Inflammatory Bowel Disease (IBD) is a chronic condition characterized by persistent mucosal inflammation driven by complex interactions among the gut microbiome, host immune genetics, and cellular metabolism. Emerging evidence highlights the central role of the Th17/Treg cell balance in maintaining intestinal immune tolerance, which is tightly regulated by microbe-derived metabolites and host metabolic pathways. In IBD, microbial dysbiosis and altered metabolite profiles disrupt this equilibrium, favoring pro-inflammatory responses. Moreover, genetic variants affecting immune regulation modulate individual susceptibility and disease course. Understanding how microbiome modulation, metabolic reprogramming, and genetic predisposition converge in IBD pathogenesis opens new avenues for precision medicine. This minireview discusses recent advances in this field, emphasizing novel microbiome-targeted strategies, metabolic interventions, and personalized immunomodulatory therapies aimed at restoring Th17/Treg homeostasis. Integrating microbiome, metabolome, and immunogenetic profiling may ultimately guide tailored treatments and improve long-term outcomes in IBD.

Tofacitinib, filgotinib, and upadacitinib are Janus kinase inhibitors (JAKis) available for ulcerative colitis (UC) refractory or intolerant to at least one advanced therapy; their comparative effectiveness in clinical practice remains uncertain. We conducted a multicenter retrospective study including adult UC patients initiating tofacitinib, filgotinib, or upadacitinib (September 2020–June 2025). Clinical remission (partial Mayo score ≤ 1), steroid-free clinical remission, biochemical remission, and endoscopic remission (Mayo endoscopic score = 0) were assessed at predefined time-points. Baseline differences were controlled using inverse probability of treatment weighting (IPTW), and time-to-event and longitudinal analyses were performed. After IPTW, the pseudo-population included 627 patients (tofacitinib = 179, filgotinib = 138, upadacitinib = 310). In the weighted cohort, clinical remission probabilities at weeks 8, 24, and 52 were 17.5

BACKGROUND:Risankizumab (RZB) is an anti-interleukin 23 (anti-IL-23) approved for the treatment of Crohn disease (CD). STUDY QUESTION:We aimed to evaluate the effectiveness and safety of RZB in the treatment of CD in real-world settings. STUDY DESIGN:We performed a retrospective review of a multicentre consortium of patients with CD treated with RZB. MEASURES AND OUTCOMES:Coprimary outcomes were clinical remission at week 12, 24, and 52 (Harvey-Bradshaw Index score of ≤4), and safety. Secondary outcomes included steroid-free clinical remission, clinical response, and endoscopic remission at 52 weeks. RESULTS:A total of 487 patients were included. The median follow-up was 24 (interquartile range: 16-38) weeks. A total of 372 (76.4%) patients achieved clinical remission at maximal follow-up. According to the treatment line in which RZB was administered, clinical remission occurred in 115/134 (85.8%) patients on second-line therapy, 112/153 (73.2%) on third-line therapy, and 145/200 (72.5%) on fourth-line therapy, with a significant difference ( P = 0.010). Adverse events occurred in 60 patients (12.6%) during follow-up; most of them were mild (50/60, 83.3%). Regarding the secondary outcomes: steroid-free clinical remission was achieved in 342 (71.8%) patients, and clinical response was observed in 443 (91.0%) patients. Six (1.2%) patients underwent surgery during follow-up. Mucosal healing was achieved in 34/67 (50.7%) patients. CONCLUSIONS:In this extensive, real-world study, RZB was effective and well tolerated in an advanced-therapy-exposed population of patients with CD and associated with favorable clinical and endoscopic outcomes.

Background Frailty is a multidimensional syndrome associated with poor outcomes and increased vulnerability, yet its assessment in inflammatory bowel diseases (IBD) remains challenging due to the absence of disease-specific tools. Aims This study aimed to develop and validate the IBD Frailty Score, a tailored instrument for evaluating frailty in patients with Crohn disease (CD) and ulcerative colitis (UC). Methods In the development phase, 28 categorical items were included in the IBD Frailty Score. This tool was tested in an exploratory cohort of 121 IBD outpatients and later validated in a prospective multicenter cohort of 512 patients across four tertiary centers. Predictive factors of frailty were identified through univariate and multivariate analyses. Results The IBD Frailty Score was feasible, with an average administration time of ∼2 minutes. It correlated positively with the Fried Frailty Phenotype, IBD Disability Index, and Charlson Comorbidity Index and showed good reproducibility (rho = 0.78) and strong diagnostic accuracy (AUC = 0.79). A cut-off score of 4 reliably distinguished fit from frail patients. Increasing age, polypharmacy, history of extraintestinal manifestations, and higher disease activity were independent risk factors for frailty. Conclusions The IBD Frailty Score is the first validated, disease-specific tool for assessing frailty in IBD. It is practical, reproducible, and correlates well with established measures.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited.

Background/Objectives: Clinically significant portal hypertension (CSPH) in cirrhotic patients impacts mortality rates and quality of life. CSPH increases the risk of systemic decompensation and could predispose to the deterioration of portal hypertension (PH)–gastric complications, such as portal hypertensive gastropathy (PHG) and portal hypertensive polyps (PHPs). In the management of CSPH with high-risk varices, endoscopic band ligation (EBL) is effective in preventing variceal bleeding. However, this procedure has several drawbacks, ranging from its inability to treat PH to the potential development of significant PH–gastric complications. The aim of our study is to evaluate endoscopic changes in PHG, PHPs, and gastric varices before and after the obliteration of esophageal varices, highlighting the potential risks of EBL. Methods: We retrospectively evaluated forty-four patients who underwent EBL for esophageal varices in emergency and elective settings, according to Baveno VII guidelines. We assessed the presence and severity of PHG, the status of gastric varices, and the number of PHPs before and after the eradication of esophageal varices. We used Fisher’s exact test and t-tests to compare the endoscopic and clinical-laboratory data statistically. A p-value < 0.05 was considered statistically significant. Results: This study found that after the eradication of varices, there was a significant worsening of PHG in 28 patients (63%) compared to before the procedure (p < 0.05). The condition remained stable in 14 patients (31%). However, it is worth noting that 90% of the patients exhibited severe PHG at baseline. Additionally, the absence of ascites and the non-administration of beta blockers at baseline were independent risk factors for worsening PHG (p < 0.05). Along with the deterioration of PHG, three patients (7%) developed gastric varices, all classified as type 1 gastroesophageal varices, and in two patients (4.5%), PHPs were formed. In particular, out of these two cases, the number of PHPs increased from one to two compared to the baseline. Conclusions: Our study underscores the association of EBL with a general worsening of PH–gastric complications and the protective effect of beta blockers in this context. Despite these promising results, future studies are needed to assess whether the worsening of PH–gastric complications is sustained over time and whether it is associated with a deterioration in clinical outcomes in patients with cirrhosis. Such evidence could help guide a more informed therapeutic decision between EBL and beta blockers.

The Farnesoid X receptor (FXR)-Fibroblast growth factor19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether subjects with prediabetes or type 2 diabetes (T2DM) have altered intestinal FXR-FGF19 signaling and barrier function, and whether high glucose (HG) exposure may cause these aberrations. Moreover, we tested beneficial effects of the FXR agonist Obeticholic acid (OCA) on intestinal FXR signaling in subjects with prediabetes and T2DM. Sixty subjects with different glucose tolerance [normal glucose tolerance (NGT, n=25), prediabetes (n=19), T2DM (n=16)] undergone to ileocolonoscopy with collection of ileal mucosa biopsies, which were used for expression profiling analysis of FXR/FGF19/TJ axis and tissue culture experiments. Individuals with prediabetes and T2DM displayed lower ileal levels of FXR and its target genes FGF19 and TJ proteins Zonula occludens-1, Occludin and Claudin-1 along with increased pro-inflammatory NF-kB activity and cytokines expression as compared to those with NGT. HG exposure on ileal explants collected from NGT subjects hampered FXR/FGF19/TJ axis. OCA treatment on ileal fragments of prediabetes/T2DM subjects was able to restore FGF19 synthesis and secretion, TJ expression, counteract NF-kB activity, and cytokines expression. In conclusion, OCA treatment counteracts T2DM-related abnormalities in intestinal FXR/FGF19/TJ axis.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized in inflammatory bowel disease (IBD) patients due to chronic inflammation and metabolic disturbances. However, reliable non-invasive biomarkers for MASLD prediction in this population are lacking. This study evaluated the predictive value of metabolic scores and lipid ratios for MASLD onset in IBD patients. Methods: An observational retrospective study was conducted on 358 IBD patients at the “Renato Dulbecco” Teaching Hospital in Catanzaro, Italy, in a period between 1 January 2021 and 31 December 2024. Clinical and laboratory data, including metabolic scores and lipid ratios, were analyzed using the chi-square and Kruskal–Wallis tests as appropriate. Post hoc comparisons were conducted using Dunn’s test. Receiver operating characteristic analysis assessed their predictive accuracy for MASLD. p < 0.05 was considered significant. Results: IBD-MASLD patients had a significantly higher body mass index (BMI, 27 ± 4 vs. 22 ± 2 kg/m2; p < 0.001), waist circumference (100 ± 11 vs. 85 ± 4 cm; p < 0.001), other anthropometric parameters, metabolic scores, and lipid ratios than IBD-only patients. The metabolic score for insulin resistance [METS-IR, area under curve (AUC = 0.754)] and waist circumference (AUC = 0.754) exhibited the highest predictive accuracy, followed by the lipid accumulation product (LAP, AUC = 0.737), BMI (AUC = 0.709), and triglyceride/high-density lipoprotein (TG/HDL, AUC = 0.701). Insulin resistance scores, including the homeostasis model assessment of insulin resistance (AUC = 0.680) and triglyceride-glucose index (AUC = 0.674), were of moderate predictive use. The visceral adiposity index (AUC = 0.664) and low-density lipoprotein/high-density lipoprotein (AUC = 0.656) showed lower discriminative ability, while the fibrosis-4 index (AUC = 0.562) had the weakest diagnostic performance. Conclusions: Our findings suggest that MASLD in IBD is primarily driven by cardiometabolic dysfunction. The introduction of the METS-IR, LAP, and TG/HDL into clinical assessments of IBD patients could prove useful in preventing liver and cardiovascular complications in this setting.

Liver cirrhosis, marked by fibrosis and nodular regeneration, triggers a cascade of events resulting in portal hypertension (PH) and, subsequently, hepatic decompensation in its final stages. PH, arising from increased intrahepatic vascular resistance, serves as a harbinger of complications such as ascites, variceal bleeding, and hepatic encephalopathy, underscoring its clinical significance. Timely diagnosis of clinically significant portal hypertension (CSPH) is of pivotal importance, prompting the exploration of noninvasive diagnostic tools such as liver stiffness and spleen stiffness measurement. β-blockers, particularly Carvedilol, emerge as stalwart therapeutic agents in managing CSPH by inducing splanchnic vasoconstriction and reducing cardiac output. However, choosing between β-blockers and endoscopic banding ligation (EBL) for variceal bleeding prophylaxis requires careful consideration, especially in decompensated cirrhosis cases. EBL, while effective in preventing variceal bleeding, has several drawbacks, ranging from its inability to effectively treat PH to its association with upper digestive tract complications such as portal hypertensive gastropathy (PHG) and portal hypertensive polyps (PHPs). This narrative review aims to underline the appropriate diagnostic and therapeutic strategies for PH and to elucidate the relationship between PH, PHG, PHPs, and the use of EBL. This investigation emphasizes the urgency for further research aimed at devising optimal management strategies for PHG and PHPs, particularly in decompensated cirrhosis. Indeed, PH in cirrhotic patients requires a multifaceted approach encompassing early diagnosis, tailored therapeutic interventions, and ongoing research efforts aimed at refining treatment strategies and improving patient outcomes.

Background: Upadacitinib (UPA), a selective anti-JAK1 agent, obtained refundability from the Italian National Health System in July 2023 for its use in patients with ulcerative colitis (UC) refractory to other therapies, including anti-TNF-α, anti-integrins, and ustekinumab. At present, no Italian data are available about its effectiveness and safety in the real world. Methods: A retrospective assessment of clinical and endoscopic activity was performed according to the Mayo score. The primary endpoints were to evaluate the effectiveness and safety of UPA. Results: We included 202 consecutive UC patients (M/F 119/83, median age 42). The clinical remission and clinical response rates were 45.5% (92/202) and 63.5% (128/202), respectively, at 8 weeks and 60.2% and 81.7%, respectively, at the end of the follow-up. Clinical remission was achieved more frequently when UPA was used as a first-line rather than a second-/third-line treatment (p = 0.609). Mucosal healing was reported in 84.6% of patients at the median follow-up time. Adverse events occurred in six patients (2.5%), whereas four patients (2%) underwent colectomy. Conclusions: This large real-world study shows that UPA is an effective and safe treatment for UC patients.

Functional disorders of the upper digestive tract, including functional dyspepsia and irritable bowel syndrome with predominant gastric symptoms, represent conditions that are highly prevalent in the general population and are associated with a marked impairment of patients' quality of life. Functional dyspepsia, characterised by symptoms such as epigastric pain, early satiety and bloating, in the absence of detectable structural abnormalities, is commonly divided into two subtypes: postprandial distress syndrome and epigastric pain syndrome, as described in the Rome IV diagnostic criteria. Although the pathogenesis of these disorders is not completely understood, it is believed that there is a complex interaction between altered gastrointestinal motility, visceral hypersensitivity, gut dysbiosis and dysfunction in the central modulation of visceral signals. Current guidelines recommend a multimodal therapeutic approach, including both pharmacological treatments and lifestyle modifications. First-line drugs for the management of functional dyspepsia include prokinetics, such as domperidone and itopride, and proton pump inhibitors, the latter being indicated mainly in patients with symptoms associated with hyperacidity. In refractory cases, numerous studies support the use of tricyclic antidepressants and serotonin modulators, which appear to bring significant symptomatic improvement. Recently, scientific interest has also turned to the role of the intestinal microbiota in the pathogenesis of functional disorders of the upper digestive tract, opening up prospects for innovative therapies, including the use of probiotics and modulation of the intestinal flora. However, current guidelines emphasize the need for further clinical evidence to consider such approaches as standard of care. In conclusion, although significant progress has been made in the understanding and treatment of these disorders, there remains much room for development with regard to targeted and personalized therapeutic strategies.

Gut microbiota changes have emerged as central players in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD). Although these diseases affect distinct primary organs, they share converging mechanisms driven by dysbiosis, including loss of beneficial short-chain fatty acid-producing taxa such as Faecalibacterium prausnitzii and Roseburia, enrichment of pro-inflammatory Enterobacteriaceae, and disruption of bile acid and tryptophan metabolism. These shifts compromise epithelial barrier integrity, promote the translocation of microbial products such as lipopolysaccharide, and trigger toll-like receptor 4-mediated activation of inflammatory cascades dominated by tumor necrosis factor-alpha, interleukin-6, and transforming growth factor-beta. In MASH, this dysbiotic environment fuels hepatic inflammation, insulin resistance, and fibrogenesis, while in IBD it sustains chronic mucosal immune activation. Shared features include impaired butyrate availability, altered bile acid pools affecting farnesoid X receptor and Takeda G protein-coupled Receptor 5 signaling, and defective aryl hydrocarbon receptor activation, all of which link microbial dysfunction to host metabolic and immune dysregulation. Understanding these overlapping pathways provides a deeper understanding of the role of the gut-liver and gut-immune axes as unifying frameworks in disease progression. This narrative review synthesizes current evidence on gut microbiota in MASH and IBD, underscoring the need for longitudinal, multi-omics studies and microbiome-targeted strategies to guide personalized therapeutic approaches.