Intestinal Lacteals Research Articles

Deletion of RAMP1 Signaling Enhances Diet-induced Obesity and Fat Absorption via Intestinal Lacteals in Mice.

Intestinal lymphatic vessels (lacteals) play a critical role in the absorption and transport of dietary lipids into the circulation. Calcitonin gene-related peptide and receptor activity-modifying protein 1 (RAMP1) are involved in lymphatic vessel growth. This study aimed to examine the role of RAMP1 signaling in lacteal morphology and function in response to a high-fat diet (HFD). RAMP1 deficient (RAMP1-/-) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 8 weeks. RAMP1-/- mice fed a HFD had increased body weights compared to WT mice fed a HFD, which was associated with high levels of total cholesterol, triglycerides, and glucose. HFD-fed RAMP1-/- mice had shorter and wider lacteals than HFD-fed WT mice. HFD-fed RAMP1-/- mice had lower levels of lymphatic endothelial cell gene markers including vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vascular growth factor VEGF-C than HFD-fed WT mice. The concentration of an absorbed lipid tracer in HFD-fed RAMP1-/- mice was higher than that in HFD-fed WT mice. The zipper-like continuous junctions were predominant in HFD-fed WT mice, while the button-like discontinuous junctions were predominant in HFD-fed RAMP1-/- mice. Deletion of RAMP1 signaling suppressed lacteal growth and VEGF-C/VEGFR3 expression but accelerated the uptake and transport of dietary fats through discontinuous junctions of lacteals, leading to excessive obesity. Specific activation of RAMP1 signaling may represent a target for the therapeutic management of diet-induced obesity.

Deletion of RAMP1 signaling enhances diet-induced obesity and fat absorption via intestinal lacteals in mice

Deletion of RAMP1 signaling enhances diet-induced obesity and fat absorption via intestinal lacteals in mice

The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.

SUMMARYIntestinal lacteals are essential lymphatic channels for absorption and transport of dietary lipids and drive the pathogenesis of debilitating metabolic diseases. However, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover an intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer ASE alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic system-dependent lipid transport. Surprisingly, activation of lymphatic system-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. Our study reveals the molecular mechanism linking gut lymphatic function to the earliest symmetry-breaking Pitx2 and highlights the important relationship between intestinal lymphangiogenesis and the gut-liver axis.

Biological functions of lymphatic vessels.

The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized. However, accumulating evidence indicates that lymphatic vessels play active and versatile roles in a tissue- and organ-specific manner during homeostasis and in multiple disease processes. This Review discusses recent advances to understand previously unidentified functions of adult mammalian lymphatic vessels, including immunosurveillance and immunomodulation upon pathogen invasion, transport of dietary fat, drainage of cerebrospinal fluid and aqueous humor, possible contributions toward neurodegenerative and neuroinflammatory diseases, and response to anticancer therapies.

A highly potent lymphatic system‐targeting nanoparticle‐cyclosporine with efficacy in a lupus mouse model

A highly potent lymphatic system‐targeting nanoparticle‐cyclosporine with efficacy in a lupus mouse model

The Role of Interstitial Matrix and the Lymphatic System in Gastrointestinal Lipid and Lipoprotein Metabolism.

This review emphasizes the events that take place after the chylomicrons are secreted by the enterocytes through exocytosis. First, we will discuss the journey of how chylomicrons cross the basement membrane to enter the lamina propria. Then the chylomicrons have to travel across the lamina propria before they can enter the lacteals. To understand the factors affecting the trafficking of chylomicron particles across the lamina propria, it is important to understand the composition and properties of the lamina propria. With different degree of hydration, the pores of the lamina propria (sponge) changes. The greater the hydration, the greater the pore size and thus the easier the diffusion of the chylomicron particles across the lamina propria to enter the lacteals. The mechanism of the entry of lacteals is discussed in considerable details. We and others have demonstrated that intestinal fat absorption, but not the absorption of protein or carbohydrates, activates the intestinal mucosal mast cells to release many products including mucosal mast cell protease II in the rat. The activation of intestinal mucosal mast cells by fat absorption involves the process of chylomicron formation since the absorption of both medium and short-chain fatty acids do not activate the mast cells. Fat absorption has been associated with increased intestinal permeability. We hypothesize that there is a link between fat absorption, activation of mucosal mast cells, and the leaky gut phenomenon (increased intestinal permeability). Microbiome may also be involved in this chain of events associated with fat absorption. This review is presented in sequence under the following headings: (1) Introduction; (2) Structure and properties of the gut epithelial basement membrane; (3) Composition and physical properties of the interstitial matrix of the lamina propria; (4) The movement of chylomicrons across the interstitial matrix of the lamina propria and importance of the hydration of the interstitial matrix of the lamina propria and the movement of chylomicrons; (5) Entry of the chylomicrons into the intestinal lacteals; (6) Activation of mucosal mast cells by fat absorption and the metabolic consequences; and (7) Link between chylomicron transport, mucosal mast cell activation, leaky gut, and the microbiome.

Chyluria: An Unending Illness- A Case Report

Chyluria is the passage of milky urine due to a lymphourinary fistula. It is secondary to lymphatic stasis caused by obstruction of the lymphatic flow. It is caused by the parasite Wuchereria bancrofti in more than 95% of cases in tropical countries. Chyluria occurs in 2% of filarial-infested patients. When an abnormal connection between intestinal lacteals and the urinary tract develops, chyluria appears. The diagnostic approach is aimed to define the site of lymphourinary fistula. It is a benign disease that can be controlled by medical treatment and dietary restrictions. A small number of patients require surgical intervention. The 45-year-old thin built woman was suffering from chyluria, flank pain in the abdomen, weakness and loss of weight for the last 10 years. The serum test for circulating adult filarial antigen was positive in moderately high titer. Antifilarial treatment was advised. The symptoms improved for three months and again relapsed.

A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions

SummaryLymphatic vessels (LVs) are important in the regulation of tissue fluid homeostasis and the pathogenesis of tumor progression. We investigated the innervation of LVs and the response to agonists and antagonists of the autonomic nervous system in vivo. While skin-draining collecting LVs express muscarinic, α1- and β2-adrenergic receptors on lymphatic endothelial cells and smooth muscle cells, intestinal lacteals express only β-adrenergic receptors and muscarinic receptors on their smooth muscle cells. Quantitative in vivo near-infrared imaging of the exposed flank-collecting LV revealed that muscarinic and α1-adrenergic agonists increased LV contractility, whereas activation of β2-adrenergic receptors inhibited contractility and initiated nitric oxide (NO)-dependent vasodilation. Tumor-draining LVs were expanded and showed a higher innervation density and contractility that was reduced by treatment with atropine, phentolamine, and, most potently, isoproterenol. These findings likely have clinical implications given the impact of lymphatic fluid drainage on intratumoral fluid pressure and thus drug delivery.

Chyluria in pregnancy: Etiology, diagnosis, and management perspective.

Chyluria is clinically described as passage of milky urine. Chyle is absorbed by intestinal lacteals and is composed of emulsified fats, few proteins, and fibrin in varying proportions. Parasitic chyluria is caused mainly by Wuchereria bancrofti infection. The incidence of chyluria in pregnancy is not uncommon in endemic regions. The literature pertaining tomedical management of chyluria in pregnancy is scant. The antifilarial drugs have potential teratogenic risk and are not recommended in pregnant patients. Hence, there is a management dilemma for managing patients with chyluria during pregnancy. In this review, we have tried to highlight the evidence-based diagnosis and management of chyluria in pregnancy.

Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds.

Endothelial cells line blood and lymphatic vessels and form intercellular junctions, which preserve vessel structure and integrity. The vascular endothelial cadherin, VE-cadherin, mediates endothelial adhesion and is indispensible for blood vessel development and permeability regulation. However, its requirement for lymphatic vessels has not been addressed. During development, VE-cadherin deletion in lymphatic endothelial cells resulted in abortive lymphangiogenesis, edema, and prenatal death. Unexpectedly, inducible postnatal or adult deletion elicited vessel bed-specific responses. Mature dermal lymph vessels resisted VE-cadherin loss and maintained button junctions, which was associated with an upregulation of junctional molecules. Very different, mesenteric lymphatic collectors deteriorated and formed a strongly hyperplastic layer of lymphatic endothelial cells on the mesothelium. This massive hyperproliferation may have been favored by high mesenteric VEGF-C expression and was associated with VEGFR-3 phosphorylation and upregulation of the transcriptional activator TAZ Finally, intestinal lacteals fragmented into cysts or became highly distended possibly as a consequence of the mesenteric defects. Taken together, we demonstrate here the importance of VE-cadherin for lymphatic vessel development and maintenance, which is however remarkably vessel bed-specific.

Chylous Ascites and Pleural Effusion Treated with Intravenous Octreotide

Chylous ascites is uncommon. A few case reports have been described in cirrhotic patients. It usually presents as refractory ascites and treatment options are limited. Use of octreotide in management of chylous ascites is limited to case reports and series.(2) We describe the case of a 59 year-old-female who presented with chylous ascites and was managed with octreotide with significant reduction in ascitic volume. A 59-year-old female with past medical history of alcoholic cirrhosis was admitted to the intensive care unit (ICU) with hypoxic respiratory failure. On examination, she had diminished breath sounds, abdominal ascites with shifting dullness. Her hypoxia was attributed to compressive atelectasis from hepatic hydrothorax and from hepato-pulmonary syndrome. She underwent diagnostic and therapeutic thoracentesis and paracentesis. Analysis of both ascitic and pleural fluid revealed presence of triglyceride containing fluid. Microbiological work up was negative. No malignant cells were identified. She was started on optimal diuretic therapy for portal hypertension. She received repeated paracentesis with removal of about 2-3 liters of fluid every 3-4 days. Because of rapid re-accumulation of ascitic fluid, a peritoneal drainage catheter was placed. She was started on treatment with octreotide at 100 micrograms three times a day for five days. Remarkable improvement in ascitic fluid production was seen. Over the five days of treatment, her ascitic fluid drainage reduced from 600 mL per day to 25 mL per day as shown in the figure (Figure 1). With this, her hypoxia improved significantly, patient was discharged. She underwent TIPSS (trans jugular intrahepatic portosystemic shunt) as outpatient and had improvement in her overall functional status. She is being evaluated for liver transplantation.2445 Figure 1. showing ascitic fluid volume by daySpontaneous chylothorax after liver cirrhosis is uncommon. Chylous ascites can occur as an initial presentation or during later stages of cirrhosis with complications from hepatocellular carcinoma, TIPSS or during procedures related to complications from cirrhosis [sclerotherapy related thoracic duct injury]. It has been attributed to portal hypertension leading to increased pressure in the small intestinal lacteals that can cause minute lymphatic rupture. Octreotide helps in improving portal hypertension and decreasing triglyceride level in ascitic fluid.

Tighter lymphatic junctions prevent obesity.

Zippering of cellular junctions in intestinal lacteals prevents fat uptake

Lymphangiectasies intestinales primitives (maladie de Waldmann)

Primary intestinal lymphangiectasia (PIL), Waldmann's disease, is a rare disorder of unknown etiology characterized by dilated intestinal lacteals leading to lymph leakage into the small-bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. The main symptom is bilateral lower limb edema. Edema may be moderate to severe including pleural effusion, pericarditis or ascites. Protein-losing enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance and diagnosis by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of biopsies. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Several B-cell lymphomas of the gastrointestinal tract or with extra-intestinal localizations were reported in PIL patients. A long-term strictly low-fat diet associated with medium-chain triglyceride and liposoluble vitamin supplementation is the cornerstone of PIL medical management. Octreotide, a somatostatin analog, have been proposed with an inconsistent efficacy in association with diet. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. A prolonged clinical and biological follow-up is recommended.

Chyluria: the state of the art.

Chyluria is the passage of chyle in the urine. The cause seems to be the rupture of retroperitoneal lymphatics into the pyelocaliceal system, giving urine a milky appearance. This communication is caused by the obstruction of lymphatic drainage proximal to intestinal lacteals, resulting in dilatation of distal lymphatics and the eventual rupture of lymphatic vessels into the urinary collecting system.This condition, if left untreated, leads to significant morbidity because of hematochyluria, recurrent renal colic, nutritional problems due to protein losses and immunosuppression resulting from lymphocyturia.In this review, we summarize the state of the art of this condition and the newest treatments available.

Intravital imaging of intestinal lacteals unveils lipid drainage through contractility.

Lacteals are lymphatic vessels located at the center of each intestinal villus and provide essential transport routes for lipids and other lipophilic molecules. However, it is unclear how absorbed molecules are transported through the lacteal. Here, we used reporter mice that express GFP under the control of the lymphatic-specific promoter Prox1 and a custom-built confocal microscope and performed intravital real-time visualization of the absorption and transport dynamics of fluorescence-tagged fatty acids (FAs) and various exogenous molecules in the intestinal villi in vivo. These analyses clearly revealed transepithelial absorption of these molecules via enterocytes, diffusive distribution over the lamina propria, and subsequent transport through lacteals. Moreover, we observed active contraction of lacteals, which seemed to be directly involved in dietary lipid drainage. Our analysis revealed that the smooth muscles that surround each lacteal are responsible for contractile dynamics and that lacteal contraction is ultimately controlled by the autonomic nervous system. These results indicate that the lacteal is a unique organ-specific lymphatic system and does not merely serve as a passive conduit but as an active pump that transports lipids. Collectively, using this efficient imaging method, we uncovered drainage of absorbed molecules in small intestinal villus lacteals and the involvement of lacteal contractibility.

Nutritional support in adults with chyle leaks

We provide a practical approach to the complex management problem of chyle leaks that occur after surgical procedures or trauma, or when they occur spontaneously in association with malignancies. The volume of chyle loss causes significant problems due to loss of fluid, electrolytes, proteins, and lymphocytes, causing deleterious effects on wound healing and immunity. Enteral feeding is not always possible as long chain fatty acids are absorbed through the intestinal lacteals, the original source of chyle. Regular diets increase the leak and delay healing. Nutritional support involves coordinated care between healthcare providers to provide a combination of various modalities, including nil by mouth, parenteral nutrition, enteral feeding with formula modifications, and oral diet.

PD37-02 PHASE 2 RESULTS OF NOVEL ORAL TESTOSTERONE REPLACEMENT THERAPY (TSX-002) IN SYMPTOMATIC HYPOGONAGAL MEN

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Medical and Non-Surgical Therapy I1 Apr 2015PD37-02 PHASE 2 RESULTS OF NOVEL ORAL TESTOSTERONE REPLACEMENT THERAPY (TSX-002) IN SYMPTOMATIC HYPOGONAGAL MEN Michael Oefelein, and Guru Betageri Michael OefeleinMichael Oefelein More articles by this author , and Guru BetageriGuru Betageri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2264AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Due to poor water solubility of testosterone and a high first pass metabolism, testosterone replacement therapy (TRT) has been provided via an inconvenient parenteral route (injections, topical patches or gels). TSX-002 is a novel, pro-liposomal oral formulation of un-modified testosterone, which when hydrated forms liposomes that are capable of being absorbed by the intestinal lacteals, thus, bypassing the portal vein and hepatic metabolism. Proof of concept has been established and Phase 2 twice daily dosing is the subject matter of this trial (NCT01717768). METHODS 17 symptomatic hypogonadal (T<300ng/dl) men were enrolled in an open-label twice daily dosing regimen of TSX-002 (120 mg) and dosed for 15 days. The primary end-point is the proportion of study subjects who maintain testosterone average concentrations (Cavg0-24) between 300 and 1050 ng/dl. Bio-analytical analysis was performed at Celerion (Lincoln, NE) using Liquid-liquid extraction with analysis/detection by LC-MS/MS. An intention to treat analysis was performed. RESULTS The average testosterone concentration (Cavg0-24) on Day 1 and 15 are (Cavg = 384.77 ng/dL) and(Cavg = 306.47 ng/dL), respectively. The DHT/testosterone ratio ranged from 0.1 to 0.25 over 24 hours, which is within the normal range of 0.05 to 0.33. No T-levels above 1500 ng/dL were observed. No Serious Adverse Events (SAE) were reported. No study subject withdrew for any drug-related reason. CONCLUSIONS 120 mg TSX-002 administered orally twice daily normalized testosterone levels, and maintained a normal DHT/T ratio in symptomatic hypogonadal men. No SAEs or supra-physiological T levels (T> 1500) were observed. The pro-liposomal formulation of unmodified T safely restores physiological levels of testosterone via twice daily oral administration. Mean pharmacokinetic parameters of serum total testosterone after 120 mg TSX-002 Day 1 Tmax Cmax Cavg24 Mean 12.8 hr 850.6 ng/dL 384.8 ng/dL Standard Deviation 9.1 hr 322.6 ng/dL 118.1 ng/dL Day 15 Mean 9.5 hr 710.6 ng/dL 306.5 ng/dL Standard Deviation 9.2 hr 321.4 ng/dL 90.8 ng/dL © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e770 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Oefelein More articles by this author Guru Betageri More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Effects of controlled ingestion of kaolinite (5%) on food intake, gut morphology and in vitro motility in rats

Geophagia is found in various animal species and in humans. We have previously shown that spontaneously ingested kaolinite interacts with the intestinal mucosa modifies nutrient absorption and slows down gastric emptying and intestinal transit in rats in vivo. However, the precise mechanisms involved are not elucidated. The aim of this work was to investigate the effects of controlled kaolinite ingestion on food intake, gut morphology and in vitro motility in rats. Male Wistar rats were fed with 5% kaolinite in standard food pellets during 7, 14 and 28 days. Body mass and food consumption were measured daily. Intestinal morphological and proteomic analyses were conducted. The length of mucosal lacteals was evaluated. Plasmatic levels of leptin and adiponectin were determined. Finally, organ bath studies were conducted to evaluate smooth muscle contractility. Food consumption was significantly increased during the first two weeks of kaolinite ingestion without any mass gain compared to controls. Kaolinite induced weak variations in proteins that are involved in various biological processes. Compared to control animals, the length of intestinal lacteals was significantly reduced in kaolinite group whatever the duration of the experiment. Leptin and adiponectin plasmatic levels were significantly increased after 14 days of kaolinite consumption. Changes in spontaneous motility and responses to electrical nerve stimulation of the jejunum and proximal colon were observed at day 14. Altogether, the present data give evidence for a modulation by kaolinite-controlled ingestion on satiety and anorexigenic signals as well as on intestinal and colonic motility.

Intestinal lymphangiectasia in adults

Intestinal lymphangiectasia in the adult may be characterized as a disorder with dilated intestinal lacteals causing loss of lymph into the lumen of the small intestine and resultant hypoproteinemia, hypogammaglobulinemia, hypoalbuminemia and reduced number of circulating lymphocytes or lymphopenia. Most often, intestinal lymphangiectasia has been recorded in children, often in neonates, usually with other congenital abnormalities but initial definition in adults including the elderly has become increasingly more common. Shared clinical features with the pediatric population such as bilateral lower limb edema, sometimes with lymphedema, pleural effusion and chylous ascites may occur but these reflect the severe end of the clinical spectrum. In some, diarrhea occurs with steatorrhea along with increased fecal loss of protein, reflected in increased fecal alpha-1-antitrypsin levels, while others may present with iron deficiency anemia, sometimes associated with occult small intestinal bleeding. Most lymphangiectasia in adults detected in recent years, however, appears to have few or no clinical features of malabsorption. Diagnosis remains dependent on endoscopic changes confirmed by small bowel biopsy showing histological evidence of intestinal lymphangiectasia. In some, video capsule endoscopy and enteroscopy have revealed more extensive changes along the length of the small intestine. A critical diagnostic element in adults with lymphangiectasia is the exclusion of entities (e.g. malignancies including lymphoma) that might lead to obstruction of the lymphatic system and "secondary" changes in the small bowel biopsy. In addition, occult infectious (e.g. Whipple's disease from Tropheryma whipplei) or inflammatory disorders (e.g. Crohn's disease) may also present with profound changes in intestinal permeability and protein-losing enteropathy that also require exclusion. Conversely, rare B-cell type lymphomas have also been described even decades following initial diagnosis of intestinal lymphangiectasia. Treatment has been historically defined to include a low fat diet with medium-chain triglyceride supplementation that leads to portal venous rather than lacteal uptake. A number of other pharmacological measures have been reported or proposed but these are largely anecdotal. Finally, rare reports of localized surgical resection of involved areas of small intestine have been described but follow-up in these cases is often limited.

Digital clubbing in primary intestinal lymphangiectasia: a case report

Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. The symptoms usually start in early infancy. We report a case of secondary hyperparathyroidism, osteopenia, monoclonal gammopathy and digital clubbing in a 57-year-old patient with a 12-year history of discontinuous diarrhea. Malabsorption with inability to gain weight, and finally weight loss and formation of leg edema were associated with protein-losing enteropathy. A low-fat diet associated with medium-chain triglyceride supplementation was clinically effective as medical management in reducing diarrhea and leg edema, and promoting weight gain. Double-balloon enteroscopy and small bowel biopsy histopathology confirmed dilated intestinal lacteals. Digital clubbing associated with primary intestinal lymphangiectasia which may causally be related to chronic platelet excess has not been reported before.