Introduction

In autoimmune atrophic gastritis (AAG), immune-mediated morpho-functional changes in gastric mucosa lead to hypo-achlorhydria and subsequent hypergastrinemia. This stimulates gastric enterochromaffin-like (ECL) cell proliferation, escalating the risk of type I gastric neuroendocrine neoplasms (gNENs). Yet, longitudinal studies on the AAG-type I gNENs association are still scanty.

Aims & Methods

Our study aims to assess in a multicentric cohort of AAG patients, the frequency and the characteristics of type I gNENs.
We conducted a multicentric, cross-sectional study from January to June 2023, prospectively enrolling consecutive patients diagnosed with AAG, from January 2000 to June 2023, who underwent at least one endoscopy. Data on demographics, clinical history, biochemical profiles, serological data, and endoscopic and histopathological findings were collected.

Results

The study included 612 patients with AAG [444 (75.2%) female, median age 66 (IQR 54-73) years]. At enrollment, 355 (58.1%) patients had ECL cell hyperplasia. Over a median follow-up of 4 (IQR 2-7) years, and after a median number of two upper GI endoscopies per patient, and a median disease duration of 7 (IQR 3-8) years, 108 patients showed 125 gNENs, corresponding to an incidence rate of 0.051 person-years. All the gNENs were well-differentiated. In 22 (18%) cases Ki 67 was not available; of the remaining 103, 86 (68.8%) cases were G1, 17 (13.6%) were G2, all of which with a Ki-67 < 10%; no G3 lesions were observed. 119 (95.2%) gNENs were located in the body/fundus. The median size was 5 (IQR 3-10) mm. 79 (73.1%) patients underwent endoscopic removal, 10 (9.2%) gastrectomy, 12 (11.1%) somatostatin analog therapy due to multifocal/recurrent disease, and 7 (6.5%) were only monitored. Patients with AAG and gNENs had significantly higher gastrin levels compared to patients without gNENs [median 874 pg/mL (IQR 362.5-1335) vs 581.5 pg/mL (IQR 281.8-1071.5), p=0.014]. However, there were no significant differences in proton-pump inhibitor use, OLGA and OLGIM stages, H. pylori status, and notably, circulating chromogranin A levels.

	AAG patients with gNENs (#108)
Sex, female (%)	78 (72.2)
Age (years), median (IQR)	68 (57-75.8)
APCA positivity, n (%)	76 (70.4)
Current smokers, n/n available (%)	19/57 (33%)
PPI treatment, n/n available (%)	10/41 (24.4%)
OLGIM, n (%)	II: 60 (56)
OLGA, n (%)	II: 76 (70)
Chromogranin A (ng/mL), median (IQR)	160 (86.9-251.5)
Gastrin (pg/mL), median (IQR)	874 (362.5-1335)

Conclusion

Type I gNENs are a relevant complication in patients with AAG. Elevated circulating gastrin levels are linked to their occurrence, with hypergastrinemia acting as a driver for abnormal proliferation of gastric ECL cells. Regular endoscopic surveillance and thorough histopathological examination are crucial in patients with AAG, serving as a key strategy for early diagnosis and treatment of gNENs.

References

1. Shah SC, Piazuelo MB, Kuipers EJ, Li D. AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: Expert Review. Gastroenterology 2021;161(4):1325-1332.e7.
2. Köseoğlu H, Duzenli T, Sezikli M. Gastric neuroendocrine neoplasms: A review. World J Clin Cases 2021;9(27):7973–85.
3. Sheikh-Ahmad M, Saiegh L, Shalata A, et al. Factors Predicting Type I Gastric Neuroendocrine Neoplasia Recurrence: A Single-Center Study. Biomedicines 2023;11(3):828.
4. Pachuashvili NV, Nagornaya DP, Tertychnyi AS. [Metachronous tumors of the stomach in a patient with autoimmune gastritis]. Arkh Patol 2023;85(1):57–61.

Introduction

Endoscopic submucosal dissection (ESD) has been routinely used for en-bloc resection of superficial lower GI neoplasms as it provides precise information on the histology, margins and invasion (lateral and deep). The meta-analysis by Fuccio et al (2017, pp 74) compared the outcomes of the Asian countries with the non-Asian countries and concluded that there was a high disparity between the two groups. There were higher R0 resections rates and lower postoperative complications, and recurrences at 12 months in the Asian setting, suggesting that the possible factors could be the low number of ESD procedures and reduced expertise in this field in the West.

Aims & Methods

We analysed the key performance indicators of Colorectal ESDs at a teaching hospital in the UK from 2017 to 2022. The procedures were performed by a single operator, who was trained in the West and has had no prior exposure to the Eastern training framework and guidelines. All procedures done between the above years were included starting from 2017 when ESD service was newly introduced in hospitals. Data was collected on R0 resections rates(deep and lateral margins free of neoplasia), post-operative bleeding and perforation rates, and recurrences/residual lesions at 6-12 months post-resection. We then compared the data with the results of the meta-analysis previously published. We then theorised the probable reasons for the disparity, based on potential contributing factors.

Results

Parameters/Setup	Our Outcomes in Percentages (2017-2022)	Asian - Fuccio et al (2017, pp 74)	Non-Asian- Fuccio et al (2017, pp 74)
R0 resection	83.1%	85.6%	71.3%
Delayed Bleeding	1.3%	2.4%	4.2%
Perforation	1.2%	4.5%	8.6%
Recurrence at 6-12 months	0%	1.1%	5.2%

The data presented in the table suggests that comparable outcomes to the Standard ESD technique in Asian countries can also be achieved in Western countries. The study analyzed data from 82 patients for R0 resection, 82 patients for delayed bleeding, 84 patients for perforation, and 38 patients for recurrence at 12 months. The discrepancy in the number of patients between the primary procedure and post-resection surveillance is attributed to various factors, including patient preferences, the need for further management of malignant lesions, and patients awaiting their follow-up appointment.

Conclusion

Our data indicate that the Eastern standards can be met in the West with regard to key performance indicators for lower GI ESD. The reasons for underperformance can't be attributed to training and exposure. The above table and analysis indicate a need for the exploration of other probable factors and an updated review of Eastern and Western standards.

References

Fuccio, L., Hassan, C., Ponchon, T., Mandolesi, D., Farioli, A., Cucchetti, A., Frazzoni, L., Bhandari, P., Bellisario, C., Bazzoli, F. and Repici, A., 2017. Clinical outcomes after endoscopic submucosal dissection for colorectal neoplasia: a systematic review and meta-analysis. Gastrointestinal endoscopy, 86(1), pp.74-86. (Accessed: 31^st March 2023)

Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that results from various factors, including genetic factors, inappropriate immune response, changes in gut microbiota balance, and oxidative stress.^{1, 2}Bifidobacterium longum is a representative bifidobacterium that exists in the human gastrointestinal tract and plays a significant role in protecting against colitis.³ Oxidative stress elicits an unfavorable environment for the survival and colonization of beneficial probiotics as well as causing tissue damage in colitis.^{4, 5}

Aims & Methods

In this study, we aimed to identify the genome characteristics, ROS-resistant properties, colonization abilities, and anti-colitic effects of the newly isolated B. longum strain (B. longum S2) from the feces of a healthy adult in South Korea. Viability of B. longum S2 against hydrogen peroxide was assessed using H₂O₂-containing media. The antioxidant activity of B. longum S2 was measured using the ABTS and DPPH assays. Colonization in the colon was observed using a scanning electron microscope. Whole genome sequencing, data assembly, and gene analysis were performed. The anti-colitic effects were evaluated in mice using 2.5% DSS-induced colitis and adoptive T cell transfer models. Bifidobacterium was administrated by oral gavage 1 × 10⁹ CFU and the disease activity index (DAI) was scored. Colon length was measured and the histopathologic score was assessed with PAS-stained colon tissue. T cells in lamina propria mononuclear cells from the small intestine, lymphocytes from the spleen, and peritoneal cavity cells were analyzed using flow cytometry. Epithelial barrier function was evaluated using a FITC-dextran permeability assay on Caco-2 cells. Gene expression and cytokine profiles were analyzed using qRT-PCR.

Results

B. longum S2 colonies in H₂O₂-containing media were observed more frequently than those of other bifidobacterium strains. The antioxidant activity of B. longum S2 on ABTS and DPPH radicals was higher than that exhibited by other bifidobacterium strains. We identified that B. longum S2 possesses oxidative response genes, such as LexA and HrcA, through pan-genome and comparative genome analysis. However, the average nucleotide identity highlights a 94.92% value with respect to B. longum ATCC, 98.65% with respect to B. longum JCM1217 and 98.64% with respect to B. longum NCTC 11818, supporting the characteristics of B. longum S2 as a novel strain of bifidobacteria. B. longum S2-treated group showed alleviation of the colitis index, including a higher survival rate, restoration of body weight loss and colon shortening, and improvement of the DAI compared to the control group. B. longum S2 treatment significantly decreased the loss of goblet cell and the histopathological score in colon tissues. B. longum S2 induced the expression of markers of Treg cells and M2 macrophages in the isolated mouse tissues. Moreover, the B. longum S2-treated group showed decreased gene expression of pro-inflammatory cytokines, including mucin gene, compared to the control group. Pre-treatment with B. longum S2 significantly reduced the TNF-α-induced permeability of intestinal epithelial cells, suggesting that B. longum S2 improves epithelial barrier function.

Conclusion

Our study revealed that the newly isolated B. longum strain, B. longum S2, possesses unique anti-colitic effects and colonization abilities, as demonstrated in both in vitro experiments and in two different mouse colitis models. These findings strongly suggest that B. longum S2 holds great promise as a potential treatment for IBD.

References

1. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307-17.
2. Blumberg RS. Environment and Genes: What Is the Interaction? Dig Dis 2016;34:20-6.
3. Yao S, Zhao Z, Wang W, et al. Bifidobacterium Longum: Protection against Inflammatory Bowel Disease. J Immunol Res 2021;2021:8030297.
4. Sanz Y, De Palma G. Gut microbiota and probiotics in modulation of epithelium and gut-associated lymphoid tissue function. Int Rev Immunol 2009;28:397-413.
5. Xiao M, Xu P, Zhao J, et al. Oxidative stress-related responses of Bifidobacterium longum subsp. longum BBMN68 at the proteomic level after exposure to oxygen. Microbiology (Reading) 2011;157:1573-1588.

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.