Introduction

Metabolic dysfunction-associated fatty liver disease (MAFLD), typically associated with obesity, is the leading cause of reversible insulin resistance, hepatic steatosis, and inflammation, which can be further progressed into unreversible fibrosis and finally liver failure when left without intervention. The necessity of timely intervention, especially changes in lifestyle, is well-recognized but is hampered by the lack of understanding of the molecular mechanisms involved.
A potential mediator of the beneficial effects of lifestyle change (less fat and carbohydrate intake, more physical exercise) is the gut microbiome¹. Lower amounts of intestinal bacteria producing short-chain fatty acids, especially members of the Lachnospiraceae and Ruminococcaceae family, have been closely associated with MAFLD and fibrosis progression^1-3, supporting the causality of the above associations.
Among the lifestyle changes suggested to counteract MAFLD, is intermittent fasting (IF)^4,5. IF is a popular dietary regimen and is typically defined by repeated temporal abstinence of food intake for 12 to 24 hours⁶. The microbiome partly mediates the potential effects of IF on liver physiology, as shown in previous studies in which we showed that one month of 16 hours daily fasting (OMIF) increases the Lachnospiraceae and Ruminococcaceae families in non-obese human volunteers⁷ as well as in healthy mice⁸. Importantly, we observed that OMIF provokes weight loss and reduces GGT levels even in healthy volunteers⁷. We, therefore, hypothesized that OMIF has beneficial effects and can potentially reverse MAFLD through modulation of the microbiome composition.

Aims & Methods

The aim of the current study was to investigate the effects of OMIF on MAFLD phenotypes and especially how changes in the microbiome influence the results. Experimental OMIF in high-fat diet-induced iC57BL/6J mice was investigated, focusing on the change of insulin resistance, liver function biomarkers (AST [aspartate aminotransferase], ALT [alanine transaminase], GGT [gamma-glutamyl tansferase] and triglycerides) and histopathology, which were correlated to the gut microbiome determined by 16S rRNA-sequencing. The protective potential of OMIF against MALFD was prospectively studied in obese volunteers. Fecal microbiota transplantation was applied to pseudo-germ-free mice. Microbial metabolite effects were tested in human MAFLD liver-derived organoids.

Results

Experimental OMIF decreased insulin resistance (p<0.001), AST, ALT, and triglycerides levels (all p<0.05), and especially improved liver pathology by 63.0% (p<0.001), as indicated by steatosis and inflammation. The results correlated with Lachnospiraceae and butyrate-producing genera, both increased by 46.9% (p=0.003) and 63.0 % (p=0.001), respectively. In obese human volunteers, OMIF caused weight loss by 3.5% (p=0.003) and improved all liver function biomarkers (p<0.001). This again correlated with Lachnospiraceae and butyrate-producing genera, both increased by 53.6% (p=0.0005) and 28.4% (p=0.001), respectively. Transplantation of stool from either OMIF-treated mice or humans led to improved insulin sensitivity, liver function, and liver pathology (all p<0.05) in recipient mice. When exposed to butyrate, the MAFLD-mimicking liver organoids showed less microvesicular fatty accumulation (p<0.001).

Conclusion

Manipulation of the gut microbiome by OMIF can contract MAFLD. The Lachnospiraceae and butyrate-producing genera-enriched communities should be considered as new therapeutic targets in MAFLD.

References

1. Asrani SK, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world. J Hepatol 2019;70:151-171.
2. Canfora EE, Meex RCR, Venema K, et al. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol 2019;15:261-273.
3. Flint HJ, Duncan SH, Scott KP, et al. Links between diet, gut microbiota composition and gut metabolism. Proc Nutr Soc 2015;74:13-22.
4. Brahe LK, Astrup A, Larsen LH. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? Obes Rev 2013;14:950-9.
5. Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol 2020;72:558-577.
6. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med 2019;381:2541-2551.
7. Su J, Wang Y, Zhang X, et al. Remodeling of the gut microbiome during Ramadan-associated intermittent fasting. Am J Clin Nutr 2021;113:1332-1342.
8. Su J, Li F, Wang Y, et al. Investigating Ramadan Like Fasting Effects on the Gut Microbiome in BALB/c Mice. Front Nutr 2022;9:832757.

Introduction

Acute kidney injury (AKI) in cirrhosis manifests as pre-renal azotemia (PRA), hepatorenal syndrome (HRS), or acute tubular necrosis (ATN), each with distinct prognosis ⁽¹⁾. Early subtype classification and outcome prediction are critical. In Decompensated Cirrhosis patients with AKI, urine NGAL (UNGAL) and urine IL-18 (UIL-18) have been evaluated for differentiating between ATN and non-ATN AKI (PRA and HRS) with conflicting results ^(2,3). The present study compared the diagnostic accuracy of UNGAL and UIL-18 for predicting ATN AKI, AKI resolution and in-hospital mortality.

Aims & Methods

Present study was conducted at a tertiary care hospital (GIPMER, India) from July 1, 2023 to December 31, 2024. Patients with Decompensated Cirrhosis having AKI stage IB or higher were included, while advanced chronic kidney disease, Hepatocellular carcinoma prior liver transplant were excluded. The AKI was diagnosed as per International Club of Ascites Consensus (2015) and classified as per clinical adjudication after volume expansion with injection Human Albumin (20%, 1 g/kg body weight) on day 3 ⁽⁴⁾. Urine NGAL (sandwich ELISA) and IL-18 (sandwich ELISA) were measured after 48 hours of volume expansion, that is on day 3 of AKI diagnosis. The primary outcome was prediction of ATN-AKI on day 3 and secondary outcomes were prediction of AKI resolution at discharge and in-hospital mortality. The Receiver-operator curve (ROC) and multivariate logistic regression were used for analysis and p value <0.05 considered statistically significant.

Results

Total of 81 Decompensated Cirrhosis patients with AKI were enrolled in study. The aetiology of AKI was 24 (29.5%) PRA, 37 (45.7%) HRS and 20 (24.7%) ATN respectively. Mean MELD Na score was 28.4+7.3 and majority (82.7%) were CTP-C. Mean Serum Creatinine was 2.85+0.95 mg/dl. Mean UNGAL was 109.7 (PRA), 206.6 (HRS) and 396.4 (ATN) ug/g Creatinine (p<0.001). Mean UIL-18 was 39.8 (PRA), 85.6 (HRS) and 139.3 (ATN) pg/ml (p<0.001). AUROC for differentiation of ATN from non-ATN for urine NGAL was 0.9 (best cut-off 236.3 ug/g Creat) and urine IL-18 was 0.88 (best cut-off 108.75 pg/ml). AKI resolution occurred in 95.8% (PRA), 81% (HRS), and 40% (ATN). Mortality was highest in ATN (50%), vs PRA (16.7%) and HRS (8.1%). AUROC of UNGAL was 0.211 and UIL-18 was 0.185 for predicting AKI resolution. AUROC of UNGAL was 0.654 and UIL-18 was 0.641 for predicting in-hospital mortality (AUROC: NGAL 0.654, IL-18 0.641). Urine NGAL ( and urine IL-18 failed to predict AKI resolution (p 0.14 and 0.27) and in-hospital mortality (p 0.06 and 0.07) in multivariate regression analysis.

Conclusion

Urine NGAL and IL-18 had good diagnostic accuracy in predicting ATN-AKI in patients with Decompensated Cirrhosis, however do not independently predict resolution of AKI and in-hospital mortality.

References

1. Tariq R, Hadi Y, Chahal K, Reddy S, Salameh H, Singal AK. Incidence, mortality and predictors of acute kidney injury in patients with cirrhosis: A systematic review and meta-analysis. J Clin Transl Hepatol. 2020;8(2):135.
2. Puthumana J, Ariza X, Belcher JM, Graupera I, Ginès P, Parikh CR. Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2017;15(7):1003-13.
3. Huelin P, Solà E, Elia C, Solé C, Risso A, Moreira R, et al. Neutrophil gelatinase-associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study. Hepatology.2019;70(1):319–33.
4. Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and
management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64(4):531–7.

Introduction

Colorectal cancer (CRC) is considered to develop through interaction of driver mutations such as APC and KRAS mutations with tumor microenvironment (TME) and inflammatory factors. Although chronic inflammation is widely recognized as a risk factor for CRC, the effect of transient and mild inflammation on tumorigenesis remains unclear. This study aimed to evaluate the effects of mild inflammation on colorectal tumorigenesis using a genetically modified mouse model.

Aims & Methods

Three genetically engineered mouse models were used: CDX2P9.5-CreER^T2;Kras^LSL-G12D/+ （KRAS mut）, CDX2P9.5-CreER^T2;Apc^flox/+（APC mut）, and CDX2P9.5-CreER^T2;Apc^flox/+;Kras^LSL-G12D/+（APCKRAS mut）. Each model was examined with and without a 5-day administration of 1.5% Dextran Sulfate Sodium (DSS). All the mice were treated with tamoxifen at 6 weeks of age, and DSS-treated groups were administered DSS at 8 weeks; subsequently, all the mice were sacrificed at 20 weeks. Location, number, size, and histological features of the tumors were analyzed. Immunofluorescence staining (F4/80, CD163, CD4, FoxP3, CD8, and Ki67) was performed to investigate changes in the TME.

Results

In the absence of DSS, no tumors were observed in either KRAS mut or APC mut mice. However, in APCKRAS mut mice, small tumors developed in the proximal colon. Upon DSS administration, no tumors were detected in KRAS mut mice, whereas APC mut and APCKRAS mut mice exhibited multiple tumors throughout the colon. Moreover, in APCKRAS mut mice, the tumors in the proximal colon were significantly more numerous and larger than those in DSS-untreated mice (number: 6.83±1.33 vs 2.14±1.21 [P<0.01], size: 2.14±0.38mm vs 2.83±0.41mm [P=0.01] ).Immunofluorescence staining revealed no substantial differences in the proximal colon tumors of APCKRAS mut mice between DSS-treated and -untreated groups. However, when APCKRAS mut and APC mut mice were compared, the former exhibited an increase in Tregs and M2 macrophages, indicating the formation of an immunosuppressive TME.

Conclusion

This study demonstrates that even mild inflammation can promote colorectal tumorigenesis in APC muttation mice.

Introduction

Capsule Endoscopy (CE) is a minimally invasive technique that allows for detailed visualization of the small bowel mucosa. Anemia and gastrointestinal (GI) bleeding are among the primary indications for CE. Accurate detection of vascular lesions is critical in this context; however, CE interpretation is time-consuming and subject to human error. Artificial intelligence (AI) has the potential to assist in this task, yet real-world studies assessing its clinical impact remain limited.

Aims & Methods

This study aimed to evaluate the performance of a deep learning convolutional neural network in detecting and identifying vascular lesions—specifically red spots and angiectasias—in complete CE videos.
We conducted a multicenter, prospective validation study comparing AI-assisted CE reading with standard, conventional interpretation. A total of 211 CE videos, acquired using three different devices across seven centers in Portugal, Spain, Brazil, and the United States, were included. Following initial standard readings, an independent expert performed AI-assisted readings using a deep learning model designed to detect and classify small bowel vascular lesions. Both reports were reviewed by a third-party expert from an independent center who adjudicated discrepant cases to establish the reference standard. Diagnostic performance was evaluated using standard metrics and the area under the receiver operating characteristic curve (AUC-ROC).

Results

AI-assisted reading identified 241 confirmed vascular lesions, compared to 158 detected through conventional reading. Sensitivity was significantly higher for AI-assisted reading (96.4% vs. 67.7%), though specificity was lower (75.7% vs. 93.5%). Overall accuracy was also higher with AI (89.7% vs. 76.1%). The AUC-ROC was 0.93 for AI-assisted and 0.78 for standard reading. Moreover, AI-assisted reading reduced the mean examination time to 316 seconds per video.

Conclusion

AI-assisted interpretation of full-length CE videos significantly outperforms conventional reading in the detection and classification of vascular lesions. The inclusion of videos from multiple CE systems addresses interoperability challenges, and the involvement of patients from four countries across two continents supports the model's generalizability and real-world clinical applicability.

Introduction

Psychological comorbidities such as anxiety and depression are common in patients with inflammatory bowel disease (IBD). Alexithymia, defined by difficulty in identifying and describing emotions, may increase symptom perception and impact disease outcomes. Its relationship with psychological distress and clinical activity remains unclear, particularly across IBD phenotypes.

Aims & Methods

This study aimed to explore the correlations between alexithymia, clinical variables, and psychopathological symptoms in patients with inflammatory bowel disease (IBD), and to compare profiles between Crohn’s disease (CD) and ulcerative colitis (UC). Patients aged 18–70 years with confirmed CD or UC were recruited from outpatient and day-hospital settings. Exclusion criteria included diagnosed psychiatric or neurological disorders, malignancy, or recent head trauma. Participants completed the Toronto Alexithymia Scale (TAS- 20), the Symptom Checklist-90-Revised (SCL-90-R) for psychological distress, and the Hospital Anxiety and Depression Scale (HADS), including both anxiety (HADS-A) and depression (HADS-D) subscales. A cut-off score of ≥51 on the TAS-20 was used to define the presence of alexithymia. Clinical and demographic data were collected, including disease activity indices, disease phenotype, endoscopic findings, extraintestinal manifestations, and current therapies. Descriptive statistics were reported as mean ± standard deviation. Analyses included t-tests, Pearson correlations, ANCOVA, and multivariate linear regression. p<0.05 considered significant.

Results

A total of 103 patients with IBD were included (CD = 45; UC = 58). The mean TAS-20 score was 45.0 ± 11.0 in CD and 42.7 ± 10.4 in UC, with no significant difference between groups. The overall prevalence of alexithymia (TAS-20 ≥ 51) was 24.3%, with comparable rates in CD (22.2%) and UC (25.9%, p = 0.845). In CD, TAS-20 scores were significantly correlated with endoscopic disease activity (CDEIS: r = 0.35, p = 0.023) and with the presence of fistulas or abscesses (r = 0.38, p = 0.042). No significant correlations were observed with CDAI, disease phenotype, or perianal disease alone. In UC, clinical disease activity independently predicted alexithymia (SCCAI: β = 7.29, p = 0.023). With regard to psychological symptoms, TAS-20 scores were significantly correlated in CD with HADS-D (r = 0.58, p < 0.001), HADS-A (r = 0.34, p = 0.021), SCL-90 GSI (r = 0.37, p = 0.012), and paranoid ideation (r = 0.43, p = 0.003). In UC, significant correlations were also observed with HADS-A (r = 0.52), HADS-D (r = 0.39), and SCL-90 GSI (r = 0.45), all with p < 0.005. In multivariate analysis, the SCL-90 GSI score independently predicted alexithymia in UC (β = 11.78, p < 0.001). The effect of diagnosis (CD vs UC) on TAS-20 scores was not significant (p = 0.079) after adjusting for anxiety and depression.

Conclusion

Alexithymia is a common trait in IBD, with comparable prevalence in CD and UC. In CD, it is associated with endoscopic disease severity and fistulizing complications, while in UC, with clinical activity. In both groups, psychological distress, especially depression, is a key correlate. These findings underscore the value of assessing emotional processing in patients with active or complicated IBD to support more targeted multidisciplinary care.