FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321757 ◽  
Author(s):  
Song-Yang Zhang ◽  
Rosa J W Li ◽  
Yu-Mi Lim ◽  
Battsetseg Batchuluun ◽  
Huiying Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Small Intestine ◽  
Bile Acids ◽  
Insulin Action ◽  
Farnesoid X Receptor ◽  
Intestinal Microbiome ◽  
Dorsal Vagal Complex ◽  
Small Intestinal ◽  
The Brain ◽  
Conjugated Bile Acids

ObjectiveConjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown.DesignWe evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel.ResultsWe found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance.ConclusionOur findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.

scholarly journals The Nonsteroidal Anti-Inflammatory Drug Ketorolac Alters the Small Intestinal Microbiota and Bile Acids Without Inducing Intestinal Damage or Delaying Peristalsis in the Rat

2021 ◽  
Vol 12 ◽  
Author(s):  
Barbara Hutka ◽  
Bernadette Lázár ◽  
András S. Tóth ◽  
Bence Ágg ◽  
Szilvia B. László ◽  
...  
Keyword(s):  
Small Intestine ◽  
Bile Acids ◽  
Intestinal Microbiota ◽  
Intestinal Bacteria ◽  
Mucosal Inflammation ◽  
Intestinal Damage ◽  
Small Intestinal ◽  
Gi Transit ◽  
Anti Inflammatory ◽  
Conjugated Bile Acids

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce significant damage to the small intestine, which is accompanied by changes in intestinal bacteria (dysbiosis) and bile acids. However, it is still a question of debate whether besides mucosal inflammation also other factors, such as direct antibacterial effects or delayed peristalsis, contribute to NSAID-induced dysbiosis. Here we aimed to assess whether ketorolac, an NSAID lacking direct effects on gut bacteria, has any significant impact on intestinal microbiota and bile acids in the absence of mucosal inflammation. We also addressed the possibility that ketorolac-induced bacterial and bile acid alterations are due to a delay in gastrointestinal (GI) transit.Methods: Vehicle or ketorolac (1, 3 and 10 mg/kg) were given to rats by oral gavage once daily for four weeks, and the severity of mucosal inflammation was evaluated macroscopically, histologically, and by measuring the levels of inflammatory proteins and claudin-1 in the distal jejunal tissue. The luminal amount of bile acids was measured by liquid chromatography-tandem mass spectrometry, whereas the composition of microbiota by sequencing of bacterial 16S rRNA. GI transit was assessed by the charcoal meal method.Results: Ketorolac up to 3 mg/kg did not cause any signs of mucosal damage to the small intestine. However, 3 mg/kg of ketorolac induced dysbiosis, which was characterized by a loss of families belonging to Firmicutes (Paenibacillaceae, Clostridiales Family XIII, Christensenellaceae) and bloom of Enterobacteriaceae. Ketorolac also changed the composition of small intestinal bile by decreasing the concentration of conjugated bile acids and by increasing the amount of hyodeoxycholic acid (HDCA). The level of conjugated bile acids correlated negatively with the abundance of Erysipelotrichaceae, Ruminococcaceae, Clostridiaceae 1, Muribaculaceae, Bacteroidaceae, Burkholderiaceae and Bifidobacteriaceae. Ketorolac, under the present experimental conditions, did not change the GI transit.Conclusion: This is the first demonstration that low-dose ketorolac disturbed the delicate balance between small intestinal bacteria and bile acids, despite having no significant effect on intestinal mucosal integrity and peristalsis. Other, yet unidentified, factors may contribute to ketorolac-induced dysbiosis and bile dysmetabolism.

scholarly journals Observations on the nature and origin of lipids in the small intestine of the sheep

1968 ◽  
Vol 22 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Aileen M. Lennox ◽  
A. K. Lough ◽  
G. A. Garton
Keyword(s):  
Fatty Acids ◽  
Small Intestine ◽  
Fatty Acid ◽  
Bile Acids ◽  
Neutral Lipids ◽  
Intestinal Lumen ◽  
Total Lipids ◽  
Total Fatty Acids ◽  
Proportional Contribution ◽  
Conjugated Bile Acids

1. Total lipids were extracted from digesta obtained from the rumen, abomasum and upper small intestine (jejunum) of each of four slaughtered sheep. The lipids were fractionated into unesterified fatty acids, neutral lipids and phospholipids and the proportional contribution of each fraction to the total fatty acids was determined.2. The contribution made by phospholipids to the total fatty acids in the digesta showed a marked increase in the samples from the small intestine compared with those from the rumen and abomasum. This increase was apparently due to the presence of biliary phospholipids.3. Total lipids and conjugated bile acids were extracted from sheep bile, the lipids were fractionated and their fatty-acid composition was determined. Phospholipids predominated and these consisted mainly of phosphatidylcholine, together with some lysophosphatidylcholine.4. Both phospholipids contained significant amounts of unsaturated C18 components which could account, at least in part, for the previously reported increament to the proportion of these acids in the digesta when it enters the upper jejunum.5. The overall fatty acid compositions of the two biliary phospholipids were very similar and, in common with other naturally occurring phosphatidylcholines, the fatty acids present in position 2 of the phosphatidylcholine of bile were found to consist almost entirely of unsaturated components.6. Total lipids and conjugated bile acids were extracted from samples of digesta obtained from three sheep with cannulas in different positions in the jejunum. Analysis of the lipids indicated that biliary phospholipids, in particular phosphatidylcholine, underwent progressive hydrolysis in the intestinal lumen.7. The distribution of conjugated bile acids, unesterified fatty acids and phospholipids between the solid (particulate) and liquid (micellar) phases of the intestinal digesta was determined. These chyme constituents were, for the most part, associated with the particulate matter and thus, at any given time, it appears that only a small fraction of the total fatty acids is available for absorption in micellar form. It is suggested that the micellar solubilization of fatty acids may be facilitated by the presence of lysophosphatidylcholine.

scholarly journals Bile Acid Uptake Transporters as Targets for Therapy

2017 ◽  
Vol 35 (3) ◽  
pp. 251-258 ◽  
Author(s):  
Davor Slijepcevic ◽  
Stan F.J. van de Graaf
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Energy Homeostasis ◽  
Sodium Taurocholate ◽  
Hepatic Uptake ◽  
Farnesoid X Receptor ◽  
Acid Uptake ◽  
Bile Acid Uptake ◽  
Uptake Transporters ◽  
Conjugated Bile Acids

Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

Use of Farnesoid X Receptor Agonists to Treat Nonalcoholic Fatty Liver Disease

2015 ◽  
Vol 33 (3) ◽  
pp. 426-432 ◽  
Author(s):  
Arun J. Sanyal
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Bile Acids ◽  
Fatty Liver Disease ◽  
Animal Studies ◽  
Farnesoid X Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Improve Insulin Resistance

Nonalcoholic fatty liver disease is a common cause of liver related morbidity and mortality. It is closely linked to underlying insulin resistance. It has recently been shown that bile acids modulate insulin signaling and can improve insulin resistance in cell based and animal studies. These effects are mediated in part by activation of farnesoid x receptors by bile acids. In human studies, FXR agonists improve insulin resistance and have recently been shown to improve NAFLD. The basis for the use of FXR agonists for the treatment of NAFLD and early human experience with such agents is reviewed in this paper.

Pancreaticobiliary factors in the modulation of small intestinal enterokinase in the rat

1986 ◽  
Vol 250 (1) ◽  
pp. G103-G108 ◽  
Author(s):  
B. M. Newman ◽  
P. C. Lee ◽  
H. Tajiri ◽  
D. R. Cooney ◽  
E. Lebenthal
Keyword(s):  
Small Intestine ◽  
Bile Acids ◽  
Common Duct ◽  
Complete Loss ◽  
Adult Rats ◽  
Brush Border Enzymes ◽  
Proximal Small Intestine ◽  
Trophic Changes ◽  
The Common ◽  
Small Intestinal

Chronic pancreaticobiliary diversion was employed to study the modulation of enterokinase in the small intestine of adult rats. Diversion resulted in apparent trophic changes of the proximal bypassed portion of the intestinal mucosa. An almost complete loss of mucosal enterokinase activity in the proximal duodenum but no increase of enterokinase in the segments distal to reentry of the common duct was found in the pancreaticobiliary-diverted rats. The effect on the enterokinase activity in the proximal segment was specific in that no other brush-border enzymes measured in that segment were decreased. The decrease in enterokinase was partially prevented by dietary supplementation with pancreatic trypsinogen and completely avoided with the addition of a combination of bile acids and trypsinogen. Supplementation with bile acid alone did not preserve the enterokinase levels in the bypassed rats. The results suggested that trypsinogen is the primary factor responsible for modulating enterokinase levels in the proximal small intestine, with bile acids acting as a modifier.

scholarly journals The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure

2020 ◽  
Vol 21 (20) ◽  
pp. 7750
Author(s):  
Anna Maria Czarnecka ◽  
Krzysztof Milewski ◽  
Jan Albrecht ◽  
Magdalena Zielińska
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Bile Acids ◽  
Tissue Expression ◽  
Farnesoid X Receptor ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
The Status ◽  
The Brain

Acute liver failure (ALF) leads to neurological symptoms defined as hepatic encephalopathy (HE). Although accumulation of ammonia and neuroinflammation are generally accepted as main contributors to HE pathomechanism, a buildup of bile acids (BA) in the blood is a frequent component of liver injury in HE patients. Recent studies have identified the nuclear farnesoid X receptor (FXR) acting via small heterodimer partner (SHP) as a mediator of BA-induced effects in the brain of ALF animals. The present study investigated the status of the BA–FXR axis in the brain and the liver, including selective changes in pertinent genes in thioacetamide (TAA)-induced ALF in Sprague–Dawley rats. FXR was found in rat neurons, confirming earlier reports for mouse and human brain. BA accumulated in blood but not in the brain tissue. Expression of mRNAs coding for Fxr and Shp was reduced in the hippocampus and of Fxr mRNA also in the cerebellum. Changes in Fxr mRNA levels were not followed by changes in FXR protein. The results leave open the possibility that mobilization of the BA–FXR axis in the brain may not be necessarily pathognomonic to HE but may depend upon ALF-related confounding factors.

Vagovagal reflex control of digestion: afferent modulation by neural and "endoneurocrine" factors

1995 ◽  
Vol 268 (1) ◽  
pp. G1-G10 ◽  
Author(s):  
R. C. Rogers ◽  
D. M. McTigue ◽  
G. E. Hermann
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Stem ◽  
Neural Control ◽  
Dorsal Vagal Complex ◽  
The Central Nervous System ◽  
Small Intestinal ◽  
Reflex Control ◽  
Control Circuits ◽  
The Brain

Vagovagal reflex control circuits in the dorsal vagal complex of the brain stem provide overall coordination of gastric, small intestinal, and pancreatic digestive functions. The neural components forming these reflex circuits are under substantial descending neural control. By adjusting the excitability of the differing components of the reflex, significant alterations in digestion control can be produced by the central nervous system. Additionally, the dorsal vagal complex is situated within a circumventricular region without a "blood-brain barrier." As a result, vagovagal reflex circuitry is also exposed to humoral influences, which can profoundly alter digestive functions by acting directly on brain stem neurons.

scholarly journals Effect of a High-Fat Diet on the Small-Intestinal Environment and Mucosal Integrity in the Gut-Liver Axis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3168
Author(s):  
Takashi Nakanishi ◽  
Hirokazu Fukui ◽  
Xuan Wang ◽  
Shin Nishiumi ◽  
Haruka Yokota ◽  
...  
Keyword(s):  
Small Intestine ◽  
Bile Acids ◽  
High Fat Diet ◽  
Small Intestinal Mucosa ◽  
High Fat ◽  
Mucosal Permeability ◽  
Mucosal Integrity ◽  
Junction Molecules ◽  
Intestinal Contents ◽  
Small Intestinal

Although high-fat diet (HFD)-related dysbiosis is involved in the development of steatohepatitis, its pathophysiology especially in the small intestine remains unclear. We comprehensively investigated not only the liver pathology but also the microbiome profile, mucosal integrity and luminal environment in the small intestine of mice with HFD-induced obesity. C57BL/6J mice were fed either a normal diet or an HFD, and their small-intestinal contents were subjected to microbial 16S rDNA analysis. Intestinal mucosal permeability was evaluated by FITC-dextran assay. The levels of bile acids in the small-intestinal contents were measured by liquid chromatography/mass spectrometry. The expression of tight junction molecules, antimicrobial peptides, lipopolysaccharide and macrophage marker F4/80 in the small intestine and/or liver was examined by real-time RT-PCR and immunohistochemistry. The abundance of Lactobacillus was markedly increased and that of Clostridium was drastically decreased in the small intestine of mice fed the HFD. The level of conjugated taurocholic acid was significantly increased and those of deconjugated cholic acid/secondary bile acids were conversely decreased in the small-intestinal contents. The expression of occludin, antimicrobial Reg IIIβ/γ and IL-22 was significantly decreased in the small intestine of HFD-fed mice, and the intestinal permeability was significantly accelerated. Infiltration of lipopolysaccharide was significantly increased in not only the small-intestinal mucosa but also the liver of HFD-fed mice, and fat drops were apparently accumulated in the liver. Pathophysiological alteration of the luminal environment in the small intestine resulting from a HFD is closely associated with minimal inflammation involving the gut-liver axis through disturbance of small-intestinal mucosal integrity.

scholarly journals The small bowel microbiome changes significantly with age and aspects of the ageing process

2022 ◽  
Vol 9 (1) ◽  
pp. 21-23
Author(s):  
Gabriela Leite ◽  
Mark Pimentel ◽  
Gillian M. Barlow ◽  
Ruchi Mathur
Keyword(s):  
Small Intestine ◽  
Small Bowel ◽  
Intestinal Microbiome ◽  
Ageing Process ◽  
Age Related ◽  
Human Ageing ◽  
Stool Samples ◽  
Older Subjects ◽  
Small Intestinal ◽  
Host Metabolism

Gut microbiome changes have been associated with human ageing and implicated in age-related diseases including Alzheimer’s disease and Parkinson’s disease. However, studies to date have used stool samples, which do not represent the entire gut. Although more challenging to access, the small intestine plays critical roles in host metabolism and immune function. In this paper (Leite et al. (2021), Cell Reports, doi: 10.1016/j.celrep.2021.109765), we demonstrate significant differences in the small intestinal microbiome in older subjects, using duodenal aspirates from 251 subjects aged 18-80 years. Differences included significantly decreased microbial diversity in older subjects, driven by increased relative abundance of phylum Proteobacteria, particularly family Enterobacteriaceae and coliform genera Escherichia and Klebsiella. Moreover, while this decreased diversity was associated with the ‘ageing process’ (comprising chronologic age, number of medications, and number of concomitant diseases), changes in certain taxa were found to be associated with number of medications alone (Klebsiella), number of diseases alone (Clostridium, Bilophila), or chronologic age alone (Escherichia, Lactobacillus, Enterococcus). Lastly, many taxa associated with increasing chronologic age were anaerobes. These changes may contribute to changes in human health that occur during the ageing process.

Sign in / Sign up

Export Citation Format

Share Document