Bridging the gap:Unveiling the crisis of physical inactivity in inflammatory bowel diseases

In this editorial we comment on the article titled“Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity:The BE-FIT-IBD study”published in a recent issue of the World Journal of Gastroen-terology 2023;29(41):5668-5682.Inflammatory bowel diseases(IBD)are emerging as a significant global health concern as their incidence continues to rise on a global scale,with detrimental impacts on quality of life.While many advances have been made regarding the management of the disease,physical inactivity in these patients represents an underexplored issue that may hold the key for further and better understanding the ramifications of IBD.Chronic pain,fatigue,and fear of exacerbating symptoms promotes physical inactivity among IBD patients,while the lack of clear guidelines on safe exercise regimens contributes to a norm of physical inactivity.Physical activity(PA)is accepted to have a positive effect on disease outcomes and quality of life,while inactivity exacerbates comorbidities like cardiovascular disease and mental health disorders.The“BE-FIT-IBD”study,focusing on PA levels and barriers in IBD patients of Southern Italy,revealed that a significant proportion(42.9%)were physically inactive.This lack of PA is attributed to barriers such as fear of flare-ups and misconceptions about exercise exacerbating the disease.The study also highlighted the need for better communication between healthcare providers and patients regarding the benefits of PA and safe incorporation into lifestyles.Moreover,physical inactivity may also contribute to disability in IBD patients,having a great impact on employment status.Of note is the fact that IBD also comes with an important psychological burden with relevant evidence suggesting that regular PA can improve mood,reduce anxiety,and enhance mental health.The“BE-FIT-IBD”study advocated for the integration of PA into IBD management,emphasizing the bidirectional link between PA and IBD.Regular exercise can influence the course of IBD,potentially reducing symptom severity and prolonging remission periods.As such,it is mandatory that healthcare providers actively educate patients,dispel misconceptions,and tailor exercise recommendations to improve the quality of life and reduce IBD-related complications.

Azathioprine monotherapy withdrawal in inflammatory bowel diseases: A retrospective mono-centric study

BACKGROUND There is no consensus on the recommended duration of and optimal time to stop azathioprine(AZA)therapy in inflammatory bowel disease(IBD).Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation.AIM To describe the events following AZA cessation.METHODS Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022.Data on therapy duration,reasons for cessation,and type of relapse after cessation were collected.Cox regression models were used to estimate the risk of relapse in different subgroups.RESULTS A total of 133 ulcerative colitis patients and 141 Crohn’s disease patients were included.Therapy with AZA was stopped in the 1st year in approximately 34%of patients but was continued for more than 10 years in approximately 10%of cases.AZA discontinuation was due to primary failure or disease relapse in 30%of patients and due to disease remission in 25.2%of patients.Most of the remaining cases stopped AZA therapy due to side effects(primarily clinical intolerance,cytopenia,and pancreatic disease).Patients who stopped AZA for clinical remission had an 83%lower risk of relapse during the observation time than other groups,with a relapse-free rate of 89%after 1 year and 79%after 2 years.CONCLUSION AZA administration is effective and safe,but it requires careful monitoring for potential minor and major side effects.Only 10%of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.

Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

Clostridioides difficile(C.difficile)is progressively colonizing humans and animals living with humans.During this process,hypervirulent strains and mutated toxin A and B of C.difficile(TcdA and TcdB)are originating and developing.While in healthy subjects colonization by C.difficile becomes a risk after the use of antibiotics that alter the microbiome,other categories of people are more susceptible to infection and at risk of relapse,such as those with inflammatory bowel disease(IBD).Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma(CKs).Therefore,in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C.difficile infection and its progression and relapses.TcdB is internalized in the cell via three receptors:chondroitin sulphate proteoglycan 4;poliovirus receptor-like 3;and Wnt receptor frizzled family.Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types,while poliovirus receptor-like 3 induces only necrosis.It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis.Therefore,in subjects with IBD there are the conditions:(1)For greater susceptibility to C.difficile infection,such as the inflammatory state,and abnormalities of the microbiome and of the immune system;(2)for the enhancement of the cytotoxic activity of TcdB+Cks;and(3)for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis.The only therapeutic approach currently possible in IBD patients is monitoring of C.difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins.The future perspective is to generate bacteriophages against C.difficile for targeted therapy.

Vaccination coverage in children with juvenile idiopathic arthritis,inflammatory bowel diseases,and healthy peers:Cross-sectional electronic survey data

BACKGROUND Patients with immune-mediated diseases,such as juvenile idiopathic arthritis(JIA)and inflammatory bowel disease(IBD)are at increased risk of developing infections,due to disease-related immune dysfunction and applying of immunosuppressive drugs.AIM To evaluate vaccine coverage in patients with IBD and JIA,and compare it with healthy children.METHODS In the cross-sectional study we included the data from a questionnaire survey of 190 Legal representatives of children with JIA(n=81),IBD(n=51),and healthy children(HC,n=58).An electronic online questionnaire was created for the survey.RESULTS There were female predominance in JIA patients and younger onset age.Parents of JIA had higher education levels.Employment level and family status were similar in the three studied groups.Patients with JIA and IBD had lower vaccine coverage,without parental rejection of vaccinations in IBD,compare to JIA and healthy controls.The main reason for incomplete vaccination was medical conditions in IBD and JIA.IBD patients had a lower rate of normal vaccine-associated reactions compared to JIA and HC.The encouraging role of physicians for vaccinations was the lowest in JIA patients.IBD patients had more possibilities to check antibodies before immune-suppressive therapy and had more supplementary vaccinations compared to JIA and HC.CONCLUSION JIA and IBD patients had lower vaccine coverage compared to HC.Physicians'encouragement of vaccination and the impossibility of discus about future vaccinations and their outcomes seemed the main factors for patients with immune-mediated diseases,influencing vaccine coverage.Further investigations are required to understand the reasons for incomplete vaccinations and improve vaccine coverage in both groups,especially in rheumatic disease patients.The approaches that stimulate vaccination in healthy children are not always optimal in children with immunemediated diseases.It is necessary to provide personalized vaccine-encouraging strategies for parents of chronically ill children with the following validation of these technics.

Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity:The“BE-FIT-IBD”study

BACKGROUND The place regular physical activity(PA)should occupy in managing patients with inflammatory bowel diseases(IBD)is unclear.AIM To assess PA levels and barriers in a southern Italian IBD population.METHODS IBD patients with non-severe disease activity[assessed with partial Mayo score for ulcerative colitis(UC)and Harvey-Bradshaw index for Crohn’s disease]were approached to receive an anonymous online questionnaire to assess PA levels using the International Physical Activity Questionnaire(IPAQ)and to assess disease activity as patient-reported outcomes 2(PRO-2)and finally to assess habits,beliefs and barriers in conducting regular PA.Clinical,anthropometric and demographic data of patients were also collected.PA was expressed as continuous units of resting metabolic rate(Met)in min/wk.Three PA groups were identified:Inactive(<700 Met min/wk),sufficiently active(700-2500 Met min/wk)and health enhancing PA(HEPA)(i.e.,HEPA active,>2500 Met min/wk)patients.RESULTS Included patients(219)showed overall PA levels of 834.5 Met min/wk,with a large proportion(94,42.9%)classified as inactive while only a minority(9,4.1%)as health-enhancing PA.Patients without dyslipidaemia(P<0.0001)or on biologics therapy(P=0.022)showed better IPAQ scores in moderate activities.UC PRO-2 correlated negatively with IPAQ intense activities scores(τ=-0.156,P=0.038).PRO-2 did not show notable sensitivity/specificity in predicting IPAQ inactivity(AUC<0.6).IBD activity did not differ between active and inactive patients(P>0.05).Active patients expressed the need to discuss PA with their gastroenterologist.Some barriers(e.g.,diagnosis of IBD and fear of flare-ups after PA)are significantly more reported by inactive patients.CONCLUSION A significant rate of physical inactivity was recorded in this setting.IPAQ showed good feasibility.PA should be an element of discussion in IBD visits assessed quickly with non-invasive questionnaires.

Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases

Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic therapeutics,and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy.Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics.Sphingosine-1-phosphate(S1P)receptor(S1PR)modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement.S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival,differentiation,migration,proliferation,immune response,and lymphocyte trafficking.T lymphocytes play an important role in regulating inflammatory responses.In inflamed IBD tissue,an imbalance between T helper(Th)and regulatory T lymphocytes and Th cytokine levels was found.The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD.S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking,lymphocyte number,lymphocyte activity,cytokine production,and contributing to gut barrier function.

Immune response modulation in inflammatory bowel diseases by Helicobacter pylori infection

Many studies point to an association between Helicobacter pylori(H.pylori)infection and inflammatory bowel diseases(IBD).Although controversial,this association indicates that the presence of the bacterium somehow affects the course of IBD.It appears that H.pylori infection influences IBD through changes in the diversity of the gut microbiota,and hence in local chemical characteristics,and alteration in the pattern of gut immune response.The gut immune response appears to be modulated by H.pylori infection towards a less aggressive inflammatory response and the establishment of a targeted response to tissue repair.Therefore,a T helper 2(Th2)/macrophage M2 response is stimulated,while the Th1/macrophage M1 response is suppressed.The immunomodulation appears to be associated with intrinsic factors of the bacteria,such as virulence factors-such oncogenic protein cytotoxin-associated antigen A,proteins such H.pylori neutrophil-activating protein,but also with microenvironmental changes that favor permanence of H.pylori in the stomach.These changes include the increase of gastric mucosal pH by urease activity,and suppression of the stomach immune response promoted by evasion mechanisms of the bacterium.Furthermore,there is a causal relationship between H.pylori infection and components of the innate immunity such as the NLR family pyrin domain containing 3 inflammasome that directs IBD toward a better prognosis.

Telemedicine in inflammatory bowel diseases:A new brick in the medicine of the future?

Inflammatory bowel disease(IBD)is a chronic digestive disease that requires continuous monitoring by healthcare professionals to determine the appropriate therapy and monitor short-term and long-term complications.The progressive development of information technology has enabled healthcare personnel to deliver care services to patients remotely.Therefore,various applications of telemedicine in IBD management have evolved,including telemonitoring,teleconsulting,teleducation,telenursing,telenutrition,and telepathology.While evidence has been provided for some telemedicine applications,targeted studies are still required.This review summarises the major studies that have evaluated telemedicine and its application in the management of IBD.

Epidemiological and clinical characteristics of inflammatory bowel diseases in Cairo,Egypt

AIM: To study the natural history, patterns and clinical characteristics of inflammatory bowel diseases (IBD) in Egypt.

Recent trends in the epidemiology of inflammatory bowel diseases:Up or down?

Inflammatory bowel disease (IBD) is traditionally con- sidered to be common in the Western world, and its incidence has sharply increased since the early 1950s. In contrast, until the last decade, low prevalence and incidence rates have been reported from other parts of the world including Eastern Europe, South America, Asia and the Pacific region. Recent trends indicate a change in the epidemiology of IBD with previously low incidence areas now reporting a progressive rise in the incidence, while in West European and North American countries the figures have stabilized or slightly increased, with decreasing incidence rates for ulcerative colitis. Some of these changes may represent differences in diagnostic practices and increasing awareness of the disease. The quality of studies is also variable. Additional epidemio- logic studies are needed to better define the burden of illness, explore the mechanism of association with envi- ronmental factors, and identify new risk factors.

Extraintestinal manifestations and complications in inflammatory bowel diseases

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory bowel diseases （IBD） that often involve organs other than those of the gastrointestinal tract. These nonintestinal affections are termed extraintestinal symptoms. Differentiating the true extraintestinal manifestations of inflammatory bowel diseases from secondary extraintestinal complications, caused by malnutrition, chronic inflammation or side effects of therapy, may be difficult. This review concentrates on frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. If possible, extraintestinal manifestations are differentiated from extraintestinal complications. Special attention is given to the more recently described sites of involvement; i.e. thromboembolic events, osteoporosis, pulmonary involvement and affection of the central nervous system.

Psychosocial issues in evidence-based guidelines on inflammatory bowel diseases: A review

AIM: To study statements and recommendations on psychosocial issues as presented in international evidence-based guidelines on the management of inflammatory bowel diseases (IBD).

Inflammatory bowel diseases: From the mystical to the cellular and now the molecular

It is of interest in an era of increasing biomedical sophisticaton to recall that a relatively short time ago, early in the 20th century, ‘simple' ulcerative colitis was an obscure ‘medical curiosity' emerging slowly from an unknown past. Crohn's disease was yet unidentified as a separate entity although careful review of the IBD literature documented its early presence, masquerading as ‘intestinal tuberculosis'. Into the 1930s, the etiology and pathogenesis of ulcerative colitis and Crohn's disease were unknown, and investigative hypotheses were scarce. Therapeutic resources were limited and treatment was primitive. At a time of limited biomedical knowledge and minimal clinical awareness, unsubstantiated views prevailed, including ‘vague reactions to foods' (sugar,margarine, corn flakes), deficiency of a ‘protective factor'in pig intestine, and psychiatric disease.

Inflammatory bowel diseases: A disease (s) of modern times? Is incidence still increasing?

Inflammatory bowel diseases (IBD) are a heterogeneous group of diseases, not always easy to diagnose, even more difficult to classify, and diagnostic criteria are not always uniform. Well done population-based studies are not abundant, and so comparisons among different geographical areas or populations are not always very reliable. In this article, we have reviewed epidemiological studies available on the world’s population while making a critical review of published data.

Neurological disorders and inflammatory bowel diseases

Extraintestinal manifestations occur in about one-third of patients living with inflammatory bowel disease(IBD) and may precede the onset of gastrointestinal symptoms by many years. Neurologic disorders associated with IBD are not frequent, being reported in 3% of patients, but they often represent an important cause of morbidity and a relevant diagnostic issue. In addition, the increasing use of immunosuppressant and biological therapies for IBD may also play a pivotal role in the development of neurological disorders of different type and pathogenesis. Hence, we provide a complete and profound review of the main features of neurological complications associated with IBD, with particular reference to those related to drugs and with a specific focus on their clinical presentation and possible pathophysiological mechanisms.

Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases

BACKGROUND： There is a growing evidence that matrix metalloproteinase （MMP）-2 and MMP-9 （gelatinases） play an important role in the pathogenesis of numerous disorders, especially with inflammatory etiology and extracellular matrix （ECM） remodeling. Despite the fact that gelatinases involve in liver cirrhosis is provided in the literature, their role in the pathogenesis of chronic pancreatitis and non-specific inflammatory bowel diseases is still under investigation. DATA SOURCES： We carried out a PubMed search of Englishlanguage articles relevant to the involvement of gelatinases in the pathogenesis of liver fibrosis, pancreatitis, and non-specific inflammatory bowel diseases. RESULTS： The decreased activity of gelatinases, especially MMP-2, is related to the development of liver fibrosis, probably due to the decrease of capability for ECM remodeling. Similar situation can be found in chronic pancreatitis; however, reports on this matter are rare. The presence of non-specific inflammatory bowel diseases results in MMP-9 activity elevation. CONCLUSION： The fluctuation of gelatinases activity during liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases is observed, but the exact role of these enzymes demands further studies.

Antioxidant and anti-inflammatory roles of tea polyphenols in inflammatory bowel diseases

Polyphenols,including phenolic acids,flavonoids,and procyanidins,are abundant in food and beverage derived from plants.Tea(Camellia sinensis)is particularly rich in polyphenols(e.g.,catechins,theaflavins,thearubigins,gallic acid,and flavonols),which are thought to contribute to the health benefits of tea.High intake of tea polyphenols has been described to prevent and/or attenuate a variety of chronic pathological conditions like cardiovascular diseases,neurodegenerative diseases,diabetes,and cancer.This review focuses on established antioxidant and anti-inflammatory properties of tea polyphenols and underlying mechanisms of their involvement in inflammatory bowel diseases(IBD).Tea polyphenols act as efficient antioxidants by inducing an endogenous antioxidant defense system and maintaining intracellular redox homeostasis.Tea polyphenols also regulate signaling pathways such as nuclear factor-κB,activator protein 1,signal transducer and activator of transcriptions,and nuclear factor E2-related factor 2,which are associated with IBD development.Accumulating pieces of evidence have indicated that tea polyphenols enhance epithelial barrier function and improve gut microbial dysbiosis,contributing to the management of inflammatory colitis.Therefore,this study suggests that supplementation of tea polyphenols could prevent inflammatory conditions and improve the outcome of patients with IBD.

From bench to bedside: Fecal calprotectin in inflammatory bowel diseases clinical setting

Fecal calprotectin(FC) has emerged as one of the most useful tools for clinical management of inflammatory bowel diseases(IBD). Many different methods of assessment have been developed and different cutoffs have been suggested for different clinical settings. We carried out a comprehensive literature review of the most relevant FC-related topics: the role of FC in discriminating between IBD and irritable bowel syndrome(IBS) and its use in managing IBD patients In patients with intestinal symptoms, due to the high negative predictive value a normal FC level reliably rules out active IBD. In IBD patients a correlation with both mucosal healing and histology was found, and there is increasing evidence that FC assessment can be helpful in monitoring disease activity and response to therapy as well as in predicting relapse, post-operative recurrence or pouchitis. Recently, its use in the context of a treat-to-target approach led to a better outcome than clinically-based therapy adjustment in patients with early Crohn's disease. In conclusion, FC measurement represents a cheap, safe and reliable test, easy to perform and with a good reproducibility. The main concerns are still related to the choice of the optimal cut-off, both for differentiating IBD from IBS, and for the management of IBD patients.

Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors(PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.

Anemia and inflammatory bowel diseases

Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease (IBD). However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are: (1) anemia is quite common in IBD; (2) although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; (3) anemia, and also iron def iciency without anemia, have important consequences in the clinical status and quality of life of the patient; (4) oral iron can lead to gastrointestinal intolerance and failure of treatment; (5) intravenous iron is an effective and safe way to treat iron deficiency; (6) erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice.