Introduction

The interplay of diet and the intestinal microbiome plays a key role in developing colorectal cancer (CRC), with westernization of diets, e.g., an increase in fat and sugar and a decrease in fiber content, being the main contributor. We recently demonstrated that the endoplasmic reticulum unfolded protein response (ER-UPR) effector activating transcription factor 6 (ATF6) is associated with early and late onset of CRC in patients. Furthermore, the overexpression of ATF6 observed in a subset of CRC patients is associated with the presence of certain gut bacteria. The specific expression of activated ATF6 (nATF6) in mouse intestinal epithelial cells (nATF6^IEC) induces spontaneous development of colonic tumors in a microbiota-dependent manner, highlighting the functional relevance of ATF6 as a novel oncogenic driver.

Aims & Methods

To elucidate the adverse role of dietary fat, sugar, and fiber in tumorigenesis, we exposed nATF6^IEC mice under SPF conditions to control (chow) and westernized diets for 7 weeks after weaning. Microbial and metabolite profiles were assessed through deep metagenomic sequencing and targeted/untargeted mass spectrometry (LC-MS) analysis. Microbiota transfer of diet-exposed mice into germ-free recipients was conducted to verify the microbiota-dependent transmissibility of tumor formation. Bismuth(II)subsalicylate (BSS) was used as a dietary additive to validate the impact of bacteria-produced H₂S on tumorigenesis.

Results

Westernized high lard (HL) diet, enriched in fat and sugar and depleted in fermentable fiber, increased tumor burden in biallelic nATF6^IEC mice. Unexpectedly, HL induced de novo tumorigenesis in otherwise tumor-free monoallelic nATF6^IEC mice. Surprisingly, modifying the HL diet by supplementing dietary fiber or lowering fat content failed to protect the HL-induced tumorigenic phenotype. Metabolite profiling clearly differentiated westernized from control diets and tumor bearing from control mice. Transferring microbiota from diet-exposed mice into germ-free nATF6^IEC mice was sufficient to trigger tumorigenesis. Metagenomic profiles of westernized diet-exposed mice identified an increased relative abundance of H₂S-producing Desulfovibrio species and genes related to dissimilatory sulfate reduction. Supplementing westernized diets with the H₂S-scavenger BSS resulted in a drastic change in microbial communities as well as the prevention of tumor formation in monoallelic nATF6^IEC mice.

Conclusion

These results highlight the ability of westernized diets to enhance nATF6-related tumorigenesis while altering metabolite and microbial profiles. Westernized diets favor the growth of sulfate-reducing Desulfovibrionaceae, possibly resulting in increased H₂S production. H₂S scavenging significantly reduces diet-induced colonic tumor susceptibility, clearly demonstrating the impact of diet in shaping cancer-related microbiome alterations.

Introduction

Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a feature ranking method based on a novel One-Class Support Vector Machine (SVM) model.

Aims & Methods

A dataset containing clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations were conducted according to the updated Sydney system. CAG patients with any missing data or a GNL diagnosis at the baseline gastroscopy were excluded from the final analysis. A Fisher score-based feature ranking method and One-Class SVM were used to select the optimal subset of baseline variables associated with GNL development, aiming to achieve average sensitivity (Se) and specificity (Sp) above 80%.

Results

Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median age 68 (35-83) years] and without GNL at follow-up [81 patients (F 72.8%), median age 59(26-84) years]. After a median follow-up of 60 (12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with both epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic symptoms at CAG diagnosis were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusion

This is the first study in which an AI model simultaneously considers clinical, endoscopic, and histological characteristics from a dataset of CAG patients, showing good sensitivity and specificity in identifying those variables associated with developing GNL. Nonetheless, we acknowledge the need for improved variable standardization and data balancing between groups to enhance model performance further.

Introduction

A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including celiac disease and inflammatory bowel disease. To date, there are no adequate treatment strategies to ameliorate impaired barrier function.
IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. IMU-856 may represent a new approach to treat gastrointestinal diseases with compromised barrier function.

Aims & Methods

This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Additionally, the Phase 1/1b study was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte mass and function, nutrient absorption, and enteroendocrine hormones like GLP-1 were analyzed to assess potential effects on gut health.

Results

IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. Treatment with IMU-856 protected against gluten-induced histologic deterioration, improved the health and metabolic function of intestinal enterocytes as measured by nutrient uptake and citrulline [1], and had positive effects on enteroendocrine cells increasing endogenous GLP-1 levels in a dose-dependent manner.

Conclusion

IMU-856 is a safe, highly selective and potent epigenetic modulator, improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.
Positive effects of IMU-856 on gut hormones and various biomarkers for overall gut health including intestinal function and integrity were observed. Therefore, IMU-856 may offer extensive potential for treatment of gastrointestinal diseases with compromised intestinal barrier function and metabolic diseases.

References

1. Daveson AJM, Stubbs R, Polasek TM, Isola J, Anderson R, Tye-Din JA, et al. Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.

Disclosure

AS, MW, EP: employees of Immunic AG, option and shareholders of Immunic, Inc.
IPO, JF, IK, SE: employees of Immunic AG, option and/or shareholders of Immunic, Inc.
HK: employee of Immunic AG, shareholder of Immunic, Inc., co-inventor of patents for the drug in investigation
DP: option holder of Immunic, Inc.
DV, AM: employees of Immunic AG and Immunic, Inc., shareholders of Immunic, Inc., co-inventors of patents for the drug in investigation