Total serum FGF-21 levels positively relate to visceral adiposity differently from its functional intact form

ObjectiveIncreased Fibroblast Growth Factor-21 (FGF-21) circulating levels have been described in obesity. In this observational study, we analysed a group of subjects with metabolic disorders to unravel the putative link between visceral adiposity and FGF-21 serum levels.MethodsTotal and intact serum FGF-21 concentration was measured with an ELISA assay respectively in 51 and 46 subjects, comparing FGF-21 levels in dysmetabolic conditions. We also tested Spearman’s correlations between FGF-21 serum levels and biochemical and clinical metabolic parameters.ResultsFGF-21 was not significantly increased in high-risk conditions such as visceral obesity, Metabolic Syndrome, diabetes, smoking, and atherosclerosis. Waist Circumference (WC), but not BMI, positively correlated with total FGF-21 levels (r=0.31, p <0.05), while HDL-cholesterol (r=-0.29, p <0.05) and 25-OH Vitamin D (r=-0.32, p <0.05) showed a significant negative correlation with total FGF-21. ROC analysis of FGF-21 in prediction of increased WC, showed that patients with total FGF-21 level over cut-off value of 161.47 pg/mL presented with impaired FPG. Conversely, serum levels of the intact form of FGF-21 did not correlate with WC and other metabolic biomarkers.ConclusionOur newly calculated cut-off for total FGF-21 according to visceral adiposity identified subjects with fasting hyperglycemia. However, waist circumference correlates with total FGF-21 serum levels but does not correlate with intact FGF-21, suggesting that functional FGF-21 does not necessarily relate with obesity and metabolic features

Bile Salt Hydrolase-Competent Probiotics in the Management of IBD: Unlocking the “Bile Acid Code”

Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient

DARK AND BRIGHT SIDE OF TARGETING THE FIBROBLAST GROWTH FACTOR RECEPTOR 4 IN THE LIVER

The Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19 are implicated in an ample range of cellular processes, including differentiation, metabolism and proliferation. Their aberrant activation has been associated to the development of hepatic tumours, acting as an oncogenic pathway. Despite the great advances in early diagnosis, and the development of new therapies, liver cancer still presents with a high mortality due to two main culprits: high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are ongoing for the treatment of patients with advanced hepatocellular carcinoma (HCC). Conversely, FGFR4-KLOTHO β activation via the use of newly generated FGF19 analogues represent a novel therapeutic strategy in patients presenting with cholestatic liver disorders and NASH and, therefore, could prevent the development of metabolic HCC. Here, we provide an updated overview of the currently available therapeutic options targeting FGFR4 in HCC and other liver diseases, highlighting the need of carefully stratifying patients' groups and personalising therapeutic strategies

Bile acids and colon cancer: Is FXR the solution of the conundrum?

Diet and lifestyle habits have a profound impact on the pathophysiology of many diseases. Colorectal cancer (CRC) is the third most common cancer worldwide and its etiology is strongly influenced by nutrition and high fat/high carbohydrate Western-style diet. Human epidemiological and animal studies have shown that colonic cancer risk is also related to faecal bile acid concentration. Abnormally high levels of bile acids (BA) trigger the colonic mucosa with a plethora of detrimental effects such as DNA oxidative damage, inflammation and hyperproliferation that highly promote CRC progression in post-initiation phase. The Farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally mediates the signalling activity of BAs. FXR regulates BA metabolism mainly maintaining BA concentrations within a physiological range, thereby preventing BA-induced cytotoxicity. In fact, loss of FXR is associated with higher BA concentrations and with a pro-tumorigenic phenotype. Here we explore the liaison connecting nutrition, intestinal epithelium renewal, BA and their nuclear receptor FXR in CRC. Moreover, we summarize evidence linking BA and CRC, as well as examine current understanding of the protumoral actions of BA and the bona fide antitumoral properties of FXR

Gut microbiota in the pathogenesis and therapeutic approaches of diabetes

The gut-liver axis plays a prominent role in the pathogenesis and therapy of metabolic diseases such as diabetes. The intestinal specific origin of several hormones that guide both inter-and post-prandial metabolism of carbohydrates and lipids, drives the attention of scientists and clinicians on the gut as a major site to intervene with novel diagnostic or prognostic markers. The role of intestinal ecology in the metabolic syndrome was postulated when gut microbiota was directly connected with inflammation, hyperinsulinemia, and diabetes. There have been several discoveries with the role of gut microbiota and gut-liver axis in diabetes. Also, there are several trials ongoing on the therapeutic efficacy of probiotic administration in diabetes and its complications. Here we point to the metabolic action of microbiota and discuss the actual state of the art on gut microbiota as a novel prognostic biomarker with a putative therapeutic role in diabetes. Copyright (c) 2023 The Author(s). Published by Elsevier B.V

Bile Salt Hydrolase-Competent Probiotics in the Management of IBD: Unlocking the “Bile Acid Code”

Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient

The central role of the gut in intensive care

Critically ill patients undergo early impairment of their gut microbiota (GM) due to routine antibiotic therapies and other environmental factors leading to intestinal dysbiosis. The GM establishes connections with the rest of the human body along several axes representing critical inter-organ crosstalks that, once disrupted, play a major role in the pathophysiology of numerous diseases and their complications. Key players in this communication are GM metabolites such as short-chain fatty acids and bile acids, neurotransmitters, hormones, interleukins, and toxins. Intensivists juggle at the crossroad of multiple connections between the intestine and the rest of the body. Harnessing the GM in ICU could improve the management of several challenges, such as infections, traumatic brain injury, heart failure, kidney injury, and liver dysfunction. The study of molecular pathways affected by the GM in different clinical conditions is still at an early stage, and evidence in critically ill patients is lacking. This review aims to describe dysbiosis in critical illness and provide intensivists with a perspective on the potential as adjuvant strategies (e.g., nutrition, probiotics, prebiotics and synbiotics supplementation, adsorbent charcoal, beta-lactamase, and fecal microbiota transplantation) to modulate the GM in ICU patients and attempt to restore eubiosis

The Liver-Gut axis in colorectal cancer development: a single center 8 years prospective study in 1145 metabolic subjects

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Intestinal FXR Activation via Transgenic Chimera or Chemical Agonism Prevents Colitis-Associated and Genetically-Induced Colon Cancer

The Farnesoid X Receptor (FXR) is the master regulator of Bile Acids (BA) homeostasis orchestrating their synthesis, transport and metabolism. Disruption of BA regulation has been linked to gut-liver axis diseases such as colorectal cancer (CRC). In this study, firstly we examined the role of constitutive activation of intestinal FXR in CRC; then we pre-clinically investigated the therapeutic potential of a diet enriched with a synthetic FXR agonist in two models of CRC (chemically-induced and genetic models). We demonstrated that mice with intestinal constitutive FXR activation are protected from AOM/DSS-induced CRC with a significant reduction of tumor number compared to controls. Furthermore, we evaluated the role of chemical FXR agonism in a DSS model of colitis in wild type (WT) and FXRnull mice. WT mice administered with the FXR activating diet showed less morphological alterations and decreased inflammatory infiltrates compared to controls. The FXR activating diet also protected WT mice from AOM/DSS-induced CRC by reducing tumors’ number and size. Finally, we proved that the FXR activating diet prevented spontaneous CRC in APCMin/+ mice via an FXR-dependent modulation of BA homeostasis. Our results demonstrate that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis

Low Adherence to Mediterranean Diet Characterizes Metabolic Patients with Gastrointestinal Cancer

Background. Gastrointestinal (GI) cancers are one of the most relevant causes of death globally, frequently associated with poor dietary patterns. The Mediterranean Diet (MedDiet) contributes to cancer prevention. To assess adherence to MedDiet, our research group validated a new score, the Chrono Med Diet Score (CMDS), that captures increased visceral adiposity. Methods. We enrolled 401 subjects who underwent an evaluation for metabolic diseases, specific screening procedures according to current guidelines, and were asked to answer to CMDS. A total of 71 new cancer cases were recorded, including 40 GI and 31 non-gastrointestinal (NON-GI) cancers. Re-sults. We found that CMDS was reduced in subjects who were diagnosed with cancers. Patients who reported a CMDS score of 12 or less had an over three times increased risk to be diagnosed GI cancers and presented increased waist circumference and triglycerides and reduced HDL-cholesterol, if compared to adherent subjects. Conclusion. Low CMDS values capture the risk for cancer diagnosis, especially for GI cancers. Thus, CMDS, along with Waist Circumference, can be considered as a bona fide marker for increased risk of cancer, requiring anticipated screening procedures for detection of premalignant and early-stage GI cancers in patients with low adher-ence to MedDiet