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Starch (Carbohydrate) Digestion and AbsorptionNutrient absorption in the enterocytes -
The food that remains undigested and unabsorbed passes into the large intestine. Absorption of the majority of nutrients takes place in the jejunum, with the following notable exceptions:. Section of duodenum : Section of duodenum with villi at the top layer. Search site Search Search.
Go back to previous article. Sign in. Learning Objectives Describe the role played by the small intestine in the absorption of nutrients.
Key Points Digested food is able to pass into the blood vessels in the wall of the small intestine through the process of diffusion. The inner wall, or mucosa, of the small intestine is covered in wrinkles or folds called plicae circulares that project microscopic finger-like pieces of tissue called villi, which in turn have finger-like projections known as microvilli.
Each villus transports nutrients to a network of capillaries and fine lymphatic vessels called lacteals close to its surface. Key Terms villi : Tiny, finger-like projections that protrude from the epithelial lining of the intestinal wall.
plicae circulares : These circular folds known as the valves of Kerckring or the valvulae conniventes are large, valvular flaps that project into the lumen of the bowel. diffusion : The act of diffusing or dispersing something, or the property of being diffused or dispersed; dispersion.
EXAMPLES Examples of nutrients absorbed by the small intestine include carbohydrates, lipids, proteins, iron, vitamins, and water. The Small Intestine The small intestine is the part of the gastrointestinal tract between the stomach and the large intestine where much of the digestion of food takes place.
Absorption of the majority of nutrients takes place in the jejunum, with the following notable exceptions: Iron is absorbed in the duodenum. Vitamin B12 and bile salts are absorbed in the terminal ileum. Water and lipids are absorbed by passive diffusion throughout the small intestine.
Two well-studied peptides governing ion and water homeostasis in the colon are vasoactive intestinal peptide VIP and peptide YY PYY. VIP, secreted from enteric neurons, signals via the G αs -coupled VIPR1 VPAC1 on epithelial cells to raise levels of intracellular cAMP.
In contrast, EEC-derived PYY acts in a paracrine fashion on colonocytes to lower cAMP via the epithelial G αi coupled receptor NPY1R 10 , 11 , 12 , Moreover, PYY has been reported to augment postprandial nutrient absorption in the small intestine We posited that the mechanism underlying malabsorptive diarrhea in patients lacking EECs might be due to loss of EEC-ENS regulatory feedback in the small intestine, thus disrupting electrogenic nutrient absorption.
Here, we find that PYY regulates normal ion transport and ion-coupled nutrient absorption in mouse and human small intestine, and that administration of exogenous PYY is sufficient to restore normal electrophysiology, nutrient absorption, and survival in EEC-deficient animals.
If EECs were required for regulating the normal electrophysiology of the small intestine, we would expect to see deranged ion transport in intestinal tissues lacking EECs. We generated EEC-deficient human small intestinal tissue by using PSC lines that had a null mutation in NEUROG3 17 , the basic helix-loop-helix transcription factor required for EEC formation in mice 18 and humans 2.
In the colon, ion and water transport is regulated by EEC-derived PYY and ENS-derived VIP. To formally test whether the PYY-VIP axis also operated in human and mouse small intestine, we performed experiments in EEC-deficient tissues without a functional ENS wherein we controlled PYY and VIP levels experimentally.
We first determined the effects of the PYY-VIP axis on small intestine by measuring CFTR-mediated ion and water efflux 20 following exposure of human HIO-derived enteroids to the potent secretagogue VIP Fig.
EEC-deficient enteroids swelled significantly more than wild-type, but blocking the PYY receptor NPY1R in wild-type enteroids mimicked the EEC-deficient response Fig.
Exogenous PYY blocked VIP-induced swelling in both wild-type and EEC-deficient enteroids in an NPY1R-dependent manner Fig. In this assay, we observed that EEC-deficient enteroids displayed impaired NHE3 function Fig.
There was no difference in expression of CFTR, SLC9A3 encoding NHE3 , VIPR1 or NPY1R between wild-type and EEC-deficient human small intestinal organoids or enteroids Fig.
Together, these data suggest that PYY plays an important role in the regulation of ion transport in the small intestine, and that the abnormal response to VIP in EEC-deficient enteroids can be normalized by the addition of exogenous PYY.
a PYY and VIP regulate ion and water transport in HIO-derived small intestinal enteroids. b EEC-deficient enteroids displayed impaired NHE3 activity. c The localization of VIPR1 and NPY1R was comparable between wild-type and EEC-deficient human intestinal epithelium.
Representative images from four independent organoids are shown. d PYY modulates the stimulatory effects of VIP in mouse and human small intestine.
Electrogenic responses to VIP were blocked by the CFTR inhibitor CFTR dotted lines. If PYY were required to regulate electrochemical transport in the small intestine, we would expect that disruption of PYY signaling in wild-type small intestinal tissue would cause abnormal basal short-circuit current I sc.
To investigate this, we isolated full thickness intestinal mucosa from in vivo matured HIOs and from the jejunum of wild-type mice and measured basal I sc in a modified Ussing chamber Chemical inhibition of NPY1R in wild-type mouse jejunum and HIOs was sufficient to elevate the basal I sc to EEC-deficient levels Supplementary Fig.
Conversely, treatment of EEC-deficient mouse and human tissues with exogenous PYY reduced the basal I sc to wild-type levels in an NPY1R-dependent manner Supplementary Fig. These data indicated that endogenous PYY signaling plays an essential role in maintaining normal electrophysiology in the small intestine.
We then investigated if PYY was required to modulate the stimulatory effects of VIP in mouse and human small intestine. We inhibited voltage-gated neuronal firing in mouse jejunum by including tetrodotoxin 10 in all experiments so that we could precisely monitor epithelial response to exogenous VIP.
Chemical inhibition of NPY1R in isolated wild-type tissues was sufficient to cause an elevated response to VIP Fig. This indicated that endogenous PYY signaling was required in the small intestine to modulate the stimulatory effects of VIP.
Consistent with this, EEC-deficient mouse and human small intestinal tissue similarly displayed an exaggerated I sc response to exogenous VIP compared to wild-type Fig. Addition of exogenous PYY to EEC-deficient small intestine was sufficient to restore the I sc to normal Fig.
These data suggested that PYY is required for maintaining a normal electrochemical response to VIP in the small intestine and that exogenous PYY can normalize this process in EEC-deficient small intestinal tissue.
Furthermore, these data suggest that imbalance of this axis may be a mechanism underlying electrolyte imbalance, diarrhea and poor nutrient absorption suffered by patients without EECs. While it is known that EECs sense nutrients, the mechanism linking sensing to the control of nutrient absorption is unclear.
A hint came from the effects of enteral feeding of EEC-deficient patients, which resulted in a massive diarrheal response. This suggests that an inability to sense luminal nutrients uncoupled the ability to adequately absorb them.
To explore this possibility, we evaluated ion-coupled nutrient absorption in EEC-deficient small intestine. We observed an accelerated initial response to luminal glucose in the presence of VIP in EEC-deficient mouse and human intestinal tissues in the Ussing chamber Fig.
This recapitulated the exacerbated diarrhea observed in patients without EECs when they were fed with carbohydrate 2. Exogenous PYY restored a normal glucose response in EEC-deficient mouse and human tissue, and inhibition of NPY1R in wild-type caused an exaggerated initial response to glucose Fig.
These data indicate that PYY is both necessary and sufficient to modulate glucose absorption in the small intestine. We found no defects in expression of SGLT1, GLUT2, Fig.
These data suggest that SGLT1 is competent to absorb glucose, but activity is dysregulated in the context of abnormal ion transport in the absence of EECs. a Schematic depicting how the PYY-VIP paracrine axis might regulate ion, water, and nutrient transport in the small intestine.
b In the absence of EECs, ion, water, and nutrient transport are dysregulated due to loss of one arm of the PYY-VIP axis. In EEC-deficient small intestine, loss of PYY results in increased chloride transport and increased water and sodium accumulation in the intestinal lumen.
Bar graphs represent the slope of the curve depicted within the boxed area. d The subcellular distribution of glucose transporters SGLT1 and GLUT2 is normal in human intestinal tissue lacking EECs. Representative images from eight independent organoids are shown.
Consistent with this, we observed a striking loss of ion-coupled dipeptide absorption when human and mouse EEC-deficient small intestine were challenged with VIP Fig. VIP has an established role in inhibition of NHE3 and PEPT1-mediated dipeptide absorption 7 , 23 , but we were surprised to find that EEC-deficient intestine remained unable to respond to dipeptide when PYY was provided Fig.
To explore this possibility, we treated enteroids with or without PYY for 1 week in vitro in the presence of VIP.
Wild-type enteroids were able to maintain their intracellular pH in the presence of VIP but EEC-deficient enteroids became significantly more acidic Fig.
However, EEC-deficient enteroids were restored to normal intracellular pH levels and normal SLC9A3 expression encoding NHE3 in the presence of PYY Fig. This suggested that long-term exposure to an imbalanced EEC-ENS axis dysregulates intestinal physiology, and that, over time, PYY may be sufficient to restore intracellular pH and dipeptide absorption in EEC-deficient small intestine.
b Expression and localization of peptide transporter PEPT1 is unchanged in EEC-deficient human small intestine. c The PYY-VIP axis regulates intracellular pH in human small intestinal cells. pHrodo MFI was analyzed by flow cytometry and normalized to vehicle-treated wild-type.
Statistics calculated by mixed effects analysis using the Holm—Sidak method. d Small intestinal EECs regulate proton transport in a paracrine fashion. Using reporter animals with mosaic loss of EECs we found that regions of jejunal epithelium that escaped recombination had normal pH as measured by pHrodo MFI.
We have demonstrated that inhibiting PYY signaling in isolated wild-type small intestinal tissues was sufficient to perturb normal electrophysiology in both human and mouse. This suggests that in vivo the mechanism of action of PYY could be paracrine rather than endocrine. PYY-expressing EECs are abundant in mouse and human small intestine 24 Supplementary Fig.
Moreover, PYY-expressing EECs extend long basal processes which underlie several neighboring epithelial cells 25 , 26 , raising the possibility that they may exert paracrine effects on whole populations of nearby enterocytes. We therefore investigated whether the effects of PYY on ion transport in the small intestine occurred via paracrine mechanisms.
To do this, we exploited the mosaicism of VillinCre mice to determine if regions of EEC-deficient epithelium had different transporter activities as compared to regions of epithelium that still had EECs. Our data suggested that treatment with PYY might restore normal carbohydrate and protein absorption in the intestines of EEC-deficient animals.
PYY can be converted to PYY 3—36 by the protease DPP4 27 , and this form of PYY has potent anorexic effects in the brain We therefore co-injected PYY 1—36 and a DPP4 inhibitor to prevent PYY cleavage and to better target the epithelial NPY1R receptor that preferentially binds the 1—36 form 10 , 12 , We simultaneously treated another group of mutant mice with vehicle, DPP4 inhibitor diluted in water.
Patients with EEC-deficiency die without total parenteral nutrition, and similarly very few EEC-deficient mice survive without treatment within the first few weeks. Treatment of mutant mice with vehicle or with PYY significantly improved survival, consistent with therapeutic administration of supportive fluids in diarrheal disease Fig.
However, only PYY injections helped animals gain body weight Fig. PYY also resulted in reduced diarrhea and improved fecal output to be nearly indistinguishable from wild-type, which was independent of intestinal motility Fig.
Statistics calculated by one-way ANOVA. g PYY improved dipeptide transport in EEC-deficient mouse and human intestine. All wild-type and untreated mutant mouse data points are the same as shown in Figs. PYY has a well-established anti-secretory role in the colon, which was likely an important factor contributing to the improvement in diarrheal symptoms observed in EEC-deficient mice.
However, our data suggested that PYY may have additional roles in nutrient and ion transport in the small intestine. Therefore, we investigated if the animals that received PYY injections had restored electrophysiology and improved nutrient absorption in the small intestine.
We found that PYY injections restored the basal I sc of jejunum to normal Fig. In addition, the response to VIP Fig. The rescue of EEC-deficient intestinal tissue also extended to the human model, where EEC-deficient HIOs were grown and matured in vivo and then host animals were injected with exogenous PYY for 10 days prior to harvest.
These EEC-deficient HIOs exposed to PYY demonstrated electrogenic response to glucose that was indistinguishable from wild-type Fig. By administering PYY to the mosaic EEC-deficient reporter mice, we found PYY injections restored intracellular pH in EEC-deficient intestinal cells to normal levels which would support PEPT1-mediated dipeptide absorption Fig.
Consistent with this, PYY-injected mouse and human small intestine displayed a significantly improved electrogenic response to dipeptides Fig. These data demonstrated functional efficacy of PYY on improved ion and nutrient transport in EEC-deficient intestine.
In this study, we found that loss of all EECs resulted in profound imbalance of ion transport in the small intestine, with subsequent impairment of nutrient absorption. We demonstrated that the peptide hormone PYY functions in the small intestine to regulate normal electrophysiology and absorption.
Chemical inhibition of the epithelial NPY1R receptor in wild-type small intestine isolated from HIOs and mouse demonstrated the requirement of this pathway in the modulation of VIP-induced ion secretion.
Administration of PYY to EEC-deficient animals resulted in improvements in survival, diarrheal symptoms, glucose absorption, and protein absorption in the absence of all other EEC peptides. Historically, mouse models have been exceedingly tolerant of loss of individual EEC populations, largely due to functional overlap between EEC-derived peptides This has rendered it difficult to assign roles of individual EEC peptides to physiologic functions.
Here, we were able to exploit a model which lacks all EECs to functionally evaluate the role of one EEC peptide, PYY. However, other peptides like somatostatin have similar activities to PYY and likely play a similar regulatory role in vivo.
Somatostatin has many systemic targets 30 and the use of the somatostatin-analogue octreotide in the treatment of chylous effusion and hyperinsulinemia causes an increased risk of necrotizing enterocolitis in infants We therefore chose to use PYY in our preclinical model of ion-coupled nutrient absorption and diarrhea.
PYY has been classically defined as a satiety hormone that acts in an endocrine manner wherein the DPP4-cleaved PYY 3—36 signals to the brain to reduce food intake However PYY 1—36 has been shown to act in a paracrine manner in the colon using combination of genetic and pharmacological approaches 10 , 12 , These findings lend some clarity on how EECs integrate their nutrient sensing function with nutrient absorption, providing us with a new way to approach management of absorptive diseases and those in which EECs are commonly dysregulated.
Human embryonic stem cell ESC line WA01 H1 was purchased from WiCell. CDH1-mRuby2 and non-reporter hESCs were used interchangeably. hESCs were maintained in feeder-free culture. Cells were passaged routinely every 4 days using Dispase STEMCELL Technologies. NSG mice were maintained on Bactrim chow for a minimum of 2 weeks prior to transplantation and thereafter for the duration of the experiment 8—14 weeks.
After ~10 weeks of in vivo growth, crypts were isolated from transplanted HIOs and plated in 3D Images were acquired using a Nikon A1 GaAsP LUNV inverted confocal microscope and NIS Elements software Nikon. qPCR primers were designed using NCBI PrimerBlast.
Primer sequences are listed in the table below. qPCR was performed using Quantitect SYBR ® Green PCR kit QIAGEN and a QuantStudio 3 Flex Real-Time PCR System Applied Biosystems.
Relative expression was determined using the ΔΔCt method and normalizing to PPIA cyclophilin A. Samples from at least three independent passages were used for quantification. The area of ten representative enteroids per well was quantified using NIS Elements software at both time points.
The outline of individual enteroids was traced manually and the area calculated by NIS Elements. Data include a minimum of three independent experiments per condition on three wild-type and three EEC-deficient HIO-derived enteroid lines.
NHE3 activity was determined by confocal live imaging of enteroids with a ratiometric pH-sensitive dye Intracellular pH was calibrated using the Intracellular pH Calibration Buffer kit Invitrogen at pH 7.
A minimum of three enteroids in three wells over two independent passages were quantified. Electrophysiological experiments were conducted using a modified Ussing chamber 22 , Mouse jejunum and transplanted HIOs were dissected and immediately placed in ice-cold Krebs-Ringer solution.
Tissues were opened to create a flat epithelial surface. Because seromuscular stripping is associated with release of cyclooxygenases and prostaglandins 22 , and prostaglandins can stimulate L-cells to release GLP1, GLP2 and PYY 37 , we performed the Ussing chamber experiments in intestinal tissue with an intact muscular layer.
Tissues were mounted into sliders 0. D-glucose and Gly-Sar were added to the luminal side of the chamber once the VIP-induced I sc had stabilized at a maximum value.
HIOEs were differentiated for 5—7 days, then were removed from Matrigel and enzymatically dissociated into single-cell suspension using 0. Monolayers were then excised from the plastic Transwell insert and mounted on a glass slide for live confocal Z-stack imaging using a Nikon A1 GaAsP LUNV inverted confocal microscope and NIS Elements software Nikon.
On the final day, enteroids were removed from Matrigel and enzymatically dissociated into single-cell suspension using 0. In all experiments, samples were labeled with either CDH1-mRuby2 or Anti-EpCam-APC BD Biosciences to distinguish epithelial cells and incubated with SYTOX Blue dead cell stain Life Technologies or 7-AAD BD Pharmingen.
Forward scatter and side scatter were used to discriminate doublets and cellular debris. A minimum of 50, events per sample was recorded using an LSR Fortessa flow cytometer BD Biosciences and data were analyzed using FACSDiva software BD Biosciences.
Mice were housed in a specific pathogen-free barrier facility in accordance with NIH Guidelines for the Care and Use of Laboratory Animals.
We established a diarrhea score, with 3 representing wet, yellow feces that smeared the perianal fur, and 0 representing normal, dry, brown, well-defined pellets.
Mutant mice which suffered from diarrhea score 3 were included in the rescue experiment. Mice were given access to solid chow on the floor of the cage beginning at postnatal day 10 and weaned at postnatal day Mice were treated daily for a minimum of 10 days after HIOs had been maturing for 8 weeks, then dissected and analyzed.
Data represents measurements taken from individual mice and biological replicates of HIOs from two human pluripotent stem cell lines. Enteroid experiments were conducted on three independent lines. Further information on research design is available in the Nature Research Reporting Summary linked to this article.
All data generated or analyzed during this study are included in the published article and Supplementary Information files. Source data are available in the Source Data file, and available upon reasonable request from the corresponding author. Gribble, F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism.
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The absorption of nutrients enterocutes partially by diffusion through iin wall Nutrient absorption in the enterocytes the entfrocytes intestine. Examples of Nutrient absorption in the enterocytes absorbed by the small intestine Energy independence goals Skinless chicken breast, lipids, proteins, iron, vitamins, and water. The small intestine is the part of the gastrointestinal tract between the stomach and the large intestine where much of the digestion of food takes place. The primary function of the small intestine is the absorption of nutrients and minerals found in food. Intestinal villus : An image of a simplified structure of the villus.
Yalong WangJn SongNuutrient Wang Boosting immune system vitality, Ting EterocytesXiaochen XiongZhen QiWei NutriejtXuerui YangYe-Guang Chen; Single-cell transcriptome analysis reveals differential nutrient absorption functions in Enterocttes intestine. J Enterocytws Med absirption February ; 2 : e The intestine plays an important role in nutrient digestion and absorption, microbe defense, and hormone secretion. Although major cell types have been identified in the mouse intestinal epithelium, cell type—specific markers and functional assignments are largely unavailable for human intestine. Here, our single-cell RNA-seq analyses of 14, epithelial cells from human ileum, colon, and rectum reveal different nutrient absorption preferences in the small and large intestine, suggest the existence of Paneth-like cells in the large intestine, and identify potential new marker genes for human transient-amplifying cells and goblet cells.
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