Introduction

Both gut microbiome dysbiosis and dysregulated RNA N6-methyladenosine (m6A) modification have been independently linked to colorectal cancer (CRC) pathogenesis. Yet, how these two key factors interact during early CRC development remains unclear.

Aims & Methods

​​​​​​Aims: This study investigates YTHDF1 as a novel link between m6A epitranscriptomics and gut microbiome dysbiosis in CRC development.
Methods: We performed comparative transcriptomic analysis of YTHDF1 expression in normal colon tissue (n = 65), adenoma (n = 69), and carcinoma (n = 74) specimens from human cohorts. Intestine-specific Ythdf1 knock-in (Ythdf1^cki) mice were generated to assess the effects of YTHDF1 on gut microbiota and metabolites by shotgun metagenomic sequencing and LC-MS/MS metabolomics, respectively. Fecal microbiota transplantation (FMT) from Ythdf1^cki mice into germ-free and antibiotic-treated SPF mice was conducted to evaluate microbiota-driven tumorigenesis. Two independent human CRC cohorts, a publicly available dataset (PRJNA941834, n = 110) and a local Hong Kong cohort (n = 208), were analyzed to correlate YTHDF1 expression with microbial shifts, particularly taxa A, a CRC-associated bacterium. MTT assays assessed the effects of taxa A and its metabolites on CRC cell proliferation in vitro. The Apc^Min/+model was used to test the tumor-promoting role of taxa A in vivo.

Results

Among m⁶A regulators, YTHDF1 exhibited progressive upregulation from adenoma to CRC, suggesting an early role in tumorigenesis. Compared to WT littermates, Ythdf1^cki mice displayed gut dysbiosis and metabolic alteration prior to tumor development, characterized by enrichment of 18 bacterial species and 21 metabolites alongside depletion of 8 bacterial species and 49 metabolites. FMT from Ythdf1^cki mice accelerated tumorigenesis in both Apc^Min/+ mice and the AOM/DSS model, including antibiotic-treated SPF or germ-free recipients. Notably, Ythdf1^cki recipients showed elevated serum levels of FITC-Dextran, LPS, and LBP, coupled with reduced expression of E-cadherin, indicating compromised gut barrier integrity. Furthermore, Ythdf1^cki FMT enhanced colonic epithelial proliferation (indicated by elevated Ki67⁺ cells per crypt) and amplified pro-inflammatory responses, including marked activation of NF-κB, IL-17, and TNF-α signalings. Similarly, fecal metabolites derived from Ythdf1^cki mice significantly enhanced CRC cell proliferation compared to WT metabolites. Together, these findings establish that intestinal YTHDF1 upregulation promotes CRC initiation by remodeling the gut microbiota and metabolome. Notably, taxa A, a CRC-enriched bacterium, showed significant expansion in both Ythdf1^cki mice and recipient mice following FMT from Ythdf1^cki donors. Consistently, we observed a significant positive correlation between both YTHDF1 mRNA (PRJNA941834 dataset, p < 0.01, Spearman' s ρ = 0.34) and protein expression (Hong Kong cohort, p < 0.05, Spearman' s ρ = 0.1705) with taxa A abundance in human CRC specimens, suggesting evolutionary conservation of YTHDF1's regulation over this bacterium from mice to humans. Further functional validation demonstrated that taxa A and its metabolites promoted CRC cell proliferation in vitro. These findings were corroborated in vivo, where taxa A significantly increased intestinal tumor burden in Apc^Min/+mice.

Conclusion

Our study identifies YTHDF1 as a novel regulator of the gut microbiota, specifically enriching taxa A, which drives CRC initiation. These findings reveal a m⁶A-microbiota axis in early colorectal tumorigenesis, offering potential therapeutic targets.

Introduction

Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined.

Aims & Methods

We obtained genome-wide association study (GWAS) summary statistics for GERD (71,522 cases, 261,079 controls) and asthma (56,167 cases, 352,255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based mendelian randomization (SMR) and transcriptome-wide association study (TWAS) were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data.

Results

We identified a significant genetic correlation between GERD and asthma (r_g = 0.37, P = 6.19×10^–38) and a significant causal effect of GERD on asthma (OR = 1.22, P = 1.54×10^-5). Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes(RBM6, SUOX, and MPHOSPH9) between GERD and asthma. Single-cell RNA sequencing analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD.

Conclusion

Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseas​​​​es.

References

1. Broers C, Tack J, Pauwels A. Review article: gastro-oesophageal reflux disease in asthma and chronic obstructive pulmonary disease. Aliment Pharmacol Ther 2018;47:176–191.
2. Eapen AA, Gupta MR, Lockey RF, et al. Gastroesophageal reflux disease, laryngopharyngeal reflux, and vocal cord dysfunction/inducible laryngeal obstruction-overlapping conditions that affect asthma. J Allergy Clin Immunol. 2024;154(6):1369-1377.
3. Bulik-Sullivan B, Finucane HK, Anttila V, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47(11):1236-1241.
4. Morrison J, Knoblauch N, Marcus JH, et al. Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat Genet 2020;52:740–747.
5. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559–575.
6. Stuart T, Butler A, Hoffman P, et al. Comprehensive Integration of Single-Cell Data. Cell 2019;177:1888-1902.e21.
7. Finucane HK, Bulik-Sullivan B, Gusev A, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet 2015;47:1228–1235.
8. Freuer D, Linseisen J, Meisinger C. Asthma and the risk of gastrointestinal disorders: a Mendelian randomization study. BMC Med 2022;20:82.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Introduction

Immune checkpoint inhibitors (ICIs) are now considered the first-line treatment for advanced melanoma and non-melanoma skin cancers. One of the most commonly reported adverse events is checkpoint inhibitor-induced liver injury (ChILI), which occurs in approximately 10% of patients. For those who develop ChILI, it remains uncertain whether permanent discontinuation of the drug is necessary or if treatment can be safely resumed after a temporary pause, either with the same agent or with a different class of ICI. This report shares our center's experience with ChILI in patients receiving care for skin neoplasms at a tertiary-level facility.

Aims & Methods

This study aimed to analyse the prevalence of ChILI among patients treated with ICIs for skin cancers at our center. We included retrospectively all consecutive patients admitted to our facility who received ICI therapy for advanced melanoma or non-melanoma skin cancer between June 2016 and April 2024. The diagnosis and severity of ChILI were evaluated using the CTCAE v5.0 criteria, and the type of liver injury was classified based on international guidelines. Liver function tests (LFTs) were collected at baseline, after three treatment cycles, and at the time of suspected ChILI onset. Data on ChILI management and outcomes were also collected.

Results

We enrolled 111 patients (32.4% female, median age 75 years), including 70 patients (63.1%) with advanced melanoma and 41 (36.9%) with locally advanced or metastatic cutaneous squamous cell carcinoma. Among them, 3 patients (2.7%) received first-line therapy with anti-CTLA-4, 106 (95.5%) with anti-PD-1, and 2 (1.8%) were treated with a combination of both. The median duration of therapy was 10 months (IQR 5–21). ChILI developed in 8 patients (7.2%) after a median of 14 treatment cycles (IQR 7–20). According to the CTCAE severity scale, one case was grade 2, three were grade 3, and four were grade 4.
Among those who developed ChILI, 3 patients tested positive for anti-nuclear antibodies (ANA), 1 had a positive extractable nuclear antigen (ENA) test, and 2 had a known autoimmune disorder prior to initiating ICI therapy. All patients discontinued ICIs upon ChILI onset. Liver function tests normalized spontaneously in 4 patients, while 4 required corticosteroid treatment. Four patients underwent drug rechallenge, and only one of them received a new class of ICI.
Regarding extrahepatic adverse events, ChILI patients more frequently exhibited diarrhea and dermatological manifestations such as papular or bullous rashes (37.5% and 50%, respectively), with a significantly higher prevalence compared to patients without ChILI (7.8% and 15.4%, respectively; p < 0.05). No significant differences in liver function test results were observed at baseline or after the third infusion between patients who developed ChILI and those who did not (p > 0.05).

Conclusion

Our study confirms the occurrence of liver toxicity associated with ICI therapy in cancer patients, with an incidence rate consistent with current international literature. The median time to ChILI onset—typically after multiple treatment cycles—supports the hypothesis of an indirect, immune-mediated mechanism rather than a direct toxic effect on the liver. Notably, we found that ChILI is often preceded by dermatological and/or gastrointestinal adverse events.
Although based on a limited patient cohort, this observation may serve as an important clinical signal, helping physicians to anticipate ChILI, intervene earlier, prevent progression to more severe presentations, and initiate appropriate management promptly.

Clinical Case Summary

A 48-year-old man was diagnosed with a 2.0x2.5 cm protrusion in the descending duodenal bulb (A). Endoscopic ultrasonography and CT scans confirmed the mass arising from the muscularis propria (B). After discussion, we chose endoscopic full-thickness resection (EFTR). A dual knife was used to incise the mucosal cap covering the lesion and gradually separating it from the muscularis propria. After resection, there is a significant full-thickness defect of approximately 1.5x2.5 cm (C). Attempts to close the wound using titanium clips were unsuccessful due to the wound's large size. The narrow space and tender wall also complicated the use of nylon ropes and titanium clips, which increased the risk of clip detachment or mucosal injury. To overcome this challenge, we innovatively used a long transparent cap from a ligation device to enhance suction. By suctioning both sides of the mucosa into the cap, we were able to manipulate the clips with enhanced suction to achieve complete closure. A thorough examination and insufflation confirmed satisfactory wound closure and luminal dilation (D) (Video). The patient was discharged five days postoperatively without any adverse events. Histopathological examination confirmed complete resection of a low-risk GIST.

Introduction

Loss of skeletal muscle mass (SMM), one of the hallmarks in the diagnosis of sarcopenia, is a frequent condition in patients with inflammatory bowel disease (IBD) and it is a negative predictor of disability and poor clinical outcomes.¹ Despite its clinical relevance, its diagnosis remains challenging due to limited access to standard methods like dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI). More practical alternative, such as bioelectrical impedance analysis (BIA) and ultrasound (US), should be investigated.^2-4

Aims & Methods

This study aims to evaluate the feasibility, reproducibility, and diagnostic accuracy of US measurement of psoas muscle thickness compared to BIA in assessing SMM in IBD patients.
US psoas muscle thickness adjusted for body mass index (BMI) was compared with BIA-derived SMM normalized to squared height. Feasibility and reproducibility between the two investigators were evaluated by intra-class correlation coefficient (ICC). SMM normalized to squared height and US thickness adjusted for BMI values were compared with Pearson’s test. Results were considered significant with a p value <0.05. The diagnostic accuracy of US psoas muscle thickness measurement in comparison to SMM with BIA was assessed by calculating sensitivity (Sens), specificity (Spec), positive and negative likelihood ratios (LR+, LR-) with their 95% confidence intervals (95% CI). This study was approved by the local Ethics Committee (no. 0049113).

Results

A total of 86 consecutive patients with IBD were prospectively enrolled, including 67.4% with CD and 32.6% with UC. The cohort had a male predominance (68.6%), with a mean age of 50.4 ± 17 years and a mean BMI of 23.68 ± 3.73 kg/m². US assessment of psoas muscle thickness was feasible in all patients. Inter-operator reproducibility was excellent with an ICC of 0.951. A significant positive correlation (r = 0.54, p < 0.0001) was observed between the US-derived psoas thickness adjusted for BMI and SMM as measured by BIA and normalized to squared height. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve (AUROC) of 0.753 for men and 0.758 for women. Sex-specific cut-offs of psoas thickness × BMI were determined (≤108.18 cm·kg/m² for men, ≤66.9 cm·kg/m² for women), yielding sensitivities of 93.5% and 78.5% and specificities of 53.6% and 69.2%, respectively. Low SMM was defined according to BIA-based thresholds normalized to height squared, with cut-offs of <6.68 kg/m² for females and <8.97 kg/m² for males, as proposed by Peine et al. ⁵

Table 1. Ultrasound psoas thickness compared to skeletal muscle mass values at bioelectrical impedance analysis

Conclusion

US measurement of psoas muscle thickness is a feasible, low-cost, non-invasive and reproducible method for evaluating SMM in IBD patients. It shows promising diagnostic accuracy compared to BIA and, since the psoas muscle is a key anatomical landmark for evaluating the terminal ileum, it could be used as a practical first-line screening tool for sarcopenia especially in routine bowel US. Further prospective studies are needed to refine cut-off values, validate findings in diverse populations, and assess the long-term prognostic implications of this technique within the framework of personalized IBD management.

References

1. Nishikawa, H. et al. Inflammatory bowel disease and sarcopenia: Its mechanism and clinical importance. Journal of Clinical Medicine vol. 10 Preprint at https://doi.org/10.3390/jcm10184214 (2021).
2. Oshima, Y., Shiga, T., Namba, H. & Kuno, S. Estimation of whole-body skeletal muscle mass by bioelectrical impedance analysis in the standing position. Obes Res Clin Pract 4, (2010).
3. Smith, R. L., Taylor, K. M., Friedman, A. B., Gibson, R. N. & Gibson, P. R. Systematic Review: Clinical Utility of Gastrointestinal Ultrasound in the Diagnosis, Assessment and Management of Patients with Ulcerative Colitis. Journal of Crohn’s and Colitis vol. 14 Preprint at https://doi.org/10.1093/ecco-jcc/jjz163 (2020).
4. Mulinacci, G. et al. P466 Ultrasound muscle assessment for sarcopenia screening in patients with Inflammatory Bowel Disease: A prospective study (SarcUS-IBD). J Crohns Colitis 18, (2024)
5. Peine, S. et al. Generation of normal ranges for measures of body composition in adults based on bioelectrical impedance analysis using the seca mBCA. Int J Body Compos Res 11, (2013).

Disclosure

No conflict of interest

Introduction

Alcoholic hepatitis (AH) is a form of acute liver injury with significant morbidity and mortality. Several scoring systems have been developed and used to predict mortality, including Maddrey’s discriminant function (MDF), model for end-stage liver disease (MELD) and modified MELD including sodium (MELD-Na).

Aims & Methods

We conducted a systematic review of Pubmed, Embase, Cochrane Library and Web of Science to compare the accuracy of these scores in AH mortality prediction. The inclusion criteria include studies evaluating MDF, MELD and MELD-Na prognostic models for mortality, either as an assessment of a single score or in combination in patients with alcohol-related hepatitis.

Results

The pooled sensitivity and specificity of MDF for mortality prediction in 28 days were 0.862 (95%CI 0.714–0.940) and 0.538 (95%CI 0.322–0.741), respectively. In 90 days were 0.862 (95%CI 0.714–0.940) and 0.538 (95%CI 0.322–0.741), respectively. The pooled sensitivity and specificity of MELD for mortality prediction in 28 days were 0.809 (95%CI 0.676–0.896) and 0.753 (95%CI 0.636–0.842), respectively. In 90 days were 0.809 (95%CI 0.676–0.896) and 0.753 (95%CI 0.636–0.842), respectively. The pooled sensitivity and specificity of MELD-Na for mortality prediction in 28 days were 0.707 (95%CI 0.520–0.842) and 0.679 (95%CI 0.474–0.832), respectively. In 90 days were 0.707 (95%CI 0.520–0.842) and 0.679 (95%CI 0.474–0.832), respectively. No significant statistical difference was observed when comparing AUC of these scores.

Conclusion

Our study demonstrated no statistical difference between the prognostic models used at the admission of a patient with alcoholic hepatitis.

Introduction

Eight hospitals in the southwest of the Netherlands collaborate to provide high quality, uniform care for inflammatory bowel disease (IBD). To achieve this, a care pathway (CP) was implemented for treating IBD with biologics and small molecules (1). The CP is a decision-support tool that provides guidelines for medication prescribing, procedures, treatment adjustments, and recommendations for follow-up.

Aims & Methods

This study aimed to evaluate the effect of a CP on patient outcomes and healthcare utilization.
A longitudinal multicentre non-randomised cohort study with a baseline observation period (December 2020 – December 2021) and a follow-up period (March 2022 – March 2023) was conducted, in which adult patients with IBD treated with biologics or small molecules were included. Outcomes were collected according to the International Consortium for Health Outcomes Measurement (ICHOM) standard set from electronic health records or through validated questionnaires. Missing data were handled using single imputation nested within a bootstrap procedure. Effect of the CP on these outcomes were analysed with case-mix adjusted (generalized) linear mixed models.

Results

A total of 1,173 patients participated in the study, with the majority being female (55%) and a median age of 45 years (IQR 33-58). Most patients had Crohn's disease (64%). The CP was associated with a 0.22 increase on the ibd-control-8 score (β=0.22, p=0.28), and an increase on the probability of achieving endoscopic/radiologic (β=0.14, p=0.29), biochemical (β=0.18, p=0.22) and patient-reported remission (β=0.19, p=0.21). Probability of clinician-reported remission decreased slightly (β=-0.09, p=0.59). Emergency room visits (β=-0.36, p=0.13), hospital admissions (β=-0.41, p=0.10), and length of stay (β=-0.09, p=0.56) reduced, although these associations were not significant. The CP had no effect on quality of life (β=0.00, p=0.83), anaemia probability (β=-0.01, p=0.95) or on nutritional status (β=-0.01, p=0.34).

Conclusion

A CP for the management of IBD with biologicals and small molecules has clinically significant potential to reduce healthcare utilization, while improving patient-reported disease control, and disease remission. These results emphasize that clinical care pathways can improve care and reduce healthcare utilisation for complex diseases. However, the adherence to the CP and whether these results lead to a reduction in healthcare costs should be further investigated.

References

(1) van Linschoten R, van Leeuwen N, Nieboer D, Birnie E, Scherpenzeel M, Verweij KE, et al. Value-based care pathway for inflammatory bowel disease: a protocol for the multicentre longitudinal non-randomised parallel cluster IBD Value study with baseline period. (2044-6055 (Electronic))

Disclosure

Drs. Visser received a speaker fee from Lilly, Prof. Dr. van der Woude reports grants from Pfizer and Janssen and personal fees from AbbVie and Celltrion, Dr. van Noord reports personal fees from Janssen, Takeda, and Falk, Dr. West reports personal fees from AbbVie, Janssen, and Pfizer outside the submitted work.