Postbiotics as Metabolites and Their Biotherapeutic Potential.

This review highlights the role of postbiotics, which may provide an underappreciated avenue doe promising therapeutic alternatives. The discovery of natural compounds obtained from microorganisms needs to be investigated in the future in terms of their effects on various metabolic disorders and molecular pathways, as well as modulation of the immune system and intestinal microbiota in children and adults. However, further studies and efforts are needed to evaluate and describe new postbiotics. This review provides available knowledge that may assist future research in identifying new postbiotics and uncovering additional mechanisms to combat metabolic diseases.

International Roadshow: New Advances in Endocrinology and Metabolic Diseases.

Dear Readers,Currently, there is a myriad of new developments in the field of endocrinology. In particular, significant strides have been made in the development of poly-agonists for the treatment of type 2 diabetes and obesity 1 2. Poly-agonists represent a novel therapeutic approach by combining multiple actions within a single molecule, targeting multiple receptors simultaneously to achieve enhanced efficacy. These innovative compounds aim to address the complex interplay of hormonal pathways involved in glucose regulation and metabolism, offering potential breakthroughs in the management of diabetes and obesity.

Orally Ingested Self-Powered Stimulators for Targeted Gut-Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

Bariatrics and endoscopic therapies for the treatment of metabolic disease: Past, present, and future.

The burden of chronic metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD) and the urgency of the epidemiological situation necessitate the development of therapies that enhance metabolic health and alter the trajectory of metabolic disease in society. Certain bariatric-metabolic surgeries have proven to be effective approaches for treating metabolic dysfunction, showing remission or significant improvements in obesity, T2DM, and MASLD-related outcomes, suggesting that these interventions might be able to "reset" a pathologically calibrated metabolic setpoint. However, considering the challenges and invasiveness of surgery, endoscopic bariatric metabolic therapies (EBMTs) have emerged with a primary focus to reconstruct or mimic anatomical and/or functional changes observed with bariatric surgery in a more broadly accessible manner. These innovative approaches offer a potentially promising solution to address significant unmet medical need in the large segment of society, which remains at risk for the consequences of metabolic diseases. In this review, we discuss therapeutic options within the EBMT space in the context of the metabolic setpoint intellectual model and provide a brief overview of current knowledge surrounding their mechanisms of action and impact on metabolic health. Finally, we explore future perspectives and directions in this exciting field.

New and emerging treatments for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading etiology of chronic liver disease worldwide, with increasing incidence and prevalence in the setting of the obesity epidemic. MASH is also a leading indication for liver transplantation, given its associated risk of progression to end-stage liver disease. A key challenge in managing MASH is the lack of approved pharmacotherapy. In its absence, lifestyle interventions with a focus on healthy nutrition and regular physical activity have been the cornerstone of therapy. Real-world efficacy and sustainability of lifestyle interventions are low, however. Pharmacotherapy development for MASH is emerging with promising data from several agents with different mechanisms of action (MOAs) in phase 3 clinical trials. In this review, we highlight ongoing challenges and potential solutions in drug development for MASH and provide an overview of available data from emerging therapies across multiple MOAs.

Adipose tissue-derived stem cells, in vivo and in vitro models for metabolic diseases.

The primary role of adipose tissue stem cells (ADSCs) is to support the function and homeostasis of adipose tissue in physiological and pathophysiological conditions. However, when ADSCs become dysfunctional in diseases such as obesity and cancer, they become impaired, undergo signalling changes, and their epigenome is altered, which can have a dramatic effect on human health. In more recent years, the therapeutic potential of ADSCs in regenerative medicine, wound healing, and for treating conditions such as cancer and metabolic diseases has been extensively investigated with very promising results. ADSCs have also been used to generate two-dimensional (2D) and three-dimensional (3D) cellular and in vivo models to study adipose tissue biology and function as well as intracellular communication. Characterising the biology and function of ADSCs, how it is altered in health and disease, and its therapeutic potential and uses in cellular models is key for designing intervention strategies for complex metabolic diseases and cancer.

Immune metabolic mechanisms of acupuncture in improving glycolipid metabolic disorders explored through pancreatic adipose tissue. / ä»Žèƒ°è ºè„‚è‚ªç»„ç»‡æŽ¢è®¨é’ˆåˆºæ”¹å–„ç³–è„‚ä»£è°¢ç— çš„å ç–«ä»£è°¢æœºåˆ¶.

Pancreatic adipose tissue serves as a crucial structural basis for the development of glycolipid metabolic disorders. Understanding the mechanisms underlying pancreatic adipose tissue infiltration and regulatory strategies is essential for early intervention in glycolipid metabolic disorders. Pancreatic adipose tissue functions as a significant medium linking systemic immune metabolism, while the pancreatic vascular system emerges as a novel target for sensing pancreatic immune responses and maintaining the body's energy homeostasis, collectively participating in the development of glycolipid metabolic disorders. Acupuncture possesses potential effects in modulating the interaction between resident macrophages and adipocytes in the pancreas, leading to the reversible reduction of excessive pancreatic adipose accumulation, with its action being vascular-dependent.

Management of long-term complications from immunosuppression.

This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well.

Gut-Brain Axis Modulation of Metabolic Disorders: Exploring the Intertwined Neurohumoral Pathways and Therapeutic Prospects.

A significant rise in metabolic disorders, frequently brought on by lifestyle choices, is alarming. A wide range of preliminary studies indicates the significance of the gut-brain axis, which regulates bidirectional signaling between the gastrointestinal tract and the cognitive system, and is crucial for regulating host metabolism and cognition. Intimate connections between the brain and the gastrointestinal tract provide a network of neurohumoral transmission that can transmit in both directions. The gut-brain axis successfully establishes that the wellness of the brain is always correlated with the extent to which the gut operates. Research on the gut-brain axis has historically concentrated on how psychological health affects how well the gastrointestinal system works. The latest studies, however, revealed that the gut microbiota interacts with the brain via the gut-brain axis to control phenotypic changes in the brain and in behavior. This study addresses the significance of the gut microbiota, the role of the gut-brain axis in management of various metabolic disorders, the hormonal and neural signaling pathways and the therapeutic treatments available. Its objective is to establish the significance of the gut-brain axis in metabolic disorders accurately and examine the link between the two while evaluating the therapeutic strategies to be incorporated in the future.

Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases.

Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPRmt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPRmt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.

Ketogenic nutritional therapy (KeNuT)-a multi-step dietary model with meal replacements for the management of obesity and its related metabolic disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-diet therapies in endocrinology and metabolism.

PURPOSE: The ketogenic nutritional therapy (KeNuT) is an effective dietary treatment for patients with obesity and obesity-related comorbidities, including type 2 diabetes, dyslipidaemia, hypertension, coronary artery disease, and some type of cancers. However, to date an official document on the correct prescription of the ketogenic diet, validated by authoritative societies in nutrition or endocrine sciences, is missing. It is important to emphasize that the ketogenic nutritional therapy requires proper medical supervision for patient selection, due to the complex biochemical implications of ketosis and the need for a strict therapeutic compliance, and an experienced nutritionist for proper personalization of the whole nutritional protocol. METHODS: This practical guide provides an update of main clinical indications and contraindications of ketogenic nutritional therapy with meal replacements and its mechanisms of action. In addition, the various phases of the protocol involving meal replacements, its monitoring, clinical management and potential side effects, are also discussed. CONCLUSION: This practical guide will help the healthcare provider to acquire the necessary skills to provide a comprehensive care of patients with overweight, obesity and obesity-related diseases, using a multistep ketogenic dietary treatment, recognized by the Club of the Italian Society of Endocrinology (SIE)-Diet Therapies in Endocrinology and Metabolism.

Liver-directed gene therapy for inherited metabolic diseases.

Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver-directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver-targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler-Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow-up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver-targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.

Human gut microbiome: Therapeutic opportunities for metabolic syndrome-Hype or hope?

Shifts in gut microbiome composition and metabolic disorders are associated with one another. Clinical studies and experimental data suggest a causal relationship, making the gut microbiome an attractive therapeutic goal. Diet, intake of probiotics or prebiotics and faecal microbiome transplantation (FMT) are methods to alter a person's microbiome composition. Although FMT may allow establishing a proof of concept to use microbiome modulation to treat metabolic disorders, studies show mixed results regarding the effects on metabolic parameters as well as on the composition of the microbiome. This review summarizes the current knowledge on diet, probiotics, prebiotics and FMT to treat metabolic diseases, focusing on studies that also report alterations in microbiome composition. Furthermore, clinical trial results on the effects of common drugs used to treat metabolic diseases are synopsized to highlight the bidirectional relationship between the microbiome and metabolic diseases. In conclusion, there is clear evidence that microbiome modulation has the potential to influence metabolic diseases; however, it is not possible to distinguish which intervention is the most successful. In addition, a clear commitment from all stakeholders is necessary to move forward in the direction of developing targeted interventions for microbiome modulation.

Liver directed adeno-associated viral vectors to treat metabolic disease.

The liver is the metabolic center of the body and an ideal target for gene therapy of inherited metabolic disorders (IMDs). Adeno-associated viral (AAV) vectors can deliver transgenes to the liver with high efficiency and specificity and a favorable safety profile. Recombinant AAV vectors contain only the transgene cassette, and their payload is converted to non-integrating circular double-stranded DNA episomes, which can provide stable expression from months to years. Insights from cellular studies and preclinical animal models have provided valuable information about AAV capsid serotypes with a high liver tropism. These vectors have been applied successfully in the clinic, particularly in trials for hemophilia, resulting in the first approved liver-directed gene therapy. Lessons from ongoing clinical trials have identified key factors affecting efficacy and safety that were not readily apparent in animal models. Circumventing pre-existing neutralizing antibodies to the AAV capsid, and mitigating adaptive immune responses to transduced cells are critical to achieving therapeutic benefit. Combining the high efficiency of AAV delivery with genome editing is a promising path to achieve more precise control of gene expression. The primary safety concern for liver gene therapy with AAV continues to be the small risk of tumorigenesis from rare vector integrations. Hepatotoxicity is a key consideration in the safety of neuromuscular gene therapies which are applied at substantially higher doses. The current knowledge base and toolkit for AAV is well developed, and poised to correct some of the most severe IMDs with liver-directed gene therapy.

The application of organoid models in research into metabolic diseases.

Metabolic diseases have become a major threat to human health worldwide as a result of changing lifestyles. The exploration of the underlying molecular mechanisms of metabolic diseases and the development of improved therapeutic methods have been hindered by the lack of appropriate human experimental models. Organoids are three-dimensional in vitro models of self-renewing cells that spontaneously self-organize into structures similar to the corresponding in vivo tissues, recapitulating the original tissue function. Off-body organoid technology has been successfully applied to disease modelling, developmental biology, regenerative medicine, and tumour precision medicine. This new generation of biological models has received widespread attention. This article focuses on the construction process and research progress with regard to organoids related to metabolic diseases in recent years, and looks forward to their prospective applications.

Unveiling the future of metabolic medicine: omics technologies driving personalized solutions for precision treatment of metabolic disorders.

Metabolic disorders are increasingly prevalent worldwide, leading to high rates of morbidity and mortality. The variety of metabolic illnesses can be addressed through personalized medicine. The goal of personalized medicine is to give doctors the ability to anticipate the best course of treatment for patients with metabolic problems. By analyzing a patient's metabolomic, proteomic, genetic profile, and clinical data, physicians can identify relevant diagnostic, and predictive biomarkers and develop treatment plans and therapy for acute and chronic metabolic diseases. To achieve this goal, real-time modeling of clinical data and multiple omics is essential to pinpoint underlying biological mechanisms, risk factors, and possibly useful data to promote early diagnosis and prevention of complex diseases. Incorporating cutting-edge technologies like artificial intelligence and machine learning is crucial for consolidating diverse forms of data, examining multiple variables, establishing databases of clinical indicators to aid decision-making, and formulating ethical protocols to address concerns. This review article aims to explore the potential of personalized medicine utilizing omics approaches for the treatment of metabolic disorders. It focuses on the recent advancements in genomics, epigenomics, proteomics, metabolomics, and nutrigenomics, emphasizing their role in revolutionizing personalized medicine.