Effectiveness of autologous emulsified stromal vascular fraction tissue injection for the treatment of complex perianal fistulas in inflammatory bowel diseases patients: a pilot study.

Complex fistulizing perianal disease is a disabling manifestation of inflammatory bowel disease (IBD), seriously compromising patients 'quality of life'. The success rate of available treatments is quite low, and nearly half of the patients will develop chronically active fistulas or experience fistula recurrence. Mesenchymal stem cell therapy has shown interesting results, but the complexity and the cost of production limit its widespread use. This study aims to report the results of the innovative use of autologous emulsified adipose-derived stromal vascular fraction tissue for treating complex fistulizing perianal disease. From March 2021 to March 2022, 10 patients underwent a two-step procedure: (1) examination under anaesthesia, with loose seton drainage and 4 weeks later and (2) curettage of the fistulous tract, internal fistula closure and an injection of autologous emulsified adipose-derived stromal vascular fraction tissue harvested from the subcutaneous layer of the patient's hip. Clinical and radiological (through magnetic resonance imaging) healing were assessed at 6 months. We included five patients affected by Crohn's disease, three by ulcerative colitis and two by indeterminate colitis. All patients were on concomitant biological therapy (50% on Infliximab). One patient required a re-treatment for a relapse and two different fistulas were separately treated in another one. Out of 12 total procedures performed, clinical healing was achieved in 10 cases (83%), while radiological healing in 6 patients (50%). No adverse events were recorded. Autologous emulsified adipose-derived stromal vascular fraction tissue can represent an effective, safe and cheap add-on therapy for patients with complex perianal fistulas in IBDs.

Monitoring the psychopathological profile of inflammatory bowel disease patients treated with biological agents: a pilot study.

BACKGROUND: Biological agents were found to alter the psychopathological profile of a small subgroup of patients treated for a variety of conditions, including inflammatory bowel disease (IBD) and psychiatric disorders. The association between the administration of biological agents and psychopathology needs to be further investigated. METHODS: In this naturalistic prospective cohort study, patients with IBD were assigned to two treatment groups, i.e., a biological agent (which also included tofacitinib) or conventional therapy. Clinician-administered scales were used to assess psychosomatic symptoms (Hamilton Depression Rating Scale [Ham-D], Hamilton Anxiety Rating Scale [Ham-A], Young Mania Rating Scale [YMRS], and Brief Psychiatric Rating Scale [BPRS]) and disease activity (Mayo Score and Harvey-Bradshaw Index [HBI]) at baseline, after one, three, and six months of treatment. Each group was assessed for the course of their scores during the observation period at each assessment point. RESULTS: Patients on biological drugs who completed three months of treatment (N.=32) and six months of treatment (N.=20) scored significantly lower on the Mayo compared to baseline. Patients on conventional treatment obtained significant drops from baseline on the HBI after one and three months of treatment (N.=30) and also at the six-month endpoint (N.=11). Both groups showed no improvement or worsening on the psychiatric rating scales. CONCLUSIONS: In this study, we found no evidence of psychiatric symptom worsening, as some literature would suggest. Our data suggest that the use of biological agents in IBD is safe.

Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis: a prospective, international st.

Background/Aims: Patients with diverticular disease (DD) frequently have abnormal bowel movements. However, it is unknown whether the entity of these alterations is associated with the severity of DD. We aimed to assess bowel habits and their relationship with the severity of DD according to Diverticular Inflammation and Complication Assessment (DICA) classification, Combined Overview on Diverticular Assessment (CODA) score, and fecal calprotectin (FC). Methods: An international, multicenter, prospective cohort study was conducted in 43 centers. A 10-point visual analog scale (VAS) was used to assess the severity of constipation and diarrhea. The association of constipation and diarrhea with DICA classification, CODA score, and basal FC was tested using non-parametric tests. Survival methods for censored observations were applied to test the association of constipation and diarrhea with the incidence of acute diverticulitis over a 3-year follow-up. Results: Of 871 patients with DD were included in the study. Of these, 208 (23.9%) and 199 (22.9%) reported a VAS score for constipation and diarrhea at least 3 at baseline, respectively. Higher constipation and diarrhea scores were associated with increasing DICA classification, CODA score and basal FC (P< 0.001). Constipation and diarrhea scores were independently associated with an increased hazard of developing acute diverticulitis (hazard ratio [HR]constipation = 1.15 per 1-VAS point increase, 95% confidence interval [CI], 1.04-1.27; P=0.004; and HRdiarrhea =1.14; 95% CI, 1.03-1.26; P=0.014, respectively). Conclusions: In newly diagnosed patients with DD, higher endoscopic and combined scores of DD severity were associated with higher scores of constipation and diarrhea at baseline. Both constipation and diarrhea were independent prognostic factors of acute diverticulitis.

Self-care in patients affected by inflammatory bowel disease and caregiver contribution to self-care (IBD-SELF): a protocol for a longitudinal observational study.

INTRODUCTION: Supporting patient self-care and the contribution of their caregivers is crucial in chronic illness care. Inflammatory bowel disease (IBD) is a chronic condition whose prevalence is expected to double, especially in Western countries. IBD symptoms can negatively impact patients' well-being, causing high anxiety, depression, stress and reduced quality of life. These symptoms also affect the health of family members and friends, who often take on caregiving roles during exacerbations. Knowledge about self-care in IBD (IBD-SELF) is limited, and few studies have explored this context. This paper outlines a research protocol for a multicentre longitudinal study to investigate patient self-care and caregiver contributions to IBD-SELF. METHODS AND ANALYSIS: A sample of 250 consecutive patients diagnosed with IBD and their caregivers will be recruited from 9 dedicated IBD units in northern, central and southern Italy during outpatient visits. Data collection will occur at baseline, 6 and 12 months after enrolment. Multivariable regressions, path analyses and structural equation models will identify predictors (eg, health literacy, caregiver burden and depression) and outcomes (use of healthcare services, disease severity and quality of life) of self-care and caregiver contributions. Dyadic analyses will control for the interdependence of dyad members. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Territorial Ethics Committee (Lazio 3) N. 0023486/23 and registered on ClinicalTrials.gov (Identifier number: NCT06015789). This study will enhance our understanding of the self-care process in the patient-caregiver dyad in IBD, aiding the design of future educational interventions and promoting greater patient and caregiver involvement in the care pathway. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT06015789.

Endoscopic Management of Strictures in Crohn's Disease: An Unsolved Case.

Crohn's disease (CD) is a chronic inflammatory disease associated with a significant burden in terms of quality of life and health care costs. It is frequently associated with several complications, including the development of intestinal strictures. Stricturing CD requires a careful multidisciplinary approach involving medical therapy and surgery, still posing a continuous management challenge; in this context, endoscopic treatment represents a valuable, in-between opportunity as a minimally invasive strategy endorsed by extensive yet heterogeneous evidence and evolving research and techniques. This review summarizes current knowledge on the role of therapeutic endoscopy in stricturing CD, focusing on evidence gaps, recent updates, and novel techniques intended for optimizing efficacy, safety, and tailoring of this approach in the view of precision endoscopy.

Crohn's Disease: Radiological Answers to Clinical Questions and Review of the Literature.

Background: Crohn's disease (CD) is a chronic, progressive inflammatory condition, involving primarily the bowel, characterized by a typical remitting-relapsing pattern. Despite endoscopy representing the reference standard for the diagnosis and assessment of disease activity, radiological imaging has a key role, providing information about mural and extra-visceral involvement. Methods: Computed Tomography and Magnetic Resonance Imaging are the most frequently used radiological techniques in clinical practice for both the diagnosis and staging of CD involving the small bowel in non-urgent settings. The contribution of imaging in the management of CD is reported on by answering the following practical questions: (1) What is the best technique for the assessment of small bowel CD? (2) Is imaging a good option to assess colonic disease? (3) Which disease pattern is present: inflammatory, fibrotic or fistulizing? (4) Is it possible to identify the presence of strictures and to discriminate inflammatory from fibrotic ones? (5) How does imaging help in defining disease extension and localization? (6) Can imaging assess disease activity? (7) Is it possible to evaluate post-operative recurrence? Results: Imaging is suitable for assessing disease activity, extension and characterizing disease patterns. CT and MRI can both answer the abovementioned questions, but MRI has a greater sensitivity and specificity for assessing disease activity and does not use ionizing radiation. Conclusions: Radiologists are essential healthcare professionals to be involved in multidisciplinary teams for the management of CD patients to obtain the necessary answers for clinically relevant questions.

Parenteral Nutrition, Inflammatory Bowel Disease, and Gut Barrier: An Intricate Plot.

Malnutrition poses a critical challenge in inflammatory bowel disease, with the potential to detrimentally impact medical treatment, surgical outcomes, and general well-being. Parenteral nutrition is crucial in certain clinical scenarios, such as with patients suffering from short bowel syndrome, intestinal insufficiency, high-yielding gastrointestinal fistula, or complete small bowel obstruction, to effectively manage malnutrition. Nevertheless, research over the years has attempted to define the potential effects of parenteral nutrition on the intestinal barrier and the composition of the gut microbiota. In this narrative review, we have gathered and analyzed findings from both preclinical and clinical studies on this topic. Based on existing evidence, there is a clear correlation between short- and long-term parenteral nutrition and negative effects on the intestinal system. These include mucosal atrophic damage and immunological and neuroendocrine dysregulation, as well as alterations in gut barrier permeability and microbiota composition. However, the mechanistic role of these changes in inflammatory bowel disease remains unclear. Therefore, further research is necessary to effectively address the numerous gaps and unanswered questions pertaining to these issues.

Multimodal dynamic ultrasound approach as predictor of response in patients with Crohn's disease treated with ustekinumab.

Background: The approval of ustekinumab (UST) has opened new options for the treatment of Crohn's disease (CD), but potential markers predicting the efficacy of this interleukin-12/23 inhibitor are lacking. Contrast-enhanced ultrasound (CEUS) is non-invasive alternative to endoscopy, demonstrating early transmural changes after treatment induction. Objectives: We conducted a prospective monocentric study aiming to explore the value of multimodal intestinal ultrasound (IUS) in predicting the response to UST in patients with active CD who have been previously exposed to anti-tumour necrosis factor α (TNFα). Design and methods: Consecutive patients with moderate-to-severe CD involving the terminal ileum who were scheduled to begin UST therapy were enrolled between January 2020 and October 2021 in the inflammatory bowel diseases outpatient centre. A complete IUS evaluation, including B-mode, Doppler, dynamic CEUS and elastography, was performed at the time of induction (T0) and after 8 (T1), 16 (T2), 24 (T3) and 48 (T4) weeks of therapy. Each IUS parameter and their variations from baseline were correlated with endoscopic response and mucosal healing after 1 year. Results: A total of 52 patients were included, 29 (55.8%) of which reached endoscopic response at T4. The univariate analysis revealed that, between T3 and T0, the percentage changes of bowel wall thickness, Limberg score, mean signal intensity, rise time, wash-in rate, C reactive protein and Harvey-Bradshaw Index were associated with long-term therapeutic outcome. Based on the above parameters, we developed an IUS score that showed a good performance in predicting 1 year-endoscopic response (area under the curve: 0.91). Conclusion: Multimodal ultrasound could be helpful to predict long-term therapeutic outcome in patients with CD treated with UST. Registration: NCT05987501.

Using ultrasound to predict how well ustekinumab works in Crohn's disease patients Background:The introduction of Ustekinumab (UST) as a treatment for Crohn's disease (CD) has provided new options, but there's a need for reliable markers predicting how well this interleukin-12/23 inhibitor will work. Contrast-enhanced ultrasound (CEUS) is a non-invasive alternative to endoscopy, showing early transmural changes post-treatment. Objectives: In a prospective monocentric study, researchers aimed to explore the value of multimodal intestinal ultrasound (IUS) in predicting UST response in patients with active CD who had previous exposure to anti-tumor necrosis factor α (TNFα). The study involved patients with moderate to severe CD in the terminal ileum, scheduled for UST therapy. Design and methods: Consecutive patients were enrolled between January 2020 and October 2021. Complete IUS evaluations, including B mode, Doppler, dynamic CEUS, and elastography, were conducted at induction (T0) and after 8 (T1), 16 (T2), 24 (T3), and 48 (T4) weeks of therapy. Various IUS parameters and their changes from baseline were correlated with endoscopic response and mucosal healing after 1 year. Results: Of the 52 patients, 29 (55.8%) achieved endoscopic response at T4. The analysis showed that changes in bowel wall thickness, Limberg score, mean signal intensity, rise time, wash-in rate, C-reactive protein, and Harvey-Bradshaw Index between T3 and T0 were associated with long-term therapeutic outcomes. An IUS score developed from these parameters demonstrated good performance in predicting 1-year endoscopic response (area under the curve: 0.91). Conclusion: The study suggests that multimodal ultrasound could be a valuable tool in predicting the long-term therapeutic outcome for patients with CD treated with UST. This non-invasive approach offers insights into treatment response, potentially aiding in personalized treatment strategies for individuals with Crohn's disease.

Navigating the Intersection: Sarcopenia and Sarcopenic Obesity in Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBDs) are intricate systemic conditions that can extend beyond the gastrointestinal tract through both direct and indirect mechanisms. Sarcopenia, characterized by a reduction in muscle mass and strength, often emerges as a consequence of the clinical course of IBDs. Indeed, sarcopenia exhibits a high prevalence in Crohn's disease (52%) and ulcerative colitis (37%). While computed tomography and magnetic resonance imaging remain gold-standard methods for assessing muscle mass, ultrasound is gaining traction as a reliable, cost-effective, and widely available diagnostic method. Muscle strength serves as a key indicator of muscle function, with grip strength test emerging nowadays as the most reliable assessment method. In IBDs, sarcopenia may arise from factors such as inflammation, malnutrition, and gut dysbiosis, leading to the formulation of the 'gut-muscle axis' hypothesis. This condition determines an increased need for surgery with poorer post-surgical outcomes and a reduced response to biological treatments. Sarcopenia and its consequences lead to reduced quality of life (QoL), in addition to the already impaired QoL. Of emerging concern is sarcopenic obesity in IBDs, a challenging condition whose pathogenesis and management are still poorly understood. Resistance exercise and nutritional interventions, particularly those aimed at augmenting protein intake, have demonstrated efficacy in addressing sarcopenia in IBDs. Furthermore, anti-TNF biological therapies showed interesting outcomes in managing this condition. This review seeks to furnish a comprehensive overview of sarcopenia in IBDs, elucidating diagnostic methodologies, pathophysiological mechanisms, and clinical implications and management. Attention will also be paid to sarcopenic obesity, exploring the pathophysiology and possible treatment modalities of this condition.

Fibrostenosing Crohn's Disease: Pathogenetic Mechanisms and New Therapeutic Horizons.

Bowel strictures are well recognized as one of the most severe complications in Crohn's disease, with variable impacts on the prognosis and often needing surgical or endoscopic treatment. Distinguishing inflammatory strictures from fibrotic ones is of primary importance due to the different therapeutic approaches required. Indeed, to better understand the pathogenesis of fibrosis, it is crucial to investigate molecular processes involving genetic factors, cytokines, alteration of the intestinal barrier, and epithelial and endothelial damage, leading to an increase in extracellular matrix synthesis, which ultimately ends in fibrosis. In such a complex mechanism, the gut microbiota also seems to play a role. A better comprehension of molecular processes underlying bowel fibrosis, in addition to radiological and histopathological findings, has led to the identification of high-risk patients for personalized follow-up and testing of new therapies, primarily in preclinical models, targeting specific pathways involving Transforming Growth Factor-ß, interleukins, extracellular matrix balance, and gut microbiota. Our review aims to summarize current evidence about molecular factors involved in intestinal fibrosis' pathogenesis, paving the way for potential diagnostic biomarkers or anti-fibrotic treatments for stricturing Crohn's disease.

Solute Transporter OCTN1/Slc22a4 Affects Disease Severity and Response to Infliximab in Experimental Colitis: Role of Gut Microbiota and Immune Modulation.

BACKGROUND: Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial etiology, still incompletely understood. OCTN1, an organic cation transporter, could have a role in modulating the inflammatory response, and some genetic polymorphisms of this molecule have been associated with increased risk of inflammatory bowel diseases. Until now, limited information exists on its potential in predicting/modulating patient's response to therapies. The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and mucosal immunity in response to infliximab therapy in murine colitis. METHODS: A dextran sodium sulphate model of colitis was used to assess the clinical efficacy of infliximab administered intravenously in ocnt1 gene knockout mice and their C57BL/6 controls. Stool, colon, and mesenteric lymph node samples were collected to evaluate differences in gut microbiota composition, histology, and T cell populations, respectively. RESULTS: Octn1 -/- influences the microbiota profile and is associated with a worse dysbiosis in mice with colitis. Infliximab treatment attenuates colitis-associated dysbiosis, with an increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1-/- mice have milder disease and a higher baseline percentage of Treg, Tmemory, Th2 and Th17 cells. CONCLUSIONS: Our data support the murine model to study OCTN1 genetic contribution to inflammatory bowel diseases. This could be the first step towards the recognition of this membrane transporter as a biomarker in inflammatory conditions and a predictor of response to therapies.

In this article, we evaluated the role of OCTN1, an organic cation transporter, in modifying gut microbiota and immune T cell populations, as well as its effects on experimental colitis and the response to infliximab treatment.

Histologic Disease Persists beyond Mucosal Healing and Could Predict Reactivation in Ulcerative Colitis.

Mucosal healing (MH) is the main target in ulcerative colitis (UC) treatment. Even if MH lowers the risk of disease reactivation, some patients still relapse. Histologic activity (HA) beyond MH could explain these cases. This study aims to assess how many patients with MH have HA and which lesions are associated with relapse. We retrospectively enrolled UC patients showing MH, expressed as a Mayo Endoscopic Subscore (MES) of 0 and 1 upon colonoscopy. We reviewed the histological reports of biopsies evaluating the presence of typical lesions of UC and assessed the number of clinical relapses after 12 months. Among 100 enrolled patients, 2 showed no histological lesions. According to univariate analysis, patients with a higher number of histological lesions at the baseline had a higher risk of relapse (OR 1.25, p = 0.012), as well as patients with basal plasmacytosis (OR 4.33, p = 0.005), lamina propria eosinophils (OR 2.99, p = 0.047), and surface irregularity (OR 4.70, p = 0.010). However, in the multivariate analysis, only basal plasmacytosis (OR 2.98, p = 0.050) and surface irregularity (OR 4.50, p = 0.024) were confirmed as risk factors for disease reactivation. HA persists in a significant percentage of patients with MH. Despite the presence of MH, patients with basal plasmacytosis and surface irregularity have a higher risk of relapse.

An integrative multi-omic analysis defines gut microbiota, mycobiota, and metabolic fingerprints in ulcerative colitis patients.

Background: Ulcerative colitis (UC) is a multifactorial chronic inflammatory bowel disease (IBD) that affects the large intestine with superficial mucosal inflammation. A dysbiotic gut microbial profile has been associated with UC. Our study aimed to characterize the UC gut bacterial, fungal, and metabolic fingerprints by omic approaches. Methods: The 16S rRNA- and ITS2-based metataxonomics and gas chromatography-mass spectrometry/solid phase microextraction (GC-MS/SPME) metabolomic analysis were performed on stool samples of 53 UC patients and 37 healthy subjects (CTRL). Univariate and multivariate approaches were applied to separated and integrated omic data, to define microbiota, mycobiota, and metabolic signatures in UC. The interaction between gut bacteria and fungi was investigated by network analysis. Results: In the UC cohort, we reported the increase of Streptococcus, Bifidobacterium, Enterobacteriaceae, TM7-3, Granulicatella, Peptostreptococcus, Lactobacillus, Veillonella, Enterococcus, Peptoniphilus, Gemellaceae, and phenylethyl alcohol; and we also reported the decrease of Akkermansia; Ruminococcaceae; Ruminococcus; Gemmiger; Methanobrevibacter; Oscillospira; Coprococus; Christensenellaceae; Clavispora; Vishniacozyma; Quambalaria; hexadecane; cyclopentadecane; 5-hepten-2-ol, 6 methyl; 3-carene; caryophyllene; p-Cresol; 2-butenal; indole, 3-methyl-; 6-methyl-3,5-heptadiene-2-one; 5-octadecene; and 5-hepten-2-one, 6 methyl. The integration of the multi-omic data confirmed the presence of a distinctive bacterial, fungal, and metabolic fingerprint in UC gut microbiota. Moreover, the network analysis highlighted bacterial and fungal synergistic and/or divergent interkingdom interactions. Conclusion: In this study, we identified intestinal bacterial, fungal, and metabolic UC-associated biomarkers. Furthermore, evidence on the relationships between bacterial and fungal ecosystems provides a comprehensive perspective on intestinal dysbiosis and ecological interactions between microorganisms in the framework of UC.

Fecal transplantation for ulcerative colitis from diet conditioned donors followed by dietary intervention results in favorable gut microbial profile compared to fecal transplantation alone.

BACKGROUND AND AIMS: Several fecal microbial transplantation (FMT) approaches for ulcerative colitis (UC) have been investigated with conflicting results. We have recently published the clinical outcomes from the CRAFT-UC Trial using FMT with the UC Exclusion Diet (UCED), compared with FMT alone. Here we aimed to compare the two FMT strategies in terms of microbial profile and function. METHODS: Subjects recruited to the CRAFT-UC study with available pre- and post-intervention fecal samples were included. Donors received diet conditioning for 14 days based on the UCED principles. Group-1 received single FMT by colonoscopy (Day 1) and enemas (Days 2 and 14) without donors' dietary conditioning (N=11). Group-2 received FMT but with donors' dietary pre-conditioning and UCED for the patients (N=10). Fecal samples were assessed by DNA shotgun metagenomic sequencing. RESULTS: Following diet conditioning, donors had depletion in metabolic pathways involved in sulfur-containing amino acids biosynthesis. Only Group-2 showed significant shifts towards the donors' microbial composition (ADONIS: R2=0.15, p=0.008) and significant increased Eubacterium_sp_AF228LB post-intervention (ß-coefficient 2.66, 95%CI 2.1-3.3, q<0.05) which was inversely correlated with fecal calprotectin (rho=-0.52, p=0.035). Moreover, pathways involved in gut inflammation and barrier function including branched chain amino acids were enriched post intervention in Group-2 and were significantly inversely correlated with fecal calprotectin. CONCLUSION: FMT from diet conditioned donors followed by the UCED led to microbial alterations associated with favorable microbial profile which correlated with decreased fecal calprotectin. Our findings support further exploration of additive benefit of dietary intervention for both donors and patients undergoing FMT as a potential treatment of UC.

Extrachromosomal Circular DNA: An Emerging Potential Biomarker for Inflammatory Bowel Diseases?

Inflammatory bowel disease (IBD) comprising ulcerative colitis and Crohn's disease is a chronic immune-mediated disease which affects the gastrointestinal tract with a relapsing and remitting course, causing lifelong morbidity. IBD pathogenesis is determined by multiple factors including genetics, immune and microbial factors, and environmental factors. Although therapy options are expanding, remission rates are unsatisfiable, and together with the disease course, response to therapy remains unpredictable. Therefore, the identification of biomarkers that are predictive for the disease course and response to therapy is a significant challenge. Extrachromosomal circular DNA (eccDNA) fragments exist in all tissue tested so far. These fragments, ranging in length from a few hundreds of base pairs to mega base pairs, have recently gained more interest due to technological advances. Until now, eccDNA has mainly been studied in relation to cancer due to its ability to act as an amplification site for oncogenes and drug resistance genes. However, eccDNA could also play an important role in inflammation, expressed both locally in the- involved tissue and at distant sites. Here, we review the current evidence on the molecular mechanisms of eccDNA and its role in inflammation and IBD. Additionally, the potential of eccDNA as a tissue or plasma marker for disease severity and/or response to therapy is evaluated.

Inflammatory Bowel Diseases and Non-Alcoholic Fatty Liver Disease: Piecing a Complex Puzzle Together.

Inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, are systemic and multifaceted disorders which affect other organs in addition to the gastrointestinal tract in up to 50% of cases. Extraintestinal manifestations may present before or after IBD diagnosis and negatively impact the intestinal disease course and patients' quality of life, often requiring additional diagnostic evaluations or specific treatments. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Current evidence shows an increased prevalence of NAFLD (and its more advanced stages, such as liver fibrosis and steatohepatitis) in IBD patients compared to the general population. Many different IBD-specific etiopathogenetic mechanisms have been hypothesized, including chronic inflammation, malabsorption, previous surgical interventions, changes in fecal microbiota, and drugs. However, the pathophysiological link between these two diseases is still poorly understood. In this review, we aim to provide a comprehensive overview of the potential mechanisms which have been investigated so far and highlight open issues still to be addressed for future studies.

Low Dose Pregabalin Improves Gastrointestinal Symptoms of Crohn's Disease.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are lifelong conditions with no definite cure. Several studies demonstrated that patients with IBD more frequently experience symptoms of common mental disorders, such as anxiety and depression, because of bidirectional communication through the gut-brain axis and the chronicity of symptoms, as well as because of impaired quality of life and reduced social functioning. However, psychological conditions of affected patients are often underestimated and not fully considered. Herein, we present the case of a 37-year-old woman with Crohn's disease and a mild depressive condition, characterized by anxious distress, tachycardia, tachypnea, tremors, sweating, avoidant behaviors, and intestinal somatizations (diarrhea), who was treated with Pregabalin upon indication of the referring psychiatrist. Following the beginning of the treatment, the patient rapidly reported an improvement in the overall clinical symptoms as well as a better management of psychic and physical anxiety with a marked reduction in diarrheal discharges under stress at work. After 6 months of Pregabalin therapy, we additionally observed an improvement in Crohn's disease activity, both clinically, in the laboratory, and endoscopically. Our case showed that patients with Crohn's disease and anxiety problems may benefit from low-dose Pregabalin medication to improve both their mental and physical condition.

Cellular and Molecular Determinants of Biologic Drugs Resistance and Therapeutic Failure in Inflammatory Bowel Disease.

The advent of biologic drugs has revolutionized the treatment of Inflammatory Bowel Disease, increasing rates of response and mucosal healing in comparison to conventional therapies by allowing the treatment of corticosteroid-refractory cases and reducing corticosteroid-related side effects. However, biologic therapies (anti-TNFα inhibitors, anti-α4ß7 integrin and anti-IL12/23) are still burdened by rates of response that hover around 40% (in biologic-naïve patients) or lower (for biologic-experienced patients). Moreover, knowledge of the mechanisms underlying drug resistance or loss of response is still scarce. Several cellular and molecular determinants are implied in therapeutic failure; genetic predispositions, in the form of single nucleotide polymorphisms in the sequence of cytokines or Human Leukocyte Antigen, or an altered expression of cytokines and other molecules involved in the inflammation cascade, play the most important role. Accessory mechanisms include gut microbiota dysregulation. In this narrative review of the current and most recent literature, we shed light on the mentioned determinants of therapeutic failure in order to pave the way for a more personalized approach that could help avoid unnecessary treatments and toxicities.

Predictors of Efficacy of Janus Kinase Inhibitors in Patients Affected by Ulcerative Colitis.

Personalised medicine and the identification of predictors of the efficacy of specific drugs represent the ultimate goal for the treatment of ulcerative colitis (UC) in order to break the current therapeutic ceiling. JAK inhibitors are a new class of advanced therapies, orally administered, showing a good profile of efficacy and safety in both randomised controlled trials (RCTs) and real-world studies. Unfortunately, to date, it is not possible to draw the ideal profile of a patient maximally benefiting from this class of drugs to guide clinicians' therapeutic choices. Baseline clinical activities and inflammatory biomarkers, as well as their early variation after treatment initiation, emerged as the main predictors of efficacy from post hoc analyses of RCTs with tofacitinib. Similar findings were also observed in the real-life studies including mainly patients with a history of pluri-refractoriness to biological therapies. At last, a few new biomarkers have been explored, even though they have not been validated in large cohorts. This paper provides a review of the current knowledge on clinical variables and biomarkers predicting response to JAK inhibitors in UC.

Adverse Food Reactions in Inflammatory Bowel Disease: State of the Art and Future Perspectives.

Limited knowledge is available about the relationship between food allergies or intolerances and inflammatory bowel disease (IBD). Clinicians frequently encounter patients who report food allergies or intolerances, and gastroenterologists struggle distinguishing between patients with organic disorders and those with functional disorders, which the patients themselves may associate with specific dietary components. This task becomes even more arduous when managing patients with significant underlying organic conditions, like IBD. The aim of this review is to summarize and emphasize any actual associations between food allergies and intolerances and inflammatory diseases, such as ulcerative colitis and Crohn's disease. Through a narrative disceptation of the current literature, we highlight the increased prevalence of various food intolerances, including lactose, fructose, histamine, nickel, and non-celiac gluten sensitivity, in individuals with IBD. Additionally, we explore the association between increased epithelial barrier permeability in IBD and the development of food sensitization. By doing so, we aim to enhance clinicians' awareness of the nutritional management of patients with IBD when facing complaints or evidence of food allergies or intolerances.