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Gut microbes in metabolic disturbances. Promising role for therapeutic manipulations?
Portincasa, P, Khalil, M, Graziani, A, Frühbeck, G, Baffy, G, Garruti, G, Di Ciaula, A, Bonfrate, L
European journal of internal medicine. 2024;:13-30
Abstract
The prevalence of overweight, obesity, type 2 diabetes, metabolic syndrome and steatotic liver disease is rapidly increasing worldwide with a huge economic burden in terms of morbidity and mortality. Several genetic and environmental factors are involved in the onset and development of metabolic disorders and related complications. A critical role also exists for the gut microbiota, a complex polymicrobial ecology at the interface of the internal and external environment. The gut microbiota contributes to food digestion and transformation, caloric intake, and immune response of the host, keeping the homeostatic control in health. Mechanisms of disease include enhanced energy extraction from the non-digestible dietary carbohydrates, increased gut permeability and translocation of bacterial metabolites which activate a chronic low-grade systemic inflammation and insulin resistance, as precursors of tangible metabolic disorders involving glucose and lipid homeostasis. The ultimate causative role of gut microbiota in this respect remains to be elucidated, as well as the therapeutic value of manipulating the gut microbiota by diet, pre- and pro- synbiotics, or fecal microbial transplantation.
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Diagnostic delay in adult coeliac disease: An Italian multicentre study.
Lenti, MV, Aronico, N, Bianchi, PI, D'Agate, CC, Neri, M, Volta, U, Mumolo, MG, Astegiano, M, Calabrò, AS, Zingone, F, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2023;(6):743-750
Abstract
BACKGROUND There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD). AIMS To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD. METHODS CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted. RESULTS Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay. CONCLUSION We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.
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Metabolic dysfunction-associated gallstone disease: expecting more from critical care manifestations.
Portincasa, P, Di Ciaula, A, Bonfrate, L, Stella, A, Garruti, G, Lamont, JT
Internal and emergency medicine. 2023;(7):1897-1918
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Abstract
About 20% of adults worldwide have gallstones which are solid conglomerates in the biliary tree made of cholesterol monohydrate crystals, mucin, calcium bilirubinate, and protein aggregates. About 20% of gallstone patients will definitively develop gallstone disease, a condition which consists of gallstone-related symptoms and/or complications requiring medical therapy, endoscopic procedures, and/or cholecystectomy. Gallstones represent one of the most prevalent digestive disorders in Western countries and patients with gallstone disease are one of the largest categories admitted to European hospitals. About 80% of gallstones in Western countries are made of cholesterol due to disturbed cholesterol homeostasis which involves the liver, the gallbladder and the intestine on a genetic background. The incidence of cholesterol gallstones is dramatically increasing in parallel with the global epidemic of insulin resistance, type 2 diabetes, expansion of visceral adiposity, obesity, and metabolic syndrome. In this context, gallstones can be largely considered a metabolic dysfunction-associated gallstone disease, a condition prone to specific and systemic preventive measures. In this review we discuss the key pathogenic and clinical aspects of gallstones, as the main clinical consequences of metabolic dysfunction-associated disease.
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Phenotyping the obesities: reality or utopia?
Portincasa, P, Frühbeck, G
Reviews in endocrine & metabolic disorders. 2023;(5):767-773
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Abstract
In this thematic issue on phenotyping the obesities, prominent international experts offer an insightful and comprehensive collection of articles covering the current knowledge in the field. In order to actually capture all the polyhedral determinants of the diverse types of obesity, the granularity of the phenotypic information acquired must be expanded in the context of a personalized approach. Whilst the use of precision medicine has been successfully implemented in areas like cancer and other diseases, health care providers are more reluctant to embrace detailed phenotyping to guide diagnosis, treatment and prevention in obesity. Given its multiple complex layers, phenotyping necessarily needs to go beyond the multi-omics approach and incorporate all the diverse spheres that conform the reality of people living with obesity. Potential barriers, difficulties, roadblocks and opportunities together with their interaction in a syndemic context are analyzed. Plausible lacunae are also highlighted in addition to pointing to the need of redefining new conceptual frameworks. Therefore, this extraordinary collection of state-ofthe-art reviews provides useful information to both experienced clinicians and trainees as well as academics to steer clinical practice and research in the management of people living with obesity irrespective of practice setting or career stage.
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The Impact of Za'atar Antioxidant Compounds on the Gut Microbiota and Gastrointestinal Disorders: Insights for Future Clinical Applications.
Khalil, M, Abdallah, H, Razuka-Ebela, D, Calasso, M, De Angelis, M, Portincasa, P
Antioxidants (Basel, Switzerland). 2023;(2)
Abstract
Since the gut microbiota plays a pivotal role in host homeostasis and energy balance, changes in its composition can be associated with disease states through the promotion of immune-mediated inflammatory disorders and increasing intestinal permeability, ultimately leading to the impairment of intestinal barrier function. Za'atar is one of the most popular plant-based foods in the Eastern Mediterranean region. Za'atar is a mixture of different plant leaves, fruits, and seeds and contains hundreds of antioxidant compounds, especially polyphenols, and fiber, with pre-clinical and clinical evidence suggesting health-promoting effects in cardiovascular and metabolic disease. Za'atar compounds have also been studied from a gastrointestinal perspective, concerning both gut microbiota and gastrointestinal diseases. Antioxidants such as Za'atar polyphenols may provide beneficial effects in the complex interplay between the diet, gut microbiota, and intestinal permeability. To our knowledge, no studies have reported the effects of the whole Za'atar mixture, however, based on the pre-clinical studies published on components and single compounds found in Za'atar, we provide a clinical overview of the possible effects on the gastrointestinal tract, focusing mainly on carvacrol, rosmarinic acid, gallic acid, and other polyphenols. We also cover the potential clinical applications of Za'atar mixture as a possible nutraceutical in disorders involving the gastrointestinal tract.
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Systematic review with meta-analysis: Branched-chain amino acid supplementation in liver disease.
van Dijk, AM, Bruins Slot, AS, Portincasa, P, Siegerink, SN, Chargi, N, Verstraete, CJR, de Bruijne, J, Vleggaar, FP, van Erpecum, KJ
European journal of clinical investigation. 2023;(3):e13909
Abstract
BACKGROUND Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. METHODS We searched MEDLINE and EMBASE for studies with BCAA supplementation with the presence of a disease-control group (placebo or no intervention) using search terms 'liver cirrhosis', 'hepatocellular carcinoma', 'branched chain amino acids' and relevant synonyms. Risk of bias was assessed using ROBINS-I and RoB 2.0 tools. Meta-analyses were performed with a random-effects model. Results were reported following EQUATOR guidelines. RESULTS Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case-control studies, 13 retrospective case-control studies: in total 2308 patients BCAA supplementation, 2876 disease-controls). Risk of bias was high/serious for almost all studies. According to meta-analyses, long-term (at least 6 months) BCAA supplementation in cirrhotic patients significantly improved event-free survival (p = .008; RR .61 95% CI .42-.88) and tended to improve overall survival (p = .05; RR .58 95% CI .34-1.00). Two retrospective studies suggested the beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA. CONCLUSIONS Prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients.
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The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease.
Di Ciaula, A, Bonfrate, L, Khalil, M, Portincasa, P
Internal and emergency medicine. 2023;(8):2181-2197
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Abstract
Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.
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Prevention of Oxidative Stress and Diseases by Antioxidant Supplementation.
Martemucci, G, Portincasa, P, Centonze, V, Mariano, M, Khalil, M, D'Alessandro, AG
Medicinal chemistry (Shariqah (United Arab Emirates)). 2023;(6):509-537
Abstract
Excessive and uncontrolled oxidative stress can damage biomacromolecules, such as lipids, proteins, carbohydrates, and DNA, by free radical and oxidant overproduction. In this review, we critically discuss the main properties of free radicals, their implications in oxidative stress, and specific pathological conditions. In clinical medicine, oxidative stress can play a role in several chronic noncommunicable diseases, such as diabetes mellitus, cardiovascular, inflammatory, neurodegenerative diseases, and tumours. Antioxidant supplements can theoretically prevent or stop the progression of diseases, but a careful literature analysis finds that more evidence is needed to dissect the ultimate beneficial effect of antioxidants versus reactive oxygen species in several diseases.
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Efficacy of canakinumab in patients with Still's disease across different lines of biologic therapy: real-life data from the International AIDA Network Registry for Still's Disease.
Vitale, A, Caggiano, V, Sfikakis, PP, Dagna, L, Lopalco, G, Ragab, G, La Torre, F, Almaghlouth, IA, Maggio, MC, Sota, J, et al
Frontiers in medicine. 2023;:1256243
Abstract
INTRODUCTION The effectiveness of canakinumab may change according to the different times it is used after Still's disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment. METHODS Patients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still's disease. Seventy-seven (51 females and 26 males) patients with Still's disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent. RESULTS No statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response (p =0.62), partial response (p =0.61), treatment failure (p >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy (p =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use (p =0.34), daily glucocorticoid dosage (p =0.47), or concomitant methotrexate dosage (p =0.43) at the last assessment during CAN treatment. CONCLUSION Canakinumab has proved to be effective in patients with Still's disease, regardless of its line of biologic treatment.
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Time to Consider the "Exposome Hypothesis" in the Development of the Obesity Pandemic.
Catalán, V, Avilés-Olmos, I, Rodríguez, A, Becerril, S, Fernández-Formoso, JA, Kiortsis, D, Portincasa, P, Gómez-Ambrosi, J, Frühbeck, G
Nutrients. 2022;(8)
Abstract
The obesity epidemic shows no signs of abatement. Genetics and overnutrition together with a dramatic decline in physical activity are the alleged main causes for this pandemic. While they undoubtedly represent the main contributors to the obesity problem, they are not able to fully explain all cases and current trends. In this context, a body of knowledge related to exposure to as yet underappreciated obesogenic factors, which can be referred to as the "exposome", merits detailed analysis. Contrarily to the genome, the "exposome" is subject to a great dynamism and variability, which unfolds throughout the individual's lifetime. The development of precise ways of capturing the full exposure spectrum of a person is extraordinarily demanding. Data derived from epidemiological studies linking excess weight with elevated ambient temperatures, in utero, and intergenerational effects as well as epigenetics, microorganisms, microbiota, sleep curtailment, and endocrine disruptors, among others, suggests the possibility that they may work alone or synergistically as several alternative putative contributors to this global epidemic. This narrative review reports the available evidence on as yet underappreciated drivers of the obesity epidemic. Broadly based interventions are needed to better identify these drivers at the same time as stimulating reflection on the potential relevance of the "exposome" in the development and perpetuation of the obesity epidemic.