Fibroblast Growth Factor 19 Concentrations Research Articles

Enteral Agonism of the Farnesoid X Receptor-Fibroblast Growth Factor 19 Axis Prevents Cholestasis in TPN-Fed Piglets

Total parenteral nutrition (TPN) administration provides necessary nutrients to infants who cannot tolerate enteral feedings. However, the use of TPN can result in cholestasis which can cause parenteral nutrition-associated liver diseases. Previous mitigation strategies for cholestasis have included administering bile acids enterally to encourage normal bile acid metabolism. The objective of this study was to determine if treatment of either ursodeoxycholic acid (UDCA), Tropifexor (TPX), or fibroblast growth factor 19 (FGF19) will prevent cholestasis in a piglet TPN model through the activation of the farnesoid X receptor (FXR)-FGF19 axis. We hypothesize that UDCA will have minimum effects on FXR while TPX, a potent FXR agonist, will significantly affect the FXR pathway, and FGF19 will reduce bile acid synthesis to alleviate cholestasis. Piglets received TPN for 3 weeks and were treated enterally with either UDCA (25 mg/kg*day) or TPX (7.5 μg/kg*day) with minimal milk-based formula (12 mL/kg*day), or daily intravenous FGF19 (0.25 mg/d) injection. Body weight gain was not different after 3 weeks. Plasma markers of cholestasis such as of total bile acids, bilirubin, and gamma-glutamyl transferase were lower in pigs that received TPX compared to the control treatment at the end of the study. Circulating levels of FGF19 and tissue concentrations of total bile acids were not different across treatments. In the ileum, TPX increased mRNA expression of FGF19, ileal lipid binding protein, and organic solute transporter α compared to the control pigs. All treatments reduced the mRNA expression of apical sodium-dependent bile acid transporter compared to the control treatment. TPX also increased mRNA expression of small heterodimer protein and bile salt export pump in the liver. Overall, we conclude that UDCA and FGF19 had minimal effects on cholestasis, whereas TPX prevented cholestasis in part via activation of the FXR-FGF19 axis in TPN fed piglets. NIDDK R01-DK094616 K01 DK129408 T32 NIH grant DK07664. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Serum fibroblast growth factor 19 level correlates inversely with clinical and endoscopic activity of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic condition with relapsing-remitting course. Diarrhea and abdominal pain are the most common IBD symptoms. Fibroblast growth factor 19 (FGF19) is an endocrine factor that inhibits hepatic bile acid production and may be used as a diagnostic marker for bile acid malabsorption. To assess serum FGF19 levels in active and inactive phases of IBD and find a potential correlation between FGF19 and disease activity. Fasting serum FGF19 levels were measured in 105 IBD patients (47 UC patients, 41 CD patients without previous ileocecal resection (NR-CD), 17 CD patients after ileocecal resection (IR-CD), and 17 control subjects). The disease activity was assessed using clinical, laboratory and endoscopic criteria. Inverse correlations were found between FGF19 level and intensity of diarrhea (in UC), abdominal pain intensity (in UC and IR-CD) and inflammatory markers (in UC and IR-CD). Moreover, FGF19 concentration was inversely correlated with clinical and endoscopic activity indices in UC and CD. Fluctuations in FGF19 level related to clinical and endoscopic activity of UC and CD revealed a clear pattern of higher values in remission than in active disease phases. Fibroblast growth factor 19 may serve as a potential diagnostic biomarker and constitute a new therapeutic target in IBD.

Liraglutide changes postprandial responses of gut hormones involved in the regulation of gallbladder motility.

Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment. In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4kg/m2 (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6mg to 3.0mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2. Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)0-240 min 24.8 vs. 48.0min× ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC0-240 min 33.7 vs. 48.5ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC0-240 min 3650 vs. 4894 min× pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC0-240 min 3760 vs. 4882 min× pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC0-240 min 762 vs. 670 min× pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC0-240 min 873 vs. 628 min× pmol/L; TR 1.39 (1.12; 1.73)]. Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.

FGF19 Is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits Lung Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic possibilities. FGF19 (fibroblast growth factor 19), an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had antifibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis, we assessed, by ELISA, FGF19 concentrations in plasma and BAL fluids obtained from control subjects and patients with IPF. In vivo, using an intravenously administered adeno11-associated virus, we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers, and profibrotic mediator expression at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGF-β-induced differentiation of primary human lung fibroblasts into myofibroblasts and the apoptosis of murine alveolar type II cells. Although FGF19 was not detected in BAL fluid, FGF19 concentration was decreased in the plasma of patients with IPF compared with control subjects. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of profibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-β-induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether, these data identify FGF19 as an antifibrotic molecule with potential therapeutic interest in fibrotic lung disorders.

Fibroblast Growth Factor 19 in Gestational Diabetes Mellitus and Fetal Growth

Fibroblast growth factor 19 (FGF19) has been implicated in glucose homeostasis. Gestational diabetes mellitus (GDM) enhances fetal insulin secretion and fetal growth. Girls weigh less and are more insulin resistant than boys at birth. We sought to assess whether FGF19 is associated with GDM and fetal growth and explore potential sex dimorphic associations. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns of GDM versus euglycemic mothers matched by infant’s sex and gestational age at birth. Cord plasma FGF19, insulin, C-peptide, proinsulin, IGF-I and IGF-II concentrations were measured. Cord plasma FGF19 concentrations were similar in GDM versus euglycemic pregnancies (mean ± SD: 43.5 ± 28.2 versus 44.5 ± 30.2 pg/mL, P=0.38). FGF19 was not correlated with IGF-I or IGF-II. FGF19 concentrations were positively correlated with birth weight (r=0.23, P=0.01) and length (r=0.21, P=0.02) z scores, C-peptide (r=0.27, P=0.002) and proinsulin (r=0.27, P=0.002) concentrations in females. Each SD increment in cord plasma FGF19 was associated with a 0.25 (0.07-0.43) increase in birth weight z score in females. In contrast, FGF19 was not correlated with birth weight or length in males. These sex dimorphic associations remained after adjusting for maternal and neonatal characteristics. The study is the first to demonstrate that GDM does not matter for cord blood FGF19 concentrations. The female specific positive correlation between FGF19 and birth weight is suggestive of a sex-dimorphic role of FGF19 in fetal growth. The observations call for more studies to validate the novel findings and elucidate the underlying mechanisms.

Metabolic Profiling of Type 2 Diabetes Patients after Bariatric Surgery by Raman Spectroscopy

Background: Bariatric surgery (BS) is an important procedure used for the treatment of morbid obesity and has been proven to improve, or even cure, type 2 diabetes mellitus (T2DM). However, of the patients with T2DM who initially go into remission, a proportion experience a relapse during the follow-up. In this context, Raman spectroscopy (RS) could be a promising technique for monitoring the metabolic profile of patients after surgical treatment with the aim of improving their postsurgical management. Methods: Fourteen obese patients with T2DM were recruited. Clinical parameters, adipokines, ghrelin, Fibroblast growth factor 19 (FGF-19) values, and Raman spectra were collected and analyzed before and after surgery. RS results were compared with profiles obtained from 23 healthy subjects (HC), to observe whether the metabolic fingerprint of bariatric patients normalized during the surgical follow-up. Results: The reduction in anthropometric measures and improved glycemic control and lipid profile after surgical treatment highlighted the benefits of BS. Consequently, adipokines, ghrelin and FGF-19 concentration returned to normal values after surgery. However, RS data highlighted an altered metabolic profile even after BS. Conclusion: RS suggests that BS does not fully restore the metabolic profile of patients in the immediate follow-up after the surgery.

High concentration of serum FGF19 at ICU admission is associated with 28-day mortality in sepsis patients

BackgroundSepsis remains associated with a high mortality rate despite recent advances in treatment. Traditional biomarkers are inadequate for stratification of patients by sepsis severity. We examined use of the baseline concentration of fibroblast growth factor 19 (FGF19) in predicting 28-day mortality from sepsis. MethodsA total of 220 consecutive adult patients with sepsis who were admitted to our intensive care unit (ICU) during 2020 were prospectively recruited. Patients were categorized as survivors or non-survivors according to status at 28 days. Baseline concentrations of FGF19 and other parameters were measured. Receiver operating characteristic (ROC) analysis was used to determine the sensitivity, specificity, predictive value, and optimal cutoff of FGF19 in prediction of survival. Prognostic factors were identified using Cox regression analysis. ResultsThe serum FGF19 concentration was much higher in non-survivors than in survivors (355.0 pg/ml [range: 37.2, 2315.6] vs. 127.3 pg/ml [5.7, 944.1]; P < 0.05]. ROC analysis indicated an FGF19 concentration of 180 pg/ml was the optimal cutoff value. Multivariable Cox regression analysis showed that FGF19 concentration and the change in sequential organ failure assessment (ΔSOFA) score at baseline were independently and significantly associated with 28-day mortality. ROC analysis indicated that FGF19 had a better predictive value than PCT or CRP. Although ΔSOFA had a better predictive value than FGF19, ΔSOFA and FGF19 together had a significantly better predictive value than ΔSOFA alone. ConclusionSepsis patients with high serum concentrations of FGF19 at ICU admission were associated with an increased risk of 28-day mortality in our ICU.

Quantification of serum fibroblast growth factor-19 concentration in healthy dogs before and after feeding.

To measure serum fibroblast growth factor-19 (FGF-19) concentration and gallbladder volume in healthy dogs before and after feeding to determine whether serum FGF-19 concentration increases following gallbladder contraction and to assess FGF-19 stability in blood samples kept under different storage conditions after collection in tubes containing no anticoagulant or in serum separator tubes. 10 healthy dogs of various ages and breeds (30 blood samples and 30 gallbladder volume measurements). Serum FGF-19 concentration was measured with a commercially available ELISA. Gallbladder volume was determined ultrasonographically. Blood samples and gallbladder measurements were obtained from the dogs after food had been withheld for 12 hours (baseline) and at 1 and 3 hours after feeding. The stability of serum FGF-19 was assessed in samples collected in tubes containing no anticoagulant or in serum separator tubes and stored at -80°C for variable intervals or 4°C for 1 or 5 days. Serum FGF-19 concentration was significantly increased from baseline at 1 and 3 hours after feeding. There was a significant decrease in gallbladder volume 1 hour after feeding, compared with baseline findings. Regardless of collection tube used, concentrations of FGF-19 in serum obtained from blood samples that were collected and immediately stored at -80°C differed significantly from concentrations in serum obtained from blood samples that had been collected and stored at 4°C for 5 days. Results indicated that postprandial gallbladder contraction results in increases of serum FGF-19 concentration in healthy dogs. Assessment of circulating FGF-19 concentration could be used to detect disruptions in the enterohepatic-biliary axis in dogs.

Downregulation of Serum and Distal Ileum Fibroblast Growth Factor19 in Bile Acid Diarrhoea Patients.

Bile acid diarrhoea or BAD is a common but little recognised cause of chronic diarrhoea. Few of these patients in China have been diagnosed due to a lack of diagnostic options. To clarify the diagnostic value of serum fibroblast growth factor19 (FGF19) in BAD patients. We reported on 60 chronic diarrhoea patients and 80 healthy volunteers (HV). Based on the 90th percentile levels of serum 7a-hydroxy-4-cholesten-3-one (C4) of HV, these patients were divided into BAD group (C4 ≥ 90th) and non-bile acid diarrhoea group (NBAD, C4 < 90th). Serum FGF19 in the two clinical groups and HV group were compared, as was distal ileum FGF19 in clinical groups. The diagnostic value of serum FGF19 for BAD was evaluated. The 90th percentile of serum C4 in HV group was 65.87ng/ml. Serum FGF19 concentrations in BAD group (Median 69.28pg/ml; n = 23) were significantly lower than those in HV (Median 122.18pg/ml; n = 80) and NBAD (Median 129.57pg/ml; n = 29) groups. FGF19 mRNA of the distal ileum in BAD group, was lower than that in NBAD group, P = 0.002. The rate of FGF19 protein low expression of distal ileum in BAD and NBAD group were 78.3% and 48.3%, P = 0.027. Using an ROC curve, statistical analysis yielded a threshold FGF19 concentration of 117.3pg/ml (AUC, 0.906; 91.3% sensitivity, 79.3% specificity) for a clinical diagnosis of BAD. Serum and distal ileum expression of FGF19 significantly decreased in BAD patients. The suggested clinical ranges for serum FGF19 < 117.3pg/ml has high sensitivity and specificity for BAD patients with a normal structural and histological ileum.

Decreased serum fibroblast growth factor 19 level is a risk factor for type 1 diabetes.

BackgroundIncreasing evidence suggests that fibroblast growth factor 19 (FGF19) is a regulator of glucose metabolism and may provide a new therapeutic target for type 1 diabetes (T1D). However, the clinical relevance of FGF19 in T1D remains unclear. In this study, we examined the relationship between the serum FGF19 concentration and T1D.MethodsThis study included 81 newly diagnosed T1D patients and 80 sex- and age-matched healthy controls. The correlation between the FGF19 concentration and clinical characteristics of T1D patients and healthy controls was investigated. Logistic regression analysis was performed to determine whether levels of FGF19 were independently associated with T1D.ResultsThe fasting serum FGF19 levels in the T1D group were significantly lower than those in the control group [159.9 (100.0–272.7) vs. 205.0 (126.9–307.9) pg/mL, P=0.008]. In all subjects, serum FGF19 levels were negatively correlated with fasting blood glucose (FBG) (r=−0.192, P=0.015). In the control group, serum FGF19 levels were positively correlated with total cholesterol (TC) (r=0.338, P=0.002) and low-density lipoprotein cholesterol (LDL-c) (r=0.300, P=0.007). In addition to sex and body mass index (BMI), FGF19 was an independent impact factor for T1D [odds ratio (OR) =0.541, P=0.023; adjusted for sex, age, BMI, presence of hypertension, and presence of dyslipidemia].ConclusionsLow serum FGF19 level is associated with T1D, which could serve as a risk factor for T1D.

Fibroblast Growth Factor 19 Levels Predict Subclinical Atherosclerosis in Men With Type 2 Diabetes.

Objective: Fibroblast growth factor 19 (FGF19) plays an indispensable role in regulating bile acid, glucose, and lipid metabolism, and alterations of its circulating concentration is associated with the development of type 2 diabetes (T2D). Atherosclerosis is directly related to the death-deriving diabetic macroangiopathy in T2D, yet relationships between FGF19 and atherosclerosis in T2D remain unclear. The aim of this study was to investigate the association of circulating FGF19 levels with the development of subclinical atherosclerosis (subAS) in patients with T2D in a 3-year prospective study.Methods: In the present study, 153 newly diagnosed T2D patients without subAS were recruited at baseline, and 137 of them completed a 3-year follow-up. FGF19 levels were measured in fasting serum samples collected at baseline and the third-year visits. Carotid, femoral, and iliac intima-media thickness (IMT) were detected by high-resolution B-mode ultrasound to determine the presence of subAS. Logistic regression analysis was applied to assess the relationship between serum FGF19 and subAS in patients with T2D.Results: At baseline, serum FGF19 levels were positively correlated with carotid IMT and iliac IMT in men (r = 0.239, P = 0.036; r = 0.309, P = 0.006). At the 3-year follow-up, 25 out of 153 patients developed subAS, and FGF19 levels in men were higher in the subAS group than in the non-subAS group [202.7 (177.9–373.6) vs. 133.4 (85.6–171.3) pg/ml, P = 0.028]. Furthermore, in men, higher baseline levels of FGF19 were independently associated with a greater risk of subAS at year 3 in patients with T2D with an odds ratio (OR) of 4.798 per 1 standard deviation (SD) of the FGF19 concentration [OR = 4.798 (95% CI, 1.680–13.706), P = 0.003]. Baseline FGF19 levels yielded an area under the receiver operating characteristic curve of 0.769 to predict the development of subAS at year 3 in men with T2D.Conclusions: Serum FGF19 levels could help in predicting the development of atherosclerosis in men with T2D.

Rapid Postnatal Upregulation of Intestinal Farnesoid X Receptor-Fibroblast Growth Factor 19 Signaling in Premature Pigs.

Bile acid (BA) homeostasis is regulated by intestinal cellular signaling involving the farnesoid X receptor (FXR) and fibroblast growth factor 19 (FGF19) secretion. Using preterm and term pigs as a model, we examined postnatal changes in expression of the FXR-FGF19 axis that is poorly characterized in human infants. Pigs delivered by caesarean section at 10-day preterm and near full term (115-day gestation) were fitted with orogastric and umbilical arterial catheters. Pigs were fed combined parenteral nutrition and minimal enteral nutrition for 5 days, followed by milk formula until 26 d days. Plasma and tissue samples were collected at days 0, 5, 11, and 26. Plasma FGF19 concentration and liver and distal intestinal gene expression of FGF19 and other FXR target genes were quantified. Plasma FGF19 levels were lower in preterm versus term newborn pigs (P < 0.05), increased markedly by 5 days, especially in preterm pigs, and decreased in both groups until day 26. Likewise, intestinal FXR and FGF19 expression was lower (P ≤ 0.05) in premature versus term newborn pigs and decreased (P ≤ 0.05) between days 5 and 26. Hepatic expression of cholesterol 7α-hydroxylase (CYP7A1) was inversely correlated with plasma FGF19 in both groups. We conclude that the activity of FXR-FGF19 axis is lower in preterm than in term newborn pigs but increases transiently and then declines by the first month of age. We also provide supportive evidence of negative feedback between plasma FGF19 and hepatic CYP7A1 expression.

The effect of acute intragastric vs. intravenous alcohol administration on inflammation markers, blood lipids and gallbladder motility in healthy men.

Ethanol intake increases plasma concentrations of triglycerides and chronic ethanol use impairs lipid metabolism and causes chronic inflammation. The gut plays an important role in metabolic handling of nutrients, including lipids, and a leaky gut associated with alcohol intake, allowing inflammatory signals to the portal vein, has been proposed to constitute a mechanism by which ethanol induces hepatic inflammation. We compared the effects of enteral and parenteral administration of ethanol on a range of circulating inflammation markers (including soluble CD163, a marker of liver macrophage activation), lipids, cholecystokinin (CCK) and fibroblast growth factor 19 (FGF19) as well as gallbladder volume. On two separate and randomized study days, we subjected healthy men (n=12) to double-blinded intragastric ethanol infusion (IGEI) and isoethanolemic intravenous ethanol infusion (IVEI). Blood was sampled and ultrasonographic evaluation of gallbladder volume was performed at frequent intervals for 4h after initiation of ethanol administration on both days. Little or no effects were observed on plasma levels of inflammation markers during IGEI and IVEI, respectively. Circulating levels of total, low-density lipoprotein and high-density lipoprotein cholesterol decreased after ethanol administration independently of the administration form. Triglyceride and very low-density lipoprotein (VLDL) cholesterol concentrations increased more after IGEI compared to IVEI. IVEI had no effect on plasma CCK and caused an increased gallbladder volume whereas IGEI elicited a CCK response (P<0.0001) without affecting gallbladder volume. Circulating FGF19 concentrations decreased equally in response to both ethanol administration forms. In conclusion, by evaluating a range of circulating inflammation markers during IGEI and IVEI we were not able to detect signs of systemic low-grade inflammation originating from the presence of ethanol in the gut. IVEI increased gallbladder volume whereas IGEI increased plasma CCK (with neutral effect on gallbladder volume), increased plasma VLDL cholesterol and triglyceride concentrations; indicating that the enteral route of administration may influence ethanol's effects on lipid metabolism.

ВПЛИВ ФАКТОРУ РОСТУ ФІБРОБЛАСТІВ 19 НА СТАН ВУГЛЕВОДНОГО ОБМІНУ У ХВОРИХ НА ЦУКРОВИЙ ДІАБЕТ 2 ТИПУ З СУПУТНЬОЮ БІЛІАРНОЮ ПАТОЛОГІЄЮ

&#x0D; &#x0D; &#x0D; This article analyzes the changes of fibroblast growth factor 19 (FRF-19) in serum content and presence of the connections between this marker and carbohydrate metabolism in patients with diabetes mellitus type 2 and chronic cholecystitis, as well as in patients with isolated chronic cholecystitis. 34 patients with type 2 diabetes mellitus and concomitant chronic cholecystitis and 31 patients with isolated chronic cholecystitis were examined in the gastroenterologic and endocrinological departments of «Regional Clinical Hospital» (Kharkiv, Ukraine). Determination of FRF-19 level was carried out by enzyme immunoassay. In patients with combined course of type 2 diabetes mellitus and concomitant chronic cholecystitis, there is a significant decrease in serum FRF-19 concentration, an increase in glycemia, insulinemia and insulin resistance, determined by the HOMA index, compared with patients with isolated chronic cholecystitis, in whom high concentrations of FRF-19 were accompanied by no disturbance of carbohydrate metabolism.&#x0D; &#x0D; &#x0D;

Differential effects of a 40-hour fast and bile acid supplementation on human GLP-1 and FGF19 responses.

Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In experiment 1: we tested 4-h mixed meal after an overnight fast and a 40-h fast. In experiment 2, we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In experiment 1, 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at specific time points. In experiment 2, administration of gDCA increased GLP-1 levels and lowered late postprandial glucose without effect on FGF19. Energy expenditure was not affected by gDCA administration. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19, where the former appeared bile acid independent and the latter bile acid dependent. Second, a single dose of gDCA increased postprandial GLP-1. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by bile acids.

Serum Concentrations of 7α-hydroxy-4-cholesten-3-one Are Associated With Bile Acid Diarrhea in Patients With Crohn’s Disease

Patients with Crohn's disease (CD) often have bile acid diarrhea (BAD), due to bile acid malabsorption following ileal resection (IR). Bile acid malabsorption increases production of 7α-hydroxy-4-cholesten-3-one (C4), a bile acid precursor. We investigated relationships between serum concentrations of C4 and BAD in patients with CD. We collected demographic data, serum samples, and information on the presence of diarrhea (>3 liquid bowel movements/day), as well as clinical, endoscopic, and histologic scores from 26 patients with CD and IR, 21 patients with CD without IR, and 37 patients with ulcerative colitis (UC). We compared serum concentrations of C4 and fibroblast growth factor 19 (FGF19) between groups. We performed area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cutoff C4 concentrations for the diagnosis of diarrhea attributable to bile acid malabsorption (BAD), defined as diarrhea and a serum concentration of FGF19 <60 pg/mL. Patients with UC had a median serum C4 concentration of 11.8 ng/mL, whereas patients with CD and IR with ileitis (documented endoscopically) had a median concentration of 100.0 ng/mL (P compared to UC < .0001) and patients with CD and IR without ileitis had a median concentration of 51.6 ng/mL (P compared to UC < .001). Patients with CD without IR did not have a significantly higher median concentration of C4 than patients with UC (P = .71), regardless of ileitis (P = .34). When endoscopic findings were confirmed histologically, similar results were found to analyses using endoscopic findings alone. A higher proportion of patients with active UC had diarrhea (72.0% vs 0 patients with inactive UC; P < .001), but their median concentrations of C4 did not differ significantly from that of patients with inactive UC (12.1 ng/mL vs 9.7 ng/mL; P = .3). A cutoff concentration of C4 of 48.3 ng/mL or greater identified patients with diarrhea attributable to bile acid malabsorption with 90.9% sensitivity, 84.4% specificity, and an AUROC 0.94. A significantly higher proportion of patients with concentrations of C4 above this cutoff had BAD (50.0%) than below this cutoff (1.8%) (P < .001). When we analyzed only patients with diarrhea, a C4 cutoff of 48.3 ng/mL identified those with low FGF19 concentrations (<60 pg/mL) with 91% sensitivity and 95.5% specificity (AUROC, 0.99). Above thiscutoff, 83.3% of patients had a serum concentration of FGF19 <60 pg/mL compared to 4.5%below this threshold (P < .0001). C4 concentrations correlated with the number of daily bowel movements (r = 0.41; P = .004) and correlated inversely with FGF19 concentrations (r= -0.72; P<.0001). We observed significantly increased serum concentrations of C4 in patients with CD with IR, compared to patients with UC. A cutoff concentration of C4 above 48.3 ng/mL identifies patients with diarrhea likely attributable to bile acid malabsorption (BAD) with an AUROC value of 0.94. Increased serum levels of bile acid precursors identify patients with diarrhea and a low serum concentration of FGF19, and concentrations of C4 correlate with daily liquid bowel movements and correlate inversely with FGF19 concentrations. C4 may be a biomarker to identify patients with diarrhea attributable to bile acid malabsorption.

Developmental regulation of the gut–liver (FGF19-CYP7A1) axis in neonates

Introduction: Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that regulates the expression of CYP7A1, the rate-limiting enzyme in bile acid (BA) synthesis pathway. Dysregulation of the FGF19-CYP7A1 (gut-liver) axis is associated with cholestatic liver disease. Infants, especially preterm infants and those with intestinal failure are at high risk for developing cholestatic liver disease. The activity of the gut–liver axis has not been characterized in this population. Our objective was to assess relationships between circulating FGF19 concentrations and CYP7A1 activity in neonates.Materials and methods: Plasma samples were obtained longitudinally from term and preterm infants (22–41-week gestation) hospitalized in a neonatal intensive care unit. Infants with congenital and acquired gastrointestinal disorders were excluded. Plasma levels of 7α-hydroxy-4-cholesten-3-one (C4), a marker of CYP7A1 activity, were quantified using HPLC-MS/MS. Plasma FGF19 concentrations were quantified by ELISA. Data were analyzed using linear regression models and structural equation modeling.Results: One hundred eighty-one plasma samples were analyzed from 62 infants. C4 concentrations were undetectable prior to 30 weeks’ gestation and, thereafter, increased with advancing gestational age and with volume of enteral feeds. They did not correlate with serum FGF19 concentrations, which decreased with advancing gestational age and volume of enteral feeds.Discussion: The activity of CYP7A1, the rate-limiting BA synthetic enzyme in adults, is developmentally regulated and undetectable in newborns less than 30 weeks’ gestation. FGF19 concentrations do not correlate with CYP7A1 activity, suggesting that the gut–liver axis is not functional in infants. High FGF19 concentrations at birth in infants less than 37 weeks’ gestation is a novel finding, and its source and role in preterm infants warrants further investigation.Rationale: The intestinal hormone, fibroblast growth factor 19 (FGF19), is a major regulator of CYP7A1, the rate limiting enzyme in bile acid (BA) synthesis. Recently, dysregulation of the gut–liver (FGF19-CYP7A1) axis has been implicated in adult cholestatic liver disease, and animal studies have shown that exogenous FGF19 protects against liver injury. Given the therapeutic potential related to this signaling pathway, we sought to characterize the association between CYP7A1 and FGF19 in term and preterm infants. We conducted a prospective, observational study that measured in vivo CYP7A1 activity and FGF19 concentrations in 62 term and preterm infants (n = 181 samples). We found that CYP7A1 activity is developmentally regulated; its activity is undetectable prior to 30 weeks’ gestation and increases with advancing gestational age and volume of enteral feeds. Contrary to expectation, we demonstrated that FGF19 is expressed at birth in preterm infants and decreases over time, even as enteral feeds increase. Using structural equation modeling, we were able to show that CYP7A1 activity does not correlate with FGF19 concentrations. Our results suggest that the gut–liver axis is not upregulated in preterm and term infants and that neonates with cholestatic liver disease will unlikely benefit from supplemental FGF19. We also report novel findings of elevated FGF19 concentrations in preterm infants at birth and speculate that there may be an extra-intestinal source of FGF19 that is developmentally expressed in these infants.

Response of fibroblast growth factor 19 and bile acid synthesis after a body weight-adjusted oral fat tolerance test in overweight and obese NAFLD patients: a non-randomized controlled pilot trial

BackgroundNon-alcoholic fatty liver disease (NAFLD) is common both in obese and overweight patients. Fibroblast growth factor 19 (FGF19), an intestinal hormone, could play a role in the complex pathogenesis of NAFLD. The aim of our study was to investigate responses of FGF19 and bile acid (BA) synthesis after a body weight-adjusted oral fat tolerance test (OFTT) in overweight and obese NAFLD patients.MethodsFor this study, we recruited 26 NAFLD patients; 14 overweight (median BMI 28.3 kg/m2), 12 obese (35.3 kg/m2) and 16 healthy controls (24.2 kg/m2). All individuals received 1 g fat (Calogen®) per kg body weight orally. Serum concentrations of FGF19 were determined by ELISA. Concentrations of BAs and BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) were measured by gas chromatography-mass spectrometry and high-performance liquid chromatography, respectively; all at 0 (baseline), 2, 4 and 6 h during the OFTT.ResultsBMI correlated negatively with fasting FGF19 concentrations (rho = − 0.439, p = 0.004). FGF19 levels of obese NAFLD patients were significantly (p = 0.01) lower in the fasting state (median 116.0 vs. 178.5 pg/ml), whereas overweight NAFLD patients had significantly (p = 0.004) lower FGF19 concentrations 2 h after the fat load (median 163.0 vs. 244.5 pg/ml), and lowest values at all postprandial time points as compared to controls. Baseline BA concentrations correlated positively with FGF19 values (rho = 0.306, p = 0.048). In all groups, we observed BA increases during the OFTT with a peak at 2 h but no change in C4 levels in overweight/obese NAFLD patients.ConclusionsReduced basal gastrointestinal FGF19 secretion and decreased postprandial response to oral fat together with blunted effect on BA synthesis indicate alterations in intestinal or hepatic FXR signaling in overweight and obese NAFLD subjects. The precise mechanism of FGF19 signaling after oral fat load needs further evaluation.Trial registrationWe have registered the trial retrospectively on 30 Jan 2018 at the German clinical trials register (http://www.drks.de/), and the following number has been assigned DRKS00013942.

Prematurity and postnatal development regulate the expression of the FXR‐FGF19 axis in neonatal pigs

The farnesoid X receptor (FXR) is a nuclear bile acid receptor that regulates bile acid homeostasis. A key FXR target is fibroblast growth factor 19 (FGF19), which functions as an endocrine hormone. FGF19 is produced in both the intestine and liver in humans and pigs, whereas mice and rats express the human ortholog FGF15 only in the intestine, thus making pigs a more relevant model of human FGF19 biology. Gut bile acids activate small intestinal FXR triggering FGF19 secretion which circulates via the portal blood to inhibit hepatic bile acid synthesis by suppressing the rate limiting enzyme in bile acid synthesis, CYP7A1, via activation of extracellular‐signal‐regulated kinases (ERK) and c‐Jun N‐terminal kinase (JNK‐1) MAP kinase pathways and the orphan nuclear receptor, small heterodimer partner (SHP). Thus, enterohepatic FXR‐FGF19 signaling functions as a negative feedback signal to regulate bile acid homeostasis. Bile acid secretion has been shown to increase with gestational age. We hypothesized that expression and activation of the intestinal FXR‐FGF19 axis would be diminished in premature vs. term pigs and increased with postnatal age. We studied piglets delivered by cesarean‐section at 10 days preterm and full term. All pigs were fitted with orogastric and umbilical arterial catheters and fed minimal enteral nutrition with bovine colostrum for 5 d and then bovine mature milk until 26 d‐of‐age. Plasma and tissue samples were collected at days 0, 5, 11, and 26 d. We developed a porcine FGF19 specific sandwich ELISA assay by cloning the porcine FGF19 gene, overexpressing the protein using a baculovirus expression system, and developing monoclonal antibodies. We quantified the plasma FGF19 concentration using the ELISA and assayed distal intestinal gene expression of FGF19 and FXR by RT qPCR. We found that plasma FGF19 levels are strikingly lower (P&lt;0.05) in premature vs. term newborn pigs. In addition, postnatal age markedly altered activity of the FXR‐FGF19 axis, where plasma FGF19 levels increased significantly 5 d after birth in preterm, but not term pigs. Plasma FGF19 levels then decreased (P&lt;0.05) significantly between 5 and 26 d‐of‐age in both preterm and term pigs. Intestinal FXR and FGF19 expression were lower (P&lt;0.05) in premature vs term newborn pigs and decreased (P&lt;0.05) between day 5 and 26 d‐of‐age. We conclude that both prematurity and postnatal age regulate the FXR‐FGF19 axis in neonatal pigs. These findings have implications for the bile acid homeostasis, FGF19 function and growth of preterm and term infants during early postnatal life.Support or Funding InformationAgricultural Research Institute, USDA‐ARS, NIH, CalPoly Summer Undergraduate Research Program (SURP), NEOMUNEThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hepatic farnesoid X receptor protein level and circulating fibroblast growth factor 19 concentration in children with NAFLD.

Treatment with the farnesoid X receptor (FXR) agonist obeticholic acid is ineffective in some patients with non-alcoholic steatohepatitis (NASH) but the explanation is uncertain. We investigated hepatic FXR expression, and measurements of fibroblast growth factor 19 (FGF19) and bile acids (BAs) in children with NAFLD to investigate relationships with NASH. 33 children with NAFLD who underwent diagnostic liver biopsy were studied. Hepatic FXR protein levels and circulating FGF19 concentrations were compared with those analysed in five control subjects with proven normal liver histology. NASH was defined by the Paediatric NAFLD Histological Score (PNHS). Binary logistic regression with adjustment for covariates and potential confounders was undertaken to test factors independently associated with: a) NASH and b) hepatic FXR protein levels. Mean±SD age was 13.7±1.9 years. Nineteen patients had NASH (PNHS≥85) and 14 did not have NASH (PNHS<85). Hepatic FXR level and plasma FGF19 concentration varied ~10-fold and 5-fold, respectively, between groups, and was highest in control subjects, intermediate in NAFLD without NASH, and lowest in NASH (between group differences P<.001 and P<.01 respectively). NASH was independently associated with both FXR protein levels (OR=0.18, 95% CI 0.09, 0.38) and FGF19 concentration (OR=0.55, 95% CI 0.20, 0.89). FXR protein levels vary markedly between normal liver, NAFLD without NASH, and NASH. Low levels of FXR are independently associated with NASH.