The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GR beta) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR(iKO)) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker

Lactulose hydrogen breath test and functional symptoms in pediatric patients

Background The role of small intestinal bacterial overgrowth (SIBO) in functional digestive disorders in the pediatric population is a matter of controversy, since methods currently used to establish this diagnosis are difficult to interpret. The aim of this work was to analyze the characteristics of the lactulose H 2 breath test (LHBT) in children with functional gastrointestinal symptoms according to more recent criteria. Methods Seventy-two patients and 17 controls were enrolled. A questionnaire was administered regarding digestive symptoms (abdominal pain, bloating, vomiting, and bowel-movement disorders). A lactose hydrogen breath test was performed to rule out lactose malabsorption and a LHBT was used to measure the time elapsed between lactulose oral ingestion and an increment of H 2 concentration of 20 ppm over basal. Results There were no differences of age and gender between patients and controls. Mean time to 20-ppm change was shorter in patients (56.3 ± 3 min) compared to

Actualización en sobrecrecimiento bacteriano intestinal y dificultades en su diagnóstico

This is a short review related with the current concepts and controversies in the diagnosis of intestinal bacterial overgrowth. This is a relatively complex entity present in diverse pathologies. Its adequate diagnosis has impact in the therapy and management of the patients with this condition

Rol del metabolismo de ácidos biliares en la sintomatología del síndrome de intestino irritable

Irritable Bowel Syndrome (IBS) is a multifactorial disease characterized by nonspecific symptoms such as abdominal pain and altered colonic transit, which may be present in other diseases such as inflammatory bowel disease and colorectal cancer, so that a differential diagnostic seems difficult. Although its origin is unknown, it is believed that psychological factors, genetic and physiological influence it. Among the hypotheses with greater force, is the exposure of the colon to bile acids by failure of regulatory mechanisms, mainly correlating with variant diarrheal IBS (IBS-D). This paper details the existing research to date attempting to find correlation between genetic variants of factors involved in the regulatory pathway of bile acids and IBS-D, particularly the study of single nucleotide polymorphisms in the gene Klotho beta

Activación de mastocitos en el intestino, una de las causas orgánicas en el síndrome de intestino irritable

Irritable bowel syndrome (IBS) is one of the most common digestive health conditions in Chile as in the Western society, which is characterized by abdominal discomfort associated with alterations in bowel habit, that lead to increased visceral hypersensitivity. It has a significant impact on our country’s social welfare and economic development, due to great deterioration in the patient’s quality of life. Although the pathophysiology of IBS is unclear, the gut-brain axis disequilibrium is involved in the disease onset. Psychosocial factors, such as stress and depression, have been linked to altered immune responses as enhanced intestinal mast cell activation, in proximity to colonic nerves, correlate with abdominal pain in IBS. This review is a brief summary of the role of increased mast cell activity in IBS, focusing specifically on influences over epithelial and neural function at the intestinal mucosa. The most promising preliminary therapeutics approaches, directed to reduce mast cell activation, are also included in this review

The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function