obesity and fatty liver disease and glucose intolerance. DUPD1 is highly expressed in the skeletal muscle. Indeed, using skeletal muscle specific conditional DUPD1 knockout mice (Dupd1^fl/flMyf6^Cre), we show that DUPD1 exerts its colitogenic effects from the skeletal muscle through modulation of autophagy, a pathway whose dysfunction is known to play a role in IBD. Importantly, a dual specificity phosphatase inhibitor (NSC-663284) inhibited DUPD1 enzyme activity and reduced DSS-induced colitis in wild type mice but not in Dupd1^-/-mice.

Conclusion

Our study identifies Dupd1 as a central gene that links IBD and obesity-associated metabolic diseases and suggests that it is a new therapeutic target in IBD, and obesity associated metabolic diseases.

Disclosure

Nothing to declare.

Introduction

Liver transplant is the only definitive treatment for chronic liver disease (CLD). Referral to a hepatologist for consideration for liver transplant should be made when a patient with CLD experiences a hepatic decompensation or has a MELD score ≥ 15. Failure to refer in a timely manner can result needing a liver transplant evaluation (LTE) in the inpatient setting while a patient is experiencing acute decompensation.

Aims & Methods

We aimed to compare the clinical presentation of patients undergoing LTE in the inpatient setting versus the outpatient setting to identify potential risk factors for requiring urgent evaluation. A list of all LTEs performed at our institution between 10/2017-8/2021 was obtained. Medical records were preliminarily reviewed for evaluation setting (Inpatient vs. Outpatients); evaluations for re-transplantation and acute liver failure were excluded. After all Inpatients (n=159) were identified, Outpatients (n=159) were selected at random to create a sample matched for age, gender, race, and ethnicity (n=318). Data were collected using our institutions electronic medical record and outside health records as obtained during LTE process. “Prior decompensations” refers to the number of the following clinical decompensations experienced prior to the time of LTE: ascites, hepatic encephalopathy (HE), variceal/acute UGIB, SBP and HRS. Categorical variables and continuous were compared between using Fisher’s Exact test, and student’s T test, respectively.

Results

Alcohol was the most common CLD etiology (42.1% Inpatient, 48.4% Outpatient). Inpatients tended to live further from our center than Outpatients (p=0.079). Inpatients had significantly higher MELD-Na scores (27.1 ± 8 vs. 13.3 ± 6; p<0.0001). Malnutrition was more common in 5.6 times more common in inpatients than outpatients (OR 5.6, 95% CI 2.9-10.8, p<0.001).. A similar proportion of patients had 1 hospitalization. But inpatients were 3 times as likely to have had ≥ 1 liver-related hospital admission prior to LTE (p<0.0001). Inpatients had significantly more prior decompensations than Outpatients prior to inpatient LTE (3.2 ± 1.4 vs. 1.8 ± 1.1, p<0.001), with the greatest differences in SBP and HRS.

Conclusion

Multiple liver-related hospitalizations and malnutrition may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

References

Multiple liver-related hospitalizations may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

Disclosure

D Devuni has received grant funding from Sequana Medical and receives grant support from the NIAAA (AA017986-11), both for research unrelated to this work.

Introduction

Endoscopic submucosal dissection (ESD) is the first-line treatment for superficial gastric lesions with a negligible or very low risk of lymph node metastasis. However, a permanent risk of developing metachronous lesions persists. We intend to analyze the risk factors associated with the development of metachronous lesions in a population of patients undergoing ESD.

Aims & Methods

Prospective cohort study conducted at a single centre, involving patients who underwent gastric ESD for lesions between 2017 and 2023, with a follow-up period of ≥ 6 months. Lesion characteristics were analyzed, including the rate of metachronous lesions, and logistic regression was performed to identify risk factors associated with the development of metachronous lesions.

Results

Included 78 ESDs performed on gastric epithelial lesions (59% female), with a mean age of 70.3±7.9 years. Regarding family history of gastric adenocarcinoma, 17.9% of patients had a first-degree relative. Among the analyzed lesions: 42.3% measured between 0-20mm, 57.7% ≥ 20mm; 12.8% were sessile, 71.8% flat and 15.4% depressed; 19.2% were located in the cardia, fundus or body, 21.8% in the incisura angularis and 59% in the antrum. Regarding histological findings: 42.3% low-grade dysplasia, 30.8% high-grade dysplasia, 23.1% intramucosal adenocarcinoma and 3.8% adenocarcinoma with submucosal invasion. Nine metachronous lesions (11.5%) were detected, with a median time of occurrence of 24 [13-32] months. In the analysis of risk factors, statistical significance was found for location outside the antrum (21.6% vs. 1.9%; p=0.002) and the presence of adenocarcinoma (23.8% vs. 7%; p=0.039), but not for size ≥20mm (13.7% vs. 5.1%; p=0.178) or ulceration of the lesion (9.1% vs. 10.1%; p=0.915). Logistic regression analysis revealed that only location outside the antrum had a significant risk for the development of metachronous lesions (OR 13.4; 95% CI: 1.4-127.1).

Conclusion

Given the permanent risk of developing metachronous lesions, the identification of associated risk factors is important as it may eventually allow for the adaptation of surveillance programs.

Introduction

No single pharmacological approach is currently available for the treatment of inflammatory bowel disease (IBD) in active and maintenance stages. As evidence is growing on the immuno-modulatory activities of the G-protein coupled receptor GPR120 and on its role in modulating the pathophysiology of IBD, its potential as a therapeutic target for this disease is worthy of exploration.

Aims & Methods

Herein, we have developed DFL23806, a new GPR120 selective small molecule agonist, and propose it as a potential therapeutic approach for IBD. We employed our in-house proprietary Exscalate platform for molecular docking simulations to define the site and mode of binding of the compound with the receptor and used in vitro studies and in vivo models (murine dextran sodium sulfate (DSS)-induced acute and chronic colitis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis models) to characterize the mechanism of action of our molecule and evaluate its therapeutic effects.

Results

DFL23806 is a selective agonist of human and mouse GPR120 that can activate both the G-protein dependent and independent signaling (β-arrestin pathway) of the receptor. DFL23806 has been designed to have high metabolic stability and reach the ileum and colon at optimal concentrations that allow for the activation of GPR120 while, notably, delaying its internalization. This can lead to prolonged periods of signal transduction compared to other commercially available GPR120 agonists and amplification of signaling effects. In vivo, intrarectal treatment with DFL23806 exerted consistent immunomodulatory action in DSS-induced acute colitis in mice. Moreover, oral treatment with DFL23806 significantly inhibited both DSS- and TNBS-induced chronic colonic inflammation and fibrosis by improving the disease activity index, endoscopic score, and reducing body weight loss and colonic tissue damage. Interestingly, DFL23806 treatment also modulated the composition of microbiota, inhibiting the concentration of pathogenic bacteria, and rescued intestinal dysbiosis induced by TNBS.

Conclusion

These results suggest that the stimulation of GPR120 could be an effective strategy for managing colitis, and that DFL23806 has great potential as a therapeutic for the treatment of IBD.

Disclosure

The authors are employees of Dompé farmaceutici s.p.a., Italy. The company has interests in the development of GPR120 selective agonist for the treatment of IBD and metabolic diseases.