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Enterohepatic circulation

Enterohepatic circulation is the physiological process by which bile acids, synthesized in the liver from cholesterol, are secreted into the bile, delivered to the small intestine to aid in digestion, and then predominantly reabsorbed for return to the liver via the portal vein, ensuring efficient recycling of these critical molecules.^[1] This cycle conserves the bile acid pool, which totals approximately 3-5 grams in humans, by reabsorbing about 95% of secreted bile acids in the terminal ileum, allowing the pool to be recycled roughly 6-10 times per day with only 0.2-0.6 grams lost in feces daily.^[2] Disruptions in this circulation can lead to conditions such as cholestasis or gallstone disease, highlighting its role in maintaining hepatic and intestinal homeostasis.^[1] The mechanism of enterohepatic circulation begins with the hepatic synthesis of primary bile acids, such as cholic acid and chenodeoxycholic acid, primarily via the enzyme cholesterol 7α-hydroxylase (CYP7A1), followed by conjugation with glycine or taurine to enhance solubility.^[2] These conjugated bile acids are actively transported from hepatocytes into bile canaliculi by the bile salt export pump (BSEP, ABCB11) and stored in the gallbladder until released into the duodenum during meals to emulsify dietary fats and facilitate absorption of lipids and fat-soluble vitamins.^[3] In the intestine, approximately 95% of bile acids are reabsorbed in the ileum through the apical sodium-dependent bile acid transporter (ASBT, SLC10A2) on enterocytes, then effluxed basolaterally via the organic solute transporter (OSTα/β, SLC51A/SLC51B) into the portal circulation.^[3] Upon reaching the liver, bile acids are taken up by hepatocytes primarily via the Na+-taurocholate cotransporting polypeptide (NTCP, SLC10A1), completing the cycle and preventing excessive loss.^[3] This process is tightly regulated by nuclear receptors, notably the farnesoid X receptor (FXR), which senses bile acid levels in the intestine and liver to suppress further synthesis through induction of fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP), thereby maintaining bile acid homeostasis and avoiding hepatotoxicity from accumulation.^[2] Gut microbiota also contribute by deconjugating and transforming primary bile acids into secondary forms like deoxycholic acid, some of which are reabsorbed and recirculated.^[2] Beyond bile acids, enterohepatic circulation applies to other endogenous compounds (e.g., bilirubin, cholesterol) and xenobiotics (e.g., certain drugs), influencing their pharmacokinetics and elimination.^[4] Physiologically, enterohepatic circulation is essential for efficient cholesterol catabolism, as bile acids represent the primary route for non-esterified cholesterol excretion (about 0.5 grams per day), and for optimizing nutrient absorption by generating micelles that solubilize hydrophobic molecules.^[2] Clinically, targeting components of this cycle—such as inhibiting ASBT for hypercholesterolemia treatment or NTCP for hepatitis B virus entry—offers therapeutic potential, though deficiencies (e.g., in BSEP) can cause progressive familial intrahepatic cholestasis and liver failure.^[3] Overall, this recycling system exemplifies the liver-intestine axis's role in metabolic efficiency and disease prevention.^[1]

Overview and Physiology

Definition and Process

Enterohepatic circulation refers to the recycling pathway by which certain endogenous substances, such as bile acids, and some exogenous substances, such as certain drugs and xenobiotics, are secreted by the liver into bile, delivered to the small intestine, reabsorbed primarily in the ileum, transported back to the liver via the portal vein, and resecreted into bile to repeat the cycle.^[1] This efficient loop minimizes the need for de novo synthesis and maintains a conserved pool of these substances within the body.^[5] The process begins in the liver, where hepatocytes take up substances from the portal and systemic blood via specific transporters. These substances are then actively secreted into bile canaliculi, modified if necessary (e.g., conjugated), and transported through intrahepatic bile ducts to the gallbladder for concentration and storage.^[5] Following a meal, cholecystokinin stimulates gallbladder contraction, releasing bile through the common bile duct into the duodenum, where it mixes with intestinal contents and progresses through the jejunum.^[5] In the terminal ileum, the majority of substances undergo active transport across the enterocytes via apical sodium-dependent bile acid transporters (ASBT), entering the portal venous circulation for return to the liver, where they are efficiently reuptaken by hepatocytes through basolateral transporters like the sodium-taurocholate cotransporting polypeptide (NTCP).^[6] Key anatomical structures involved include the liver (hepatocytes and canaliculi), bile ducts, gallbladder, small intestine (duodenum and ileum), and portal vein.^[5] This circulation is highly efficient, with approximately 95% of bile acids—the primary substances involved—reabsorbed in the ileum, resulting in 6–10 cycles per day and conserving the bile acid pool while limiting daily losses to about 0.2–0.6 g.^[6]^[5]

Physiological Significance

The enterohepatic circulation is essential for resource conservation in the body, as it enables the reabsorption of approximately 95% of bile acids from the intestine back to the liver, maintaining a compact bile acid pool of 2–4 grams in humans despite daily fecal losses of only 0.2–0.6 grams. This high-efficiency recycling, primarily occurring in the terminal ileum, drastically reduces the demand for de novo hepatic synthesis, which would otherwise require substantial energy and cholesterol—key resources that are limited and critical for other physiological processes. By minimizing synthesis to just 5% of the pool per day, the circulation prevents excessive cholesterol depletion and supports metabolic homeostasis.^[7]^[8] This process also amplifies the liver's secretory output, permitting a small bile acid pool to facilitate a much larger daily biliary secretion of 12–18 grams through 6–10 recycling cycles, which is vital for generating adequate bile flow to emulsify dietary lipids effectively. Such amplification ensures that hepatic production, limited by enzymatic capacity, can meet the high demands of digestion without overburdening the liver, thereby enhancing the overall efficiency of bile-mediated functions.^[9]^[1] Beyond these mechanisms, enterohepatic circulation integrates liver metabolism with intestinal nutrient handling, synchronizing bile acid availability with meals to optimize the absorption of fats and fat-soluble vitamins through micelle formation and transport. This linkage promotes digestive efficiency and broader homeostasis by coordinating organ systems in real time. Evolutionarily, the circulation emerged as an adaptive strategy in vertebrates for managing lipophilic compounds, with bile salt recycling and gallbladder storage traceable to ancient jawless fish, enabling diverse species to adapt lipid digestion to varying diets and environments.^[8]^[10]

Key Components and Substances

Bile Acids

Bile acids are steroidal molecules derived from cholesterol that serve as the primary endogenous substances facilitating enterohepatic circulation. Synthesized in the liver, they are secreted into bile, stored in the gallbladder, released into the duodenum to aid lipid digestion, and largely reabsorbed in the ileum for return to the liver via the portal vein, recycling up to 95% of the pool daily. This efficient recirculation maintains a stable bile acid pool while minimizing cholesterol loss, with only a small fraction excreted in feces to balance synthesis. Their amphipathic nature, featuring a hydrophobic steroid nucleus and hydrophilic side chain, enables detergent-like functions critical to this process.^[6]^[11] Primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), are directly synthesized in the liver, while secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), form through bacterial 7α-dehydroxylation in the colon. The amphipathic structure of these bile acids allows them to form mixed micelles with phospholipids and fatty acids in the intestinal lumen, solubilizing dietary lipids for efficient enzymatic digestion and absorption. In humans, the total bile acid pool size is approximately 2-4 g, with a daily fecal loss of 0.2-0.6 g that is compensated by hepatic synthesis to maintain homeostasis.^[12]^[6]^[13] Bile acid synthesis primarily occurs via the classic neutral pathway in hepatocytes, initiated by the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1), which hydroxylates cholesterol at the 7α position to form 7α-hydroxycholesterol. Subsequent enzymatic steps convert this intermediate into CA and CDCA, which are then conjugated with glycine or taurine at the carboxyl group to enhance solubility and reduce toxicity, forming bile salts that are actively secreted into bile canaliculi. In the intestine, these conjugated bile acids facilitate micelle formation to promote lipid emulsification. Reabsorption occurs predominantly in the ileum via the apical sodium-dependent bile acid transporter (ASBT), which actively transports them into enterocytes against a concentration gradient. From there, bile acids enter the portal circulation and are taken up by hepatocytes primarily through the sodium-taurocholate cotransporting polypeptide (NTCP) for conjugated species and organic anion-transporting polypeptides (OATPs) for unconjugated ones, completing the enterohepatic loop.^[14]^[15]^[16] The bile acid pool's size and composition are tightly regulated, with feedback mechanisms preventing overaccumulation. Activation of the farnesoid X receptor (FXR) by bile acids in the ileum and liver induces expression of fibroblast growth factor 19 (FGF19 in humans), which suppresses hepatic CYP7A1 transcription, thereby inhibiting de novo synthesis and maintaining pool stability. This FXR-mediated repression is essential for adapting to dietary lipid intake and conserving energy.^[15]^[17]

Bilirubin

Bilirubin, a yellow pigment derived from the catabolism of heme, primarily originates from the breakdown of hemoglobin in senescent red blood cells, accounting for approximately 80% of total production, with the remaining 20% coming from other heme-containing proteins such as myoglobin and cytochromes.^[18] This process occurs mainly in the reticuloendothelial system, including the spleen, liver, and bone marrow, where heme oxygenase converts heme to biliverdin, which is then reduced to unconjugated (indirect) bilirubin by biliverdin reductase.^[18] Unconjugated bilirubin is lipid-soluble and tightly bound to albumin in plasma for transport to the liver, where it undergoes conjugation to become water-soluble for excretion. In the hepatocytes, unconjugated bilirubin is conjugated with glucuronic acid by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), forming predominantly bilirubin diglucuronide (with a mono- to di-glucuronide ratio of about 1:4), referred to as conjugated (direct) bilirubin.^[18] This conjugated form is actively secreted into bile via the multidrug resistance-associated protein 2 (MRP2) transporter at the canalicular membrane and delivered to the intestine through the biliary system.^[19] In the distal ileum and colon, gut bacteria produce β-glucuronidase, which deconjugates bilirubin back to its unconjugated form; this is further reduced to colorless urobilinogen by anaerobic bacteria.^[18] A portion of urobilinogen undergoes enterohepatic recirculation, with 10-20% reabsorbed into the portal circulation, returned to the liver for reconjugation and re-excretion, which helps maintain bilirubin homeostasis and prevents unconjugated hyperbilirubinemia.^[18] The remainder—about 80-90%—is either oxidized to urobilin in the gut and excreted in feces (imparting the typical brown color) or reabsorbed but directed to the kidneys for urinary elimination as urobilin.^[19] Bilirubin shares hepatic uptake transporters, such as organic anion-transporting polypeptides (OATPs), with bile acids, facilitating coordinated handling in the enterohepatic circulation.^[18] Normal serum total bilirubin levels range from 0.3 to 1.2 mg/dL, with unconjugated bilirubin comprising the majority (typically 0.2-0.8 mg/dL) and conjugated levels below 0.3 mg/dL; elevations in either fraction can signal disruptions in production, conjugation, or excretion, though detailed clinical implications are addressed elsewhere.^[18]

Drugs and Xenobiotics

Drugs and other exogenous compounds, known as xenobiotics, can participate in enterohepatic circulation through uptake by hepatocytes, secretion into bile via canalicular transporters, and subsequent reabsorption from the intestinal lumen back into the portal circulation. This process often involves hepatic conjugation followed by intestinal deconjugation, allowing for repeated cycling that extends the systemic exposure and prolongs the elimination half-life of these substances. For instance, morphine undergoes biliary excretion primarily as morphine-3-glucuronide, which is deconjugated by intestinal bacteria and reabsorbed, contributing to its prolonged presence in circulation. Similarly, rifampin is rapidly eliminated into bile after absorption and undergoes enterohepatic recirculation, with deacetylation in the intestine reducing reabsorption efficiency. Key transporters mediate the efflux of drugs and xenobiotics during this circulation. In the liver, multidrug resistance-associated protein 2 (MRP2, also known as ABCC2) plays a central role in biliary efflux by transporting conjugated and unconjugated substrates into the bile canaliculi. In the intestine, P-glycoprotein (P-gp, encoded by ABCB1) facilitates efflux from enterocytes back into the lumen, potentially limiting reabsorption but also contributing to overall recirculation dynamics for certain compounds. Representative examples of drugs that utilize enterohepatic circulation include antibiotics such as erythromycin, which exhibits significant biliary secretion and intestinal reabsorption, leading to accumulation upon repeated dosing. Statins, like pitavastatin, also undergo this process, with hepatic uptake, biliary excretion, and partial reabsorption enhancing their hepatic targeting while minimizing systemic exposure. Hormones, including steroid hormones and thyroid hormones, similarly experience recycling through biliary elimination and intestinal uptake, which helps maintain their physiological levels. Environmental xenobiotics, such as polychlorinated biphenyls (PCBs), can accumulate via enterohepatic circulation due to their lipophilicity and resistance to metabolism, involving hepatic uptake, biliary secretion, and repeated intestinal reabsorption that leads to prolonged tissue retention. This cycling, exemplified by PCB126, can result in sustained exposure even from non-oral routes, exacerbating bioaccumulation in organs like the liver and adipose tissue.

Functions and Regulation

Roles in Digestion and Homeostasis

Enterohepatic circulation plays a pivotal role in digestion by facilitating the emulsification of dietary fats through bile acids, which form mixed micelles essential for the solubilization, digestion, and absorption of lipids in the small intestine.^[11] These micelles also enhance the uptake of fat-soluble vitamins such as A, D, E, and K, ensuring their efficient delivery to the bloodstream for systemic utilization.^[11] Additionally, bilirubin, recycled via this pathway, contributes to the intestinal antioxidant environment by exerting cytoprotective effects that complement other defenses like glutathione, thereby mitigating oxidative stress in the gut lumen.^[19] In terms of homeostasis, enterohepatic circulation maintains a stable bile acid pool of approximately 2-4 grams in humans, enabling consistent bile flow to support ongoing digestive demands without excessive hepatic production.^[8] This recycling process regulates cholesterol homeostasis by balancing hepatic synthesis with fecal losses, as bile acids derived from cholesterol catabolism promote its excretion and prevent accumulation.^[20] The high efficiency of reabsorption—exceeding 95% daily—conserves the bile acid pool, minimizing the liver's synthetic workload and optimizing energy allocation across fed and fasting states.^[6] The gut microbiome integrates deeply with enterohepatic circulation through bacterial modifications of bile acids and bilirubin, which alter their chemical properties and influence reabsorption rates, signaling capabilities, and overall metabolic flux.^[21] For instance, microbial deconjugation and transformation of primary bile acids into secondary forms modulate their solubility and receptor interactions, fine-tuning host lipid metabolism and nutrient handling.^[22] Similarly, gut bacteria reduce bilirubin to urobilinogen, affecting its enterohepatic cycling and antioxidant contributions in the intestinal milieu.^[19] This bidirectional interplay ensures adaptive homeostasis, with microbial activity shaping the bile acid pool's composition to align with dietary and physiological needs.^[23]

Regulatory Mechanisms

The enterohepatic circulation is tightly regulated by molecular signaling pathways that respond to bile acid levels to maintain homeostasis. In the ileum, bile acids activate the farnesoid X receptor (FXR), a nuclear receptor that induces the expression and release of fibroblast growth factor 19 (FGF19) from enterocytes into the portal circulation.^[24] This hormone then travels to the liver, where it binds to the FGFR4 receptor on hepatocytes, leading to the inhibition of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.^[25] This FXR-FGF19 axis serves as a key enterohepatic signal to coordinate intestinal bile acid sensing with hepatic production.^[26] Hormonal controls further modulate the physical aspects of enterohepatic circulation, particularly bile storage and flow. Cholecystokinin (CCK), secreted by I cells in the duodenum in response to dietary fats and proteins, binds to CCK receptors on gallbladder smooth muscle, triggering contraction and the release of stored bile into the duodenum to facilitate nutrient absorption.^[27] Complementing this, secretin, released from S cells in the duodenal mucosa upon acidification, stimulates bicarbonate secretion from biliary and pancreatic ductular cells, thereby increasing the volume and alkalinity of bile flow to optimize its composition during circulation.^[28] These hormones ensure synchronized bile delivery timed to digestive needs.^[5] Regulation of bile acid transport proteins occurs primarily at the transcriptional level through nuclear receptor interactions. In the ileum, FXR activation induces the expression of small heterodimer partner (SHP), a corepressor that inhibits liver receptor homolog-1 (LRH-1)-mediated transcription of the apical sodium-dependent bile acid transporter (ASBT/SLC10A2), thereby fine-tuning ileal reabsorption efficiency.^[29] Similarly, in hepatocytes, the FXR-SHP pathway represses LRH-1-driven expression of the Na+/taurocholate cotransporting polypeptide (NTCP/SLC10A1), controlling sinusoidal uptake and preventing intracellular bile acid overload.^[30] These mechanisms allow dynamic adjustment of transport capacity in response to circulating bile acid concentrations.^[31] Central to these regulations are negative feedback loops that limit bile acid synthesis and accumulation to avert hepatotoxicity. The FXR-FGF19 signaling pathway exemplifies this by suppressing CYP7A1 activity when ileal bile acid levels rise, reducing de novo production and sustaining the bile acid pool through efficient recycling rather than over-synthesis.^[32] Additional loops involve SHP-mediated repression of biosynthetic genes, ensuring that enterohepatic recirculation maintains pool size without excessive hepatic burden.^[26] This integrated feedback preserves bile acid homeostasis across the gut-liver axis.^[29]

Clinical and Pharmacological Aspects

Associated Disorders

Cholestasis represents a key pathological disruption of enterohepatic circulation, characterized by impaired bile flow from the liver to the small intestine, resulting in the accumulation of bile acids within hepatocytes and systemic circulation. This backlog triggers inflammatory responses in the liver and contributes to symptoms such as intense pruritus, often localized to the palms and soles, due to the detergent-like effects of accumulated bile salts on skin nerve endings. In primary biliary cholangitis (PBC), an autoimmune disorder primarily affecting middle-aged women, progressive damage to intrahepatic bile ducts leads to early disturbances in bile secretion and enterohepatic bile salt recirculation, causing duodenal bile acid deficiency, fat malabsorption, and steatorrhea alongside elevated serum cholesterol as a compensatory mechanism.^[33]^[34] Gallstone formation, or cholelithiasis, arises from imbalances in enterohepatic circulation that alter bile composition, promoting supersaturation of cholesterol or bilirubin. Disruptions in bile acid transporters, such as reduced reabsorption efficiency in the ileum, diminish the bile acid pool, impairing cholesterol solubilization and leading to cholesterol gallstones, while excessive bilirubin from hemolytic conditions or pigment overload can form pigment stones. Bacterial deconjugation of bile acids in the gut further exacerbates these imbalances by altering the pool's hydrophobicity and promoting precipitation in the gallbladder.^[35] Short bowel syndrome, often resulting from extensive ileal resection, severely impairs enterohepatic circulation by eliminating the primary site of bile acid reabsorption, leading to bile acid malabsorption. In cases with resection of less than 100 cm of terminal ileum, excess bile acids spill into the colon, stimulating water and electrolyte secretion and causing choleretic diarrhea with urgency and incontinence. More extensive resections deplete the bile acid pool, reducing hepatic secretion and causing steatorrhea due to inadequate fat emulsification, compounded by malabsorption of fat-soluble vitamins.^[36] Genetic defects in key components of enterohepatic circulation can manifest as rare inborn errors, such as mutations in the apical sodium-dependent bile acid transporter gene (SLC10A2, encoding ASBT), which cause primary bile acid malabsorption. This autosomal recessive condition disrupts ileal reuptake, resulting in a contracted bile acid pool, chronic watery diarrhea from infancy, and steatorrhea, though serum bile acid levels remain typically normal due to compensatory hepatic overproduction. Similarly, mutations in the farnesoid X receptor gene (NR1H4, encoding FXR) lead to progressive familial intrahepatic cholestasis type 5, impairing bile acid homeostasis and transport regulation, causing severe cholestasis, pruritus, and markedly elevated serum bile acids (hypercholanemia) with progression to liver failure in childhood.^[37]^[38] Diagnosis of disorders disrupting enterohepatic circulation relies on targeted tests to assess bile acid dynamics and malabsorption. Elevated fasting serum total bile acids (>10 μmol/L) indicate cholestasis or hypercholanemia, confirming hepatic retention or synthetic dysregulation, while normal levels with symptoms suggest malabsorptive issues. Fecal fat analysis, measuring >7 g/24 hours on a 100 g fat diet, detects steatorrhea from bile acid deficiency, and direct quantification of total fecal bile acids exceeding 2337 μmol over 48 hours, or a proportion of primary bile acids (cholic acid + chenodeoxycholic acid) greater than 4% of total fecal bile acids, via 48-hour collection while on a 100 g fat diet confirms malabsorption in conditions like short bowel syndrome.^[39]^[40]^[41] Disruptions in circulation may also contribute to unconjugated hyperbilirubinemia and jaundice in severe cases.

Impact on Drug Therapy

Enterohepatic circulation significantly influences drug pharmacokinetics by recycling substances between the liver and intestine, thereby extending the systemic exposure and half-life of certain medications. This process involves biliary excretion followed by intestinal reabsorption, which can lead to multiple plasma concentration peaks and prolonged pharmacological effects, particularly for drugs that undergo conjugation and deconjugation cycles. In clinical practice, this prolongation necessitates careful dose adjustments, especially in patients with renal impairment, where enterohepatic circulation serves as a complementary non-renal elimination pathway, potentially amplifying drug accumulation if renal clearance is compromised. For instance, drugs like rifampicin, which rely on this route, may exhibit altered disposition in such conditions, requiring monitoring to avoid toxicity.^[42]^[4] Drug interactions mediated by enterohepatic circulation are a critical consideration in therapy, as agents that interrupt this cycle can substantially reduce drug reabsorption and efficacy. Bile acid sequestrants such as cholestyramine bind to bile acids and certain drugs in the intestinal lumen, preventing their reuptake and accelerating fecal excretion. This interaction is particularly relevant for cardiac glycosides; for example, cholestyramine interrupts the enterohepatic recycling of digitoxin, reducing its plasma levels and tissue accumulation, which has been shown to protect against lethal intoxication in animal models by increasing survival rates from 0% to 70% in pretreated rats. Similar effects occur with digoxin, where coadministration lowers bioavailability, often requiring dose increases or timing separations (e.g., administering other drugs 1 hour before or 4 hours after cholestyramine) to maintain therapeutic levels. These interactions underscore the need for vigilance in polypharmacy, especially for drugs with low therapeutic indices.^[43]^[44] Therapeutic strategies increasingly target enterohepatic circulation to modulate bile acid dynamics and improve outcomes in specific disorders. Inhibitors of the apical sodium-dependent bile acid transporter (ASBT), such as elobixibat, disrupt bile acid reabsorption in the ileum, interrupting the cycle and increasing colonic bile acid levels to stimulate motility; clinical trials in chronic idiopathic constipation demonstrate increased bowel movements (from 2.9 to 5.3 per week) and improved stool consistency without significant adverse effects. Conversely, farnesoid X receptor (FXR) agonists, such as obeticholic acid (withdrawn from the US market in September 2025 due to safety concerns and unmet confirmatory endpoints), enhance bile acid homeostasis by activating FXR in hepatocytes and enterocytes, suppressing synthesis and promoting excretion; in the POISE trial (2015), obeticholic acid reduced alkaline phosphatase levels by approximately 20-25% versus ~3% with placebo in primary biliary cholangitis (PBC) patients unresponsive to ursodeoxycholic acid. However, obeticholic acid was voluntarily withdrawn from the US market in September 2025, with a clinical hold placed on ongoing trials, though it remains available in other regions such as the EU. These targeted interventions highlight the potential to harness enterohepatic regulation for both gastrointestinal and hepatobiliary therapies.^[45]^[46]^[47] In cholestatic patients, impaired enterohepatic circulation alters the disposition of drugs like oral contraceptives and antibiotics, complicating management. Estrogens in oral contraceptives undergo significant enterohepatic recycling, but in cholestasis—particularly in genetically susceptible individuals with MDR3 dysfunction—administration can exacerbate intrahepatic bile flow obstruction, leading to severe cholestasis as seen in cases of progressive familial intrahepatic cholestasis type 3 unmasked by pill use. Similarly, antibiotics such as rifampicin, which depend on biliary excretion and reabsorption, exhibit prolonged half-lives and elevated plasma concentrations in cholestasis due to reduced clearance, increasing toxicity risk and necessitating dose reductions; rifampicin's role in treating pruritus in chronic cholestasis further illustrates this bidirectional impact, where therapeutic benefits must balance pharmacokinetic changes. These examples emphasize personalized dosing in liver disease to mitigate adverse outcomes.^[48]^[49]^[50]

Modeling and Advances

Pharmacokinetic Models

Pharmacokinetic models of enterohepatic circulation (EHC) are essential for simulating the recycling of drugs, bile acids, and other compounds between the liver and intestine, enabling predictions of systemic exposure and duration of action. Basic model types include compartmental models, which simplify the system into interconnected liver-intestine loops with parameters for biliary excretion, intestinal reabsorption, and transit delays, and physiologically based pharmacokinetic (PBPK) models, which incorporate anatomical and physiological details such as organ volumes, blood flows, and transporter kinetics for more mechanistic simulations across species. Compartmental models, often implemented in population pharmacokinetic analyses, treat EHC as a feedback loop with discrete compartments for plasma, bile, and gut, facilitating parameter estimation from plasma concentration-time data. In contrast, PBPK models integrate EHC within a full-body framework, accounting for species-specific differences in biliary secretion and gut motility, as demonstrated in simulations for mycophenolic acid across rats, dogs, and humans. These approaches build on the bile acid circuit, where up to 95% of bile acids are recycled per cycle, providing a foundational template for drug modeling.^[4] Key equations in these models quantify the extent and timing of recycling. The extent of EHC can be estimated as f_{eh} = 1 - \frac{AUC_{non-entero}}{AUC_{entero}}, where AUC_{entero} is the area under the plasma concentration-time curve with EHC and AUC_{non-entero} without it (e.g., in bile-cannulated models), providing a measure of the contribution of recirculation to overall exposure. For temporal dynamics, differential equations incorporate an enterohepatic delay, such as \frac{dC}{dt} = -k_e C + k_r C(t - \tau), where C is plasma concentration, k_e is the elimination rate constant, k_r is the reabsorption rate constant, and \tau represents the transit time through the biliary and intestinal pathways (typically 1-6 hours in humans). This time-lag formulation captures plasma rebounds and non-exponential decay, as validated in simulations for drugs like digitoxin.^[51] Applications of these models focus on predicting pharmacokinetic alterations due to EHC, particularly the prolongation of the area under the curve (AUC), which can increase drug exposure by 20-100% depending on the recycling efficiency and dosing regimen. For instance, models simulate how EHC extends the half-life of compounds like indomethacin, aiding dose optimization in clinical settings. Commercial software such as GastroPlus and Simcyp implements these frameworks, with GastroPlus using a gallbladder compartment for bile storage and release timed to meals, and Simcyp enabling population-based simulations that account for variability in transporter expression to forecast drug interactions. Despite their utility, these models have limitations, including assumptions of constant reabsorption fractions that overlook diurnal variations in bile flow or meal effects, potentially overestimating steady-state exposure. Additionally, most ignore inter-individual variability from the gut microbiome, which modulates deconjugation and reabsorption of conjugates, leading to up to 50% differences in EHC extent for drugs like mycophenolate as observed in transplant patients.

Recent Research Developments

Recent studies have elucidated the critical role of the gut microbiome in enterohepatic circulation through bile acid deconjugation, particularly influencing secondary bile acid production and its implications for inflammatory bowel disease (IBD). Gut bacteria, including species like Clostridium scindens, perform 7α-dehydroxylation to convert primary bile acids into secondary forms such as deoxycholic acid, which modulate immune responses and intestinal barrier integrity.^[52] In IBD patients, depletion of key deconjugating bacteria disrupts this process, leading to altered bile acid signaling that exacerbates inflammation, as observed in 2024 metagenomic analyses showing Clostridium scindens prevalence variations correlating with disease severity.^[53] A 2025 study further demonstrated that Clostridium scindens-derived secondary bile acids promote mucosal healing in colitis models by restoring bile acid homeostasis via enterohepatic recirculation.^[52] These findings highlight microbiome-targeted interventions, such as fecal microbiota transplantation, as potential therapies to normalize deconjugation and secondary bile acid profiles in IBD.^[54] Advancements in therapeutics have focused on modulating enterohepatic circulation to treat metabolic disorders. Farnesoid X receptor (FXR) agonists, key regulators of bile acid synthesis and transport, have shown promise in non-alcoholic steatohepatitis (NASH). Cilofexor, an intestinally biased FXR modulator, demonstrated improved liver histology and reduced fibrosis in phase II trials, with ongoing 2025 studies combining it with semaglutide to enhance bile acid-mediated lipid metabolism.^[55] These trials reported significant decreases in alanine aminotransferase levels and hepatic fat content, underscoring FXR's role in enterohepatic feedback to mitigate NASH progression.^[56] Apical sodium-dependent bile acid transporter (ASBT) inhibitors, which interrupt ileal reabsorption to increase fecal bile acid excretion, continue to be explored for hypercholesterolemia, though recent developments emphasize their application in hereditary cholestatic conditions such as progressive familial intrahepatic cholestasis (PFIC), where phase III trials have shown efficacy and cholesterol-lowering side effects.^[57]^[58] Technological innovations in imaging have enabled real-time visualization of enterohepatic dynamics. In 2024, positron emission tomography/computed tomography (PET/CT) using the bile acid analog tracer ^{11}C-CSAR provided quantitative assessment of bile acid transport in healthy volunteers, revealing uptake patterns that mirror endogenous enterohepatic circulation without disrupting physiology.^[59] This micro-dose approach allows for non-invasive measurement of hepatic extraction and biliary excretion rates, offering superior resolution over traditional methods for evaluating transport kinetics in liver diseases.^[59] Emerging research addresses environmental and cellular factors influencing circulation efficiency. High-fat diets have been shown to reduce circulating bile acid pools by impairing microbiome-mediated deconjugation and reabsorption, leading to dysregulated enterohepatic flux and increased hepatic steatosis in 2024 murine models.^[60] Single-cell RNA sequencing in 2025 publications has uncovered hepatocyte heterogeneity in bile acid transport expression, with zonal variations in transporters like NTCP and BSEP contributing to differential responses in fibrotic livers.^[61] These insights suggest dietary interventions and precision targeting of hepatocyte subpopulations could optimize circulation under modern lifestyle pressures.

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This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes.
[17]
Mechanism of Tissue-specific Farnesoid X Receptor in Suppressing ...
Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile-acid synthesis by reducing the expression levels of genes.
[18]
Physiology, Bilirubin - StatPearls - NCBI Bookshelf - NIH
Conjugation of bilirubin to the water-soluble form involves the disruption of the hydrogen bonds, an essential process for its elimination by the liver and ...
[19]
Bilirubin in the Liver to Gut Signaling Axis - PMC - PubMed Central
Enterohepatic circulation of bilirubin occurs exclusively from the bacterial de-conjugated form because conjugated bilirubin is bulky, highly polar, and soluble ...
[20]
Bile Acid and Cholesterol Metabolism in Atherosclerotic ...
Dec 30, 2020 · The liver plays a central role in maintaining whole body cholesterol homeostasis via catabolism of cholesterol to bile acids, as well as biliary cholesterol ...
[21]
Bile Acids and the Gut Microbiome - PMC - NIH
We examine the latest research on the emerging bile acid-gut microbiome axis and its role in health and disease.
[22]
Review: microbial transformations of human bile acids - Microbiome
Jun 14, 2021 · Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition ... This enterohepatic circulation is very efficient, ...
[23]
Review: Mechanisms of How the Intestinal Microbiota Alters ... - NIH
When the blood concentration of digitoxin reaches a toxic level, it would be advantageous to inhibit the enterohepatic circulation of digitoxin.
[24]
Bile Acids as Hormones: The FXR-FGF15/19 Pathway - PMC
Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF) 15/19, an atypical FGF that functions as a hormone.
[25]
Bile acids activate fibroblast growth factor 19 signaling in human ...
These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism.
[26]
Discovery of farnesoid X receptor and its role in bile acid metabolism
FXR signaling was proposed as a mechanism of feedback regulation of the rate-limiting enzyme for bile acid synthesis, cholesterol 7α-hydroxylase (CYP7A1). The ...2. Nuclear Receptor Gene... · 4. Bile Acid Synthesis In... · 16. Bile Acids And Fxr-Based...
[27]
Physiology, Biliary - StatPearls - NCBI Bookshelf
Mechanism. The process of bile secretion is driven by 2 hormones, cholecystokinin (CCK) and secretin. CCK is secreted by the I cells of the small intestine ...
[28]
Physiology, Bile Secretion - PubMed
The hormone secretin also plays an important role in bile flow into the small intestine. By stimulating biliary and pancreatic ductular cells to secrete ...
[29]
FXR signaling in the enterohepatic system - PMC - PubMed Central
Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption ...Introduction · Role Of Fxr In Cancer And... · Abbreviations
[30]
FXR and PXR: Potential therapeutic targets in cholestasis - PMC - NIH
The FXR-SHP axis also negatively regulates bile acid uptake systems in the gut and liver, including the reabsorption of bile acids in the ileal enterocytes by ...Fxr And Pxr: Potential... · 2. Fxr (farnesoid X... · 4. Pxr (pregnane X Receptor)
[31]
Transcriptional integration of metabolism by the nuclear sterol ...
A regulatory cascade of the nuclear receptors, FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell. 2000;6:517–526. doi: 10.1016/s1097-2765(00) ...
[32]
Bile acids: regulation of synthesis - PubMed - NIH
The enterohepatic circulation of bile acids exerts important ... However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown.
[33]
Features of Lipid Metabolism Disorders in Primary Biliary Cholangitis
Nov 25, 2022 · A progressive disorder in the processes of bile secretion and enterohepatic bile salts circulation in patients with PBC already in its early ...
[34]
Cholestasis-Associated Pruritus and Its Pruritogens - Frontiers
Pruritus is often one of the first symptoms of cholestatic liver disease, while bile salts levels are still relatively low (52, 53). During late stages of the ...
[35]
The mechanism of enterohepatic circulation in the ... - PubMed
In conclusion, disturbances of enterohepatic circulation may account for pathogenesis of gallstones diseases, including BAs transporters and their regulatory ...
[36]
Bile Acid Malabsorption Caused by Ileal Resection - JAMA Network
The increased passage of bile acids into the colon causes diarrhea. In patients with large resections, bile acid malabsorption is severe, and increase in bile ...
[37]
Primary bile acid malabsorption caused by mutations in the ileal ...
These findings establish that SLC10A2 mutations can cause PBAM and underscore the ileal Na+/bile acid cotransporter's role in intestinal reclamation of bile ...Missing: hypercholanemia | Show results with:hypercholanemia
[38]
Mutations in the nuclear bile acid receptor FXR cause progressive ...
Feb 18, 2016 · Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases.
[39]
Cholestasis Workup: Laboratory Studies, Imaging Studies, Procedures
Aug 5, 2024 · Qualitative serum and urine bile acids by mass spectroscopy are used to identify genetically determined errors in bile acid synthesis. The total ...Laboratory Studies · Imaging Studies
[40]
Identifying diarrhea caused by bile acid malabsorption - Mayo Clinic
Feb 20, 2018 · The first test option is the fecal bile acid excretion test. It quantifies individual and total bile acids in a 48-hour stool collection. Leslie ...
[41]
Drug enterohepatic circulation and disposition - ScienceDirect.com
Enterohepatic circulation (EHC) prolongs the half-life of a drug in blood. EHC represents a complementary nonrenal route to excrete unwanted substances.
[42]
Interruption of the enterohepatic circulation of digitoxin by ...
Cholestyramine was found to bind substantial quantities of digitoxin-3H and digoxin-3H in vitro and this binding was only modestly inhibited by the presence of ...
[43]
Cholestyramine Resin - StatPearls - NCBI Bookshelf - NIH
Apr 26, 2025 · ... drug's long-term efficacy remains unclear. The inhibition of enterohepatic circulation by cholestyramine makes it an effective drug in the ...Continuing Education Activity · Indications · Administration · Adverse Effects
[44]
Safety and Efficacy of Elobixibat, an Ileal Bile Acid Transporter ...
Jul 30, 2022 · The results suggested that elobixibat was well-tolerated and efficacious in elderly patients with chronic constipation and can be administered before any meals.
[45]
Obeticholic Acid: A Farnesoid X Receptor Agonist for Primary Biliary ...
Conclusions: OCA is the first FXR agonist approved for the treatment of PBC. Ongoing research to evaluate clinical outcomes with OCA is currently underway.
[46]
Factors affecting the enterohepatic circulation of oral contraceptive ...
Oral contraceptive steroids may undergo enterohepatic circulation, but it is relevant for only estrogens, because these compounds can be directly conjugated ...
[47]
Progressive familial intrahepatic cholestasis type 3 revealed by oral ...
Second, women with intrahepatic cholestasis of pregnancy due to a mutation in ABCB4 have an increased risk of developing cholestasis under oral contraceptives, ...
[48]
Rifampin - StatPearls - NCBI Bookshelf - NIH
Nov 12, 2023 · Metabolism: Rifampin undergoes enterohepatic circulation. Furthermore, the drug acts as an inducer of enzymes, including CYP3A4, CYP2C9 ...
[49]
Bile acid 7α-dehydroxylating bacteria accelerate injury-induced ...
Mar 10, 2025 · Our study highlights Clostridium scindens as a promising biotherapeutic to restore bile acid homeostasis and promote mucosal healing following colon injury.Missing: deconjugation | Show results with:deconjugation
[50]
Depletion of key gut bacteria predicts disrupted bile acid metabolism ...
Dec 13, 2024 · The gut microbiome plays a key role in bile acid (BA) metabolism, where a diversity of metabolic products contribute to human health and disease ...
[51]
Novel approaches in IBD therapy: targeting the gut microbiota-bile ...
May 20, 2024 · Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship.
[52]
Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in ...
Jan 8, 2025 · The goals of this clinical study are to learn more about the study drugs, semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/ ...
[53]
Farnesoid X Receptor (FXR) Agonists and Protein Kinase ... - MDPI
Summary of key clinical trials on FXR agonists in NAFLD/NASH. Cilofexor. Another FXR agonist, cilofexor, was evaluated in a phase II, randomized, controlled ...
[54]
New treatment options for hereditary cholestasis syndromes - EASL
Discussions will cover: Clinical presentation of PFIC; Current therapeutic options; The introduction of IBAT/ASBT inhibitors and their impact; Clinical trials ...
[55]
NCT06610695 | PET/CT Scans Using the Tracer 11C-Csar, a Bile ...
Sep 24, 2024 · Methods 11C-CSAR PET/CT 11C-CSAR is injected intravenously in micro-doses and enters the enterohepatic circulation of endogenous bile acids [3], ...Missing: SPECT | Show results with:SPECT
[56]
High-Fat Diet-Induced Decreased Circulating Bile Acids Contribute ...
Feb 25, 2024 · This study revealed a significant effect of long-term HFD feeding on the decreased circulating BA pool in mice, which impaired lipid homeostasis and gut ...
[57]
Spatial transcriptomics of healthy and fibrotic human liver at single ...
Jan 2, 2025 · Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, ...Missing: enterohepatic circulation