Role In Enterohepatic Circulation Research Articles

Regulating the absorption and excretion of perfluorooctane sulfonate and its alternatives through influencing enterohepatic circulation

Enterohepatic circulation has been reported to play a significant role in the bioaccumulation of PFASs. In this study, the tissue distribution and excretion of PFOS and its alternatives, namely 6:2 and 8:2 fluorotelomer sulfonic acid (FTSA) was investigated using a mouse assay with a focus on role of enterohepatic circulation. Liver was the primarily accumulating organ for PFOS and 8:2 FTSA (33.4 % and 25.8 % of total doses absorbed after 14 days), whereas 65 % of 6:2 FTSA was excreted via urine within 24 h. Peak levels of 8:2 FTSA and PFOS were found in the gallbladder, implying the important role of enterohepatic circulation in PFASs reabsorption. The role of enterohepatic circulation was further evaluated through co-exposure of 8:2 FTSA and PFOS with medicines (namely metformin (MET) and ursodeoxycholic acid (UDCA)). MET reduced accumulation of 8:2 FTSA and PFOS in the liver by 68.6 % and 65.8 %, through down-regulation of bile acid transporter (Asbt) and enhancement of fecal excretion. Conversely, UDCA raised their concentrations by 21.9 % and 34.6 % compared to that exposed solely to PFASs. A strong positive correlation was identified between PFASs serum levels and Asbt expression. This study illuminated PFAS bioaccumulation mechanisms and suggested potential strategies to mitigate the exposure risks.

Laparoscopic ileocecal-sparing hemicolectomy for cancer of hepatic flexure and proximal transverse colon: A single arm prospective study.

e15650 Background: Traditional right hemicolectomy（TRH）is the standard operation for right colon cancer. The resection includes intestines from the terminal ileum to the middle of the transverse colon, as well as the ileocecum. The ileocecum is considered to have a “valve-like” function to reduce intestinal reflux and the incidence of diarrhea, which also play an important role in enterohepatic circulation and intestinal immunity. As for cancers in hepatic region and proximal transverse colon, is it possible to preserve ileocecum and ensure the oncological curative? Methods: We previously reported the procedure of laparoscopic ileocecal-sparing right hemicolectomy (LISH). The lymphatic adipose tissue around ileocolic artery and vein（ICA/ICV）,including 201d(lymph node around colic branch of ICA), 202, 203LN, was dissected. The colic branches of ICA/ICV were selectively ligated. The main trunk, cecal branches and ileal branches of ICA/ICV were preserved. The right colic artery/vein and middle colic artery/vein were ligated at roots，which was the same as TRH. End-to-end anastomosis between cecum and transverse colon was applied through an opening at the bottom of cecum. This was a single arm prospective study (NCT04479111) to evaluate the feasibility of LISH. Patients with hepatic flexure and proximal transverse colon cancer, aged 18-75, without distant metastasis were included. Primary endpoint was postoperative complications and 1-year local recurrence; secondary endpoints included rate of conversion to TRH, lymphadenectomy and complete mesocolic excision (CME) quality, surgical margin and 1-year disease-free survival (DFS) rate. Results: As of Jan.16th, 2022, 31 patients had been enrolled，including 9 patients with stage I, 9 patients with stage II and 13 patients with stage III. All enrolled patients received LISH successfully. The rate of high-quality lymphadenectomy (harvested LN > 12) was 96.8% and high-quality CME (Grade I/II) was 100%. All patients had negative resection margin and adequate proximal resection margin (median 9.1cm). 201d/202/203 lymph nodes were evaluated separately, and no metastatic 201d/202/203 LN were detected. Clavien-Dindo grade I adverse events within 90 days were occurred in 6 patients (19.4%), including wound infection(n = 2), anemia(n = 2), diarrhea(n = 1) and intestinal obstruction(n = 1). 1-year local recurrence rate is 0%, while 1-year DFS rate is 96.77%, only 1 stage III patient was diagnosed as ovarian metastases 9 months after radical operation. Conclusions: In this study, we provide a new radical operation choice for patients with hepatic flexure and proximal transverse colon cancer. LISH presented good perioperative safety，operation quality，and preliminary oncological safety within 1 year. We are launching a multicenter phase III study to verify the result and further explore the long-term oncological outcome. Clinical trial information: NCT04479111 .

Substrate binding in the bile acid transporter ASBTYf from Yersinia frederiksenii.

Apical sodium-dependent bile acid transporter (ASBT) retrieves bile acids from the small intestine and plays a pivotal role in enterohepatic circulation. Currently, high-resolution structures are available for two bacterial ASBT homologs (ASBTNM from Neisseria meningitides and ASBTYf from Yersinia frederiksenii), from which an elevator-style alternating-access mechanism has been proposed for substrate transport. A key concept in this model is that the substrate binds to the central cavity of the transporter so that the elevator-like motion can expose the bound substrate alternatingly to either side of the membrane during a transport cycle. However, no structure of an ASBT has been solved with a substrate bound in its central cavity, so how a substrate binds toASBT remains to be defined. In this study, molecular docking, structure determination and functional analysis were combined to define and validate the details of substrate binding in ASBTYf. The findings provide coherent evidence to provide a clearer picture of how the substrate binds in the central cavity of ASBTYf that fits the alternating-access model.

Defining Substrate Binding Site in Sodium-Dependent Bile Acid Transporters

Bile acids are stored in the gallbladder and excreted into the digestive tract where they assist absorption of lipids and vitamins. Bile acids are synthesized from cholesterol in the liver before they are stored and entered into the small intestine. In the small intestine, more than 95% of the bile acids are absorbed and sent back to the liver through a process known as enterohepatic circulation. In humans, there are two Na+-dependent transporters that play an essential role in enterohepatic circulation—Na+-taurocholate co-transporting polypeptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT). NTCP and ASBT share 35% sequence identity and both belong to the solute carrier 10 (Slc10A) family of secondary transporters. NTCP, in addition to its role in bile acid transport, is required for infection of hepatitis B virus because it serves as a co-receptor for human hepatitis B and D virus. ASBT is crucial to enterohepatic circulation as it has been correlated to multiple digestive illnesses, and has become a potential drug target for hypercholesterolaemia, type 2 diabetes, and constipation. Crystals structures of two bacterial homologs of human ASBT, ASBTNm and ASBTYf, have been reported, however, the two reports differ in their definition of the bile acid binding site. We will better define the bile acid binding site and its selectivity to various bile acids by making mutations to solvent exposed residues on the ASBTYf transporter and measure binding and transport of bile acids. These studies will give a better understanding of the substrate binding site of ASBT.

Association of serum bilirubin in newborns affected by jaundice with gut microbiota dysbiosis

Background and aimsBreast milk jaundice (BMJ) is common and benign, but neonatal cholestasis (NC) is rare and not benign, so early differentiation between NC and non-NC jaundice is important and may facilitate diagnosis and treatment. Gut microbiota plays an important role in enterohepatic circulation, which in turn plays an important role in the secretion of bilirubin. We aimed to determine the composition of gut microbiota in patients with NC and BMJ, and to identify the gut microbiota composition associated with NC and BMJ. MethodsData on age, gender, delivery, feeding mode, serum total bilirubin, direct bilirubin, and liver function were collected for NC patients, BMJ patients and healthy controls, respectively. Shotgun metagenomic sequencing and metagenome-wide association were performed. ResultsForty NC patients, 16 patients affected by BMJ, and 14 healthy controls (CON) without jaundice were enrolled. A significant increase in species richness, especially Bacteroides, was found in NC patients. The abundances of potentially pathogenic species and KEGG orthologies (KOs) of virulence factor genes were positively correlated with serum bilirubin level. The abundances of nine species of Bifidobacterium and three KOs of galactose metabolism were significantly decreased in the jaundice group (NC and BMJ) and were negatively correlated with serum bilirubin level. ConclusionsThe gut microbiota in NC patients is characterized by a significant increase in species richness, possibly due to the proliferation of potentially pathogenic species.Additionally, the gut microbiota in jaundice patients is characterized by a decreased abundance of Bifidobacterium. Decreased Bifidobacterium has been associated with elevated bilirubin and abnormal gut microbiota galactose metabolic pathway. Further, ten bacteria species were identified as potential biomarker of jaundice. Key pointsQuestion Is there any alteration of gut microbiotain neonatal cholestasis patients? Does gut microbiota have any involvement in the occurrence of neonatal cholestasis or breast milk jaundice?Findings The alteration of gut microbiota in neonatal cholestasis patients mainly manifested as a significant increase in species richness and an increased abundance of potentially pathogenic species, while the main manifestation in jaundice patients was a significant decrease in Bifidobacterium which may be involved in the metabolism of bilirubin through the galactose metabolic pathway.Meaning The results suggest that an imbalance of gut microbiota exist in neonatal cholestasis and breast milk jaundice patients, primarily in the form of a substantial reduction in the abundance of Bifidobacterium, suggesting the possibility of intervention treatment for neonatal cholestasis and breast milk jaundice by supplementing probiotics.

Physiopathology of multiple organ dysfunctions in severely monocrotophos-poisoned rabbits

ObjectiveAcute organophosphorus pesticides poisoning has a serious threat on people's health. This study aimed to investigate the pathogenesis and molecular mechanism of multiple organ dysfunction syndrome (MODS) in severely monocrotophos-poisoned rabbits. MethodsChinchilla rabbits were used to build the monocrotophos-poisoned animal model via subcutaneous abdominal injection. Acetylcholinesterase activity was determined using the dithiobisnitrobenzoic acid enzyme kinetics method, and the free organophosphorus (FOP) toxic substances content was analyzed using the enzyme inhibition method. The contents of tumor necrosis factor (TNF-α), interleukin 1-β (IL-β) and thromboxane B2 (TXB2) in the plasma and tissue homogenates were determined via radioimmunoassay. ResultsTwenty-four hours after exposure, in comparison to the plasma, blood cells and homogenates of various tissues, the bile had a significantly different FOP content (P < 0.05). In different phases, HE staining results confirmed that several degrees of pathological lesions (such as hemorrhage, edema, degeneration and necrosis) were detected in FOP poisoned rabbits. The TXB2 and TNF contents in plasma were significantly higher than those of the control (P < 0.05). Except for the intercostal muscle, all of the tissues had significantly higher TXB2 contents than the control. The TNF contents of the liver and lung and the IL-1β contents of the liver and kidney were significantly higher than those of the control (P < 0.05). ConclusionFOP stored in the gallbladder may play important role in enterohepatic circulation. In MODS rabbits, caused by OP poisoning, the TXB2 and TNF-α may play important role in inflammatory response and complement and coagulation systems respectively.

The Significance of Enterohepatic Circulation in the Causation Neonatal Hyperbilirubinemia

Sir, This is in reference to the study by Rana et al.[1] A robust triple-blind design, appropriate sample-size, and statistical methods–sensitivity analysis and effect-size estimation– employed by the authors could well make the investigation a landmark study evaluating the role of zinc in the prevention of hyperbilirubinemia in neonates. However, the study simultaneously conjures-up an important question about the role of enterohepatic circulation (EHC) in the causation of neonatal jaundice which may also have implications on the physiological doctrine for the intervention tested. Overproduction of bilirubin from heme is considered the most prevalent mechanism of neonatal hyperbilirubinemia apart from impaired uptake, conjugation, and EHC. We have limited instances where EHC is considered the prime mechanism for jaundice, e.g., pyloric stenosis, lower intestinal atresia, paralytic ileus, and meconium-plug-syndrome (virtually no removal of bilirubin due to distal obstruction). There is limited data to suggest that the resorption of bilirubin from the intestine can be a major cause of neonatal physiologic jaundice [2]. It has been stated that neonatal hyperbilirubinemia is exacerbated–if not caused–by enhanced bilirubin resorption through EHC [3]. In fact, more obvious than EHC, a markedly reduced UDP-glucuronyl transferase activity is noted in pyloric stenosis [3]. Enhanced EHC induced by human milk has a putative role in prolonging ‘breastmilk jaundice’ [4]. In the past, various strategies have been employed to counteract EHC with inconsistent results, in terms of the incidence and severity of jaundice [5]. Consequently, it is advised that such interventions are at the best used as an adjuvant, along with more established modalities like phototherapy [6]. The results of the present study by Rana et al., showing no significant reduction in the incidence of hyperbilirubinemia, requirement of phototherapy and mean STB (serum total bilirubin) at 72 h, are in line with the outcomes of previous studies employing other agents. Therefore, although past studies have suggested that EHC may play a significant role in the bilirubin metabolism, it appears less likely that EHC is a major cause of neonatal hyperbilirubinemia, though it may play some contributory role in prolonging physiological jaundice. Therefore, negative results of these studies probably have a bearing on the underlying doctrine of ‘prevention of hyperbilirubinemia by clogging-up EHC’, irrespective of the agent (agar, charcoal, cholestyramine or zinc) employed. Other limitations of the study were the use of nonstandardized oral zinc dose, lack of serum zinc level monitoring, inadequate reporting of the adequacy of breastfeeding and vomited and/or skipped doses, and delayed initiation of the intervention.

A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.

Cholestasis, or impaired bile flow, is an important but poorly understood manifestation of liver disease. Two clinically distinct forms of inherited cholestasis, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), were previously mapped to 18q21. Haplotype analysis narrowed the candidate region for both diseases to the same interval of less than 1 cM, in which we identified a gene mutated in BRIC and PFIC1 patients. This gene (called FIC1) is the first identified human member of a recently described subfamily of P-type ATPases; ATP-dependent aminophospholipid transport is the previously described function of members of this subfamily. FIC1 is expressed in several epithelial tissues and, surprisingly, more strongly in small intestine than in liver. Its protein product is likely to play an essential role in enterohepatic circulation of bile acids; further characterization of FIC1 will facilitate understanding of normal bile formation and cholestasis.

Enterohepatic circulation is essential for regular cycling of duodenal migrating motor complexes in dogs

The role of enterohepatic circulation and specific bile acids in the initiation and caudad migration of duodenal migrating motor complexes (MMCs) was investigated in conscious dogs. All dogs had spontaneous duodenal MMCs that migrated to the terminal ileum when bile flow was intact. During the first 3 days after total external biliary diversion, no MMCs originated in the duodenum. Instead, all MMCs originated in the jejunum and migrated to the ileum. During the next 4 days of total external biliary diversion, 81% of the MMCs originated in the jejunum and 19% in the duodenum. When normal bile flow was restored after 9 days of total external biliary diversion, regular duodenal MMCs resumed after a delay of 126 ± 27 minutes. Perfusion of individual bile acids or dogs' own bile, but not saline or alkaline solution, into the duodenum or perfusion of dogs' own bile directly into the ileum during total external biliary diversion restarted duodenal MMCs with a time lag of about 2 hours. The authors conclude that intact enterohepatic circulation is essential for the initiation of regular duodenal MMCs.

Basal biliary secretion in conscious chicken and role of enterohepatic circulation

1. 1. Enterohepatic circulation of bile salt role. its interruption effects, gallbladder contribution and importance of some electrolytes, on total biliary secretion of chicken have been investigated. 2. 2. The gallbladder, in spite of its anatomical disposition, behaves exactly like that of mammals. When the vesicular duct is tied there is a retrograde now of bile from gallbladder, although it causes no change in the results if a cholecystokinetic stimulus is not introduced. 3. 3. The role of the enterohepatic circulation is important in this species. The results leave out electrolyte loss and indicate bile salt concentration decay as cause of hyposecretion after bile drainage, which agrees with lack of change of flow independent of bile salt. 4. 4. Recovery of all parameters when bile is placed in duodenum shows that the observed effects are genuine and that animals were in good physiological state.

Effect of entekohepatic circulation on the pharmacokinetics of spironolactone in man.

100 μCi 3H-spironolactone together with 300 mg unlabeled drug were administered orally to 8 patients, 24 h after choledochotomy with subsequent complete drainage of bile for a further 96 h by means of a special tube. To evaluate the role of entero-hepatic circulation, the excretion of tritiated substances in bile was investigated and their kinetics in plasma and urine were compared with that of controls.

Biliary excretion and biotransformation of pentaerythritol trinitrate in rats

A study was made of the biliary excretion of 14C-pentaerythritol trinitrate in the rat to elucidate the possible role of enterohepatic circulation in the prolonged action of the drug. The biliary drug excretion consisted entirely of metabolites which were previously unknown, namely, the glucuronides of pentaerythritol mononitrate, dinitrate and trinitrate. Drug radioactivity entered the bile faster after intravenous than after oral dosing. This difference (51% vs. 30% of the dose in 4 hr) was entirely due to pentaerythritol dinitrate glucuronide; the pentaerythritol trinitrate glucuronide level was approximately the same (9.5% of the dose in 4 hr). Enterohepatic circulation was indicated by the observation that 2.5 times more drug radioactivity was excreted into the urine by intact rats than by biliary cannulated rats. A comparison of the biliary and urinary excretion products of pentaerythritol trinitrate suggests that the enterohepatic circulation provides the opportunity for gastrointestinal resorption and recirculation of the free drug.