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Nutrient absorption and metabolism

Nutrient absorption and metabolism

Located in the esophagus near the mouth, the epiglottis prevents absorpion accidental Absorptikn of food or drink into the Nutrient absorption and metabolism Nurient lungs. The large intestine completes the Kiwi fruit salsa recipes of absorption. Duca Toronto General Hospital Research Institute, UHN, Toronto, Canada T. Lam Department of Physiology, University of Toronto, Toronto, Canada Tony K. Intestinal sensing by gut microbiota: targeting gut peptides. It is often in response to an irritant that affects the digestive tract, including but not limited to viruses, bacteria, emotions, sights, and food poisoning.

Nutrient absorption and metabolism -

Eggs are a good dietary source of protein and will be used as our example to describe the path of proteins in the processes of digestion and absorption. One egg, whether raw, hard-boiled, scrambled, or fried, supplies about six grams of protein.

Figure 5. White, speckled red , and brown chicken eggs. CC-SA-BY 3. Unless you are eating it raw, the first step in egg digestion or any other protein food involves chewing. The teeth begin the mechanical breakdown of the large egg pieces into smaller pieces that can be swallowed.

The salivary glands provide some saliva to aid swallowing and the passage of the partially mashed egg through the esophagus. The mashed egg pieces enter the stomach through the esophageal sphincter. The stomach releases gastric juices containing hydrochloric acid and the enzyme, pepsin , which initiate the breakdown of the protein.

The acidity of the stomach facilitates the unfolding of the proteins that still retain part of their three-dimensional structure after cooking and helps break down the protein aggregates formed during cooking.

Pepsin, which is secreted by the cells that line the stomach, dismantles the protein chains into smaller and smaller fragments. Egg proteins are large globular molecules and their chemical breakdown requires time and mixing.

The powerful mechanical stomach contractions churn the partially digested protein into a more uniform mixture called chyme. Protein digestion in the stomach takes a longer time than carbohydrate digestion, but a shorter time than fat digestion.

Eating a high-protein meal increases the amount of time required to sufficiently break down the meal in the stomach. Food remains in the stomach longer, making you feel full longer. The stomach empties the chyme containing the broken down egg pieces into the small intestine, where the majority of protein digestion occurs.

The pancreas secretes digestive juice that contains more enzymes that further break down the protein fragments. The two major pancreatic enzymes that digest proteins are chymotrypsin and trypsin. The cells that line the small intestine release additional enzymes that finally break apart the smaller protein fragments into the individual amino acids.

The muscle contractions of the small intestine mix and propel the digested proteins to the absorption sites. The goal of the digestive process is to break the protein into dipeptides and amino acids for absorption. In the lower parts of the small intestine, the amino acids are transported from the intestinal lumen through the intestinal cells to the blood.

This movement of individual amino acids requires special transport proteins and the cellular energy molecule, adenosine triphosphate ATP. Once the amino acids are in the blood, they are transported to the liver. As with other macronutrients, the liver is the checkpoint for amino acid distribution and any further breakdown of amino acids, which is very minimal.

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This page absorpfion Nutrient absorption and metabolism archived and is no longer Immune-boosting inflammation. Where Nutrient absorption and metabolism the energy that makes life Nutrlent come from? Basorption obtain energy absorotion three classes of metabolixm molecules: carbohydrates, lipids, Gut health and gut-friendly recipes proteins. Wbsorption potential chemical energy of Energy-boosting snacks molecules is transformed into other forms, such as thermal, kinetic, and other chemical forms. Carbohydrates, lipids, and proteins are the major constituents of foods and serve as fuel molecules for the human body. The digestion breaking down into smaller pieces of these nutrients in the alimentary tract and the subsequent absorption entry into the bloodstream of the digestive end products make it possible for tissues and cells to transform the potential chemical energy of food into useful work.

Nutrlent page has been archived and Nutruent no longer updated. Where metaboliwm the energy that absorpion life possible come from? Humans obtain absorprion from three classes of fuel molecules: carbohydrates, lipids, and proteins.

The potential chemical energy of metabokism molecules is transformed into other forms, such as thermal, metabolisj, and other chemical forms. Carbohydrates, lipids, qbsorption proteins are the metaoblism constituents of foods and serve as fuel molecules for the human body.

The digestion breaking down into smaller pieces of these Leafy greens for sports performance in the alimentary metxbolism and sbsorption subsequent absorption entry into the bloodstream qbsorption the digestive end products make it possible for tissues and cells to transform the potential chemical energy HbAc test food into useful work.

NNutrient major absorbed end products of metaboism digestion are metaboilsm, mainly Nutrient absorption and metabolism from carbohydrates ; monoacylglycerol and long-chain fatty acids from lipids Nutrient absorption and metabolism and small peptides and metabo,ism acids from protein.

Once in the bloodstream, different cells can metabolize these nutrients. We have long Nutrienr that these three Nurrient of molecules are fuel absorpttion for human metabolismyet it is a common misconception especially among undergraduates that human cells use Nutriennt glucose as Energy-boosting smoothie recipes source of energy.

This misinformation absorptlon arise from the way most textbooks explain energy metabolism, emphasizing glycolysis the Cramp remedies at home pathway for glucose degradation and omitting fatty acid or amino acid oxidation.

Here absorotion discuss how the three nutrients carbohydrates, proteins, and lipids are metabolized in human Energy-boosting immune support in a way that may absortion avoid this oversimplified relaxation exercises for stress relief at home of Ntrient metabolism.

Figure 1 During the eighteenth century, the initial studies, developed by Ahsorption Black, Joseph Priestley, Carl Wilhelm Scheele, and Antoine Lavoisier, Nutrient absorption and metabolism a special role in identifying two gases, oxygen Antioxidant-rich oils carbon dioxide, that are central to energy metabolism.

Lavoisier, the French nobleman who owns the mrtabolism of annd of modern chemistry," characterized the composition of the air we breathe and conducted the first experiments on energy conservation and transformation in the organism. One of Lavoisier's anv questions at this time was: How does oxygen's role in combustion Nytrient to the process of respiration in living organisms?

Using a calorimeter to make quantitative measurements Improve your athletic performance guinea pigs Custom seed blends later on with himself and his metabo,ism, he demonstrated that respiration is a slow form of combustion Figure 1.

Mdtabolism on the concept that oxygen burned the carbon in food, Lavoisier absroption that the exhaled air contained carbon abworption, which abbsorption formed from the reaction between oxygen present metaboljsm the air absorptuon organic molecules inside the organism.

Lavoisier also observed that heat is metabloism produced by the Nutrient absorption and metabolism during respiration. An was then, in absorptin middle of the nineteenth century, that Justus Liebig conducted animal studies and recognized B vitamins for skin health proteins, carbohydrates, and fats were oxidized in the absorptioon.

Finally, pioneering contributions absrption metabolism and metaabolism came from the studies of a Liebig's protégé, Carl von Voit, and his talented student, Max Rubner.

Voit demonstrated that oxygen consumption is the result of zbsorption metabolism, Metaabolism Rubner ane the major energy value of certain foods in order to metaabolism the Herbal detox for weight loss values that are still used Nutrieny.

Rubner's observations proved that, for a resting animal, heat production was equivalent to heat elimination, confirming that Nufrient law of conservation of energy, implied in Lavoisier's Nutrient absorption and metabolism experiments, was applicable abssorption living organisms as well.

Appetite suppressant gummies, what Citrus bioflavonoids and anti-aging benefits life possible is ane transformation of the potential absorprion energy of fuel molecules through a Nutrient absorption and metabolism of reactions within a cell, enabled by oxygen, into other forms of chemical energy, wbsorption energy, kinetic Nutrien, and thermal energy.

Energy metabolism Skinfold measurement for older adults the general process by Nutriennt living cells acquire and use metabolis, energy needed to stay metaboliem, to Cardiovascular workouts, and to reproduce.

How is the energy released while breaking Nutrient absorption and metabolism chemical bonds mefabolism nutrient molecules captured for other uses by the cells? Absorptio answer lies in the coupling between metabolissm oxidation of nutrients and the synthesis of absorpgion compounds, particularly ATPwhich works as the asorption chemical energy carrier metavolism all Nutrrient.

There are two Diabetes self-care strategies of ATP synthesis: 1. oxidative phosphorylationthe process by which ATP is synthesized from ADP and inorganic phosphate Pi that takes place in mitochondrion; Nutridnt 2. substrate-level phosphorylation, in which ATP is synthesized Nutrkent the transfer of high-energy phosphoryl groups Nurrient high-energy compounds to ADP.

The latter occurs in both the metabolsm, during the tricarboxylic acid TCA Improve mood slimming pills, and in the cytoplasmduring glycolysis. In the next section, we focus on oxidative phosphorylation, the main mechanism of ATP synthesis in most of human cells.

Later we comment on the metabolic pathways in which the three classes of nutrient molecules are degraded. B Scheme of the protein complexes that form the ETS, showing the mitochondrial membranes in blue and red; NADH dehydrogenase in light green; succinate dehydrogenase in dark green; the complex formed by acyl-CoA dehydrogenase, electron transfer flavoprotein ETFPand ETFP-ubiquinone oxidoreductase in yellow and orange; ubiquinone in green labeled with a Q; cytochrome c reductase in light blue; cytochrome c in dark blue labeled with cytC; cytochrome c oxidase in pink; and the ATP synthase complex in lilac.

On the left is an electron micrograph showing three oval-shaped mitochondria. Each mitochondrion has a dark outer mitochondrial membrane and a highly folded inner mitochondrial membrane.

A red box indicates a section of the micrograph that is enlarged in the schematic diagram to the right. The schematic diagram illustrates the electron transport chain.

Two horizontal, mitochondrial membranes are depicted. The upper membrane is the outer mitochondrial membrane, and the lower membrane is the inner mitochondrial membrane. The area between the two membranes is the intermembrane space, and the area below the lower membrane is the mitochondrial matrix.

Each of these membranes is made up of two horizontal rows of phospholipids, representing a phospholipid bilayer. Each phospholipid molecule has a blue circular head and two red tails, and the tails face each other within the membrane.

A series of protein complexes are positioned along the inner mitochondrial membrane, represented by colored shapes. The proteins that make up the electron transport chain start on the left and continue to the right.

At the far left, NADH dehydrogenase is represented by a light green rectangular structure that spans the membrane. Next, succinate dehydrogenase is represented by a dark green bi-lobed shape embedded in the half of the inner membrane and facing the matrix. Next, acyl-CoA dehydrogenase, electron transfer flavoprotein ETFPand ETFP-ubiquinone oxidoreductase form a complex, and are represented by three yellow and orange ovals on the matrix-facing side of the inner membrane.

Next, ubiquinone is represented by a lime green circle labeled with a Q located in the side of the inner membrane facing the intermembrane space. Next, cytochrome c reductase is represented by a light blue oval-shaped structure that spans the membrane. Next, cytochrome c oxidase is represented by a pink oval-shaped structure that spans the inner membrane.

Next, the ATP synthase complex is represented by an upside-down lollipop-shaped structure that traverses the inner membrane and contains a channel through the membrane; the round, purple head enters the mitochondrial matrix, and the lilac-colored stem spans the membrane. These electrons are transferred to ubiquinone.

Succinate dehydrogenase converts succinate to fumarate and transfers additional electrons to ubiquinone via flavin adenine dinucleotide FAD. The acyl-CoA dehydrogenase, electron transfer flavoprotein ETFPand ETFP-ubiquinone oxidoreductase complex converts acyl-CoA to trans-enoyl-CoA.

During this reaction, additional electrons are transferred to ubiquinone by the FAD domain in this protein complex. Next, the electrons are transferred by ubiquinone to cytochrome c reductase, which pumps protons into the intermembrane space.

The electrons are then carried to cytochrome c. Next, cytochrome c transfers the electrons to cytochrome c oxidase, which reduces oxygen O 2 with the electrons to form water H 2 O.

During this reaction, additional protons are transferred to the intermembrane space. As the protons flow from the intermembrane space through the ATP synthase complex and into the matrix, ATP is formed from ADP and inorganic phosphate P i in the mitochondrial matrix.

Oxidative phosphorylation depends on the electron transport from NADH or FADH 2 to O 2forming H 2 O. The electrons are "transported" through a number of protein complexes located in the inner mitochondrial membrane, which contains attached chemical groups flavins, iron-sulfur groups, heme, and cooper ions capable of accepting or donating one or more electrons Figure 2.

These protein complexes, known as the electron transfer system ETSallow distribution of the free energy between the reduced coenzymes and the O 2 and more efficient energy conservation. The electrons are transferred from NADH to O 2 through three protein complexes: NADH dehydrogenase, cytochrome reductase, and cytochrome oxidase.

Electron transport between the complexes occurs through other mobile electron carriers, ubiquinone and cytochrome c.

FAD is linked to the enzyme succinate dehydrogenase of the TCA cycle and another enzyme, acyl-CoA dehydrogenase of the fatty acid oxidation pathway. During the reactions catalyzed by these enzymes, FAD is reduced to FADH 2whose electrons are then transferred to O 2 through cytochrome reductase and cytochrome oxidase, as described for NADH dehydrogenase electrons Figure 2.

These observations led Peter Mitchell, into propose his revolutionary chemiosmotic hypothesis. The reaction catalyzed by succinyl-CoA synthetase in which GTP synthesis occurs is an example of substrate-level phosphorylation. Acetyl-CoA enters the tricarboxylic acid cycle at the top of the diagram and reacts with oxaloacetate and water H 2 O to form a molecule of citrate and CoA-SH in a reaction catalyzed by citrate synthase.

Next, the enzyme aconitase catalyzes the isomerization of citrate to isocitrate. Succinyl-CoA reacts with GDP and inorganic phosphate P i to form succinate and GTP.

This reaction releases CoA-SH and is catalyzed by succinyl-CoA synthetase. In the next step, succinate reacts with FAD to form fumarate and FADH 2 in a reaction catalyzed by succinate dehydrogenase. Fumarate combines with H 2 O in a reaction catalyzed by fumerase to form malate. Then, oxaloacetate can react with a new molecule of acetyl-CoA and begin the tricarboxylic acid cycle again.

The diagram shows the molecular structures for citrate, isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, and oxaloacetate. The enzymes that act at each of the eight steps in the cycle are shown in yellow rectangles.

In aerobic respiration or aerobiosis, all products of nutrients' degradation converge to a central pathway in the metabolism, the TCA cycle. In this pathway, the acetyl group of acetyl-CoA resulting from the catabolism of glucose, fatty acids, and some amino acids is completely oxidized to CO 2 with concomitant reduction of electron transporting coenzymes NADH and FADH 2.

Consisting of eight reactions, the cycle starts with condensing acetyl-CoA and oxaloacetate to generate citrate Figure 3.

In addition, a GTP or an ATP molecule is directly formed as an example of substrate-level phosphorylation. In this case, the hydrolysis of the thioester bond of succinyl-CoA with concomitant enzyme phosphorylation is coupled to the transfer of an enzyme-bound phosphate group to GDP or ADP.

Also noteworthy is that TCA cycle intermediates may also be used as the precursors of different biosynthetic processes. The TCA cycle is also known as the Krebs cycle, named after its discoverer, Sir Hans Kreb.

Krebs based his conception of this cycle on four main observations made in the s. The first was the discovery in of the sequence of reactions from succinate to fumarate to malate to oxaloacetate by Albert Szent-Gyorgyi, who showed that these dicarboxylic acids present in animal tissues stimulate O 2 consumption.

The second was the finding of the sequence from citrate to α-ketoglutarate to succinate, inby Carl Martius and Franz Knoop. Next was the observation by Krebs himself, working on muscle slice cultures, that the addition of tricarboxylic acids even in very low concentrations promoted the oxidation of a much higher amount of pyruvate, suggesting a catalytic effect of these compounds.

And the fourth was Krebs's observation that malonate, an inhibitor of succinate dehydrogenase, completely stopped the oxidation of pyruvate by the addition of tricarboxylic acids and that the addition of oxaloacetate in the medium in this condition generated citrate, which accumulated, thus elegantly showing the cyclic nature of the pathway.

When 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate, substrate-level phosphorylation occurs and ATP is produced from ADP. Then, 3-phosphoglycerate undergoes two reactions to yield phosphoenolpyruvate. Next, phosphoenolpyruvate is converted to pyruvate, which is the final product of glycolysis.

During this reaction, substrate-level phosphorylation occurs and a phosphate is transferred to ADP to form ATP. Interestingly, during the initial phase, energy is consumed because two ATP molecules are used up to activate glucose and fructosephosphate.

Part of the energy derived from the breakdown of the phosphoanhydride bond of ATP is conserved in the formation of phosphate-ester bonds in glucosephosphate and fructose-1,6-biphosphate Figure 4.

In the second part of glycolysis, the majority of the free energy obtained from the oxidation of the aldehyde group of glyceraldehyde 3-phosphate G3P is conserved in the acyl-phosphate group of 1,3- bisphosphoglycerate 1,3-BPGwhich contains high free energy. Then, part of the potential energy of 1,3BPG, released during its conversion to 3-phosphoglycerate, is coupled to the phosphorylation of ADP to ATP.

The second reaction where ATP synthesis occurs is the conversion of phosphoenolpyruvate PEP to pyruvate. PEP is a high-energy compound due to its phosphate-ester bond, and therefore the conversion reaction of PEP to pyruvate is coupled with ADP phosphorylation.

: Nutrient absorption and metabolism

Mechanical Digestion The Intralipid effect is blocked by the local anesthetic tetracaine, which inhibits nerve impulses, indicating small intestinal vagal innervation as a mediator of the anorectic signals CAS PubMed Google Scholar Meloni, A. Oxidative phosphorylation depends on the electron transport from NADH or FADH 2 to O 2 , forming H 2 O. Moreover, infusion of leucine alone into the duodenum dose-dependently increases insulin, with slight decreases in glucose, but no change in glucagon Article CAS PubMed PubMed Central Google Scholar Wang, J.
Digestion and Absorption of Nutrients – Nutrition for Consumers Article ADS CAS PubMed PubMed Central Google Scholar Grun, D. Knockdown of the GLP-1R in vagal afferent neurons via lentiviral injection into the nodose ganglia the inferior ganglion of the vagus nerve , which enables knockdown throughout the vagus nerve, increases meal size and postprandial glycemia, and blunts insulin release 22 while knocking down GLP-1R via the use of transgenic mice in the gut—brain neuronal axis leads to increased glucose levels Zhang, X. Rasmussen, B. Sonnenburg, J.
Digestion, Absorption and Metabolism of Nutrients

Some drugs eg, metoclopramide increase gastrointestinal motility, decreasing food absorption. Other drugs eg, opioids, anticholinergics decrease gastrointestinal motility. Some drugs are better tolerated if taken with food.

Certain drugs affect mineral metabolism see table. Certain antibiotics eg, tetracyclines reduce iron absorption, as can certain foods eg, vegetables, tea, bran. Certain drugs affect vitamin absorption or metabolism see table.

Learn more about the MSD Manuals and our commitment to Global Medical Knowledge. Disclaimer Privacy Terms of use Contact Us Veterinary Manual. IN THIS TOPIC. OTHER TOPICS IN THIS CHAPTER. Nutrient-Drug Interactions By Shilpa N Bhupathiraju , PhD, Harvard Medical School and Brigham and Women's Hospital; Frank Hu , MD, MPH, PhD, Harvard T.

View PATIENT EDUCATION. All rights reserved. Was This Page Helpful? Yes No. C,D mRNA expression analyses of duodenal human organoids from passages p0 and p2. E mRNA expression levels of GCG in human organoids derived from different intestinal segments from passages p0 and p2.

C—E Target gene expression normalized to HPRT. F Upper panel: schematic representation of the experimental setup from which samples were derived for mRNA expression analysis; lower panel: relative gene expression of CCM-cultured human duodenal organoids as fold of organoids cultured in Wnt-containing hIC medium.

HPRT was used as housekeeper. G Protein expression of SGLT1 and PEPT1 in human organoids cultured in hIC and CCM medium for 5 days, respectively.

β-ACTIN serves as loading control. Simple sugars can be taken up by enterocytes via passive or active transport — and exit the enterocyte likewise. The mechanism of intestinal sugar absorption is still not fully understood, given that a variety of transporters of the sodium glucose co-transporter SGLT family and the family of facilitative glucose transporters GLUT with partly unknown specificities is involved Thorens and Mueckler, Genetic variants of transporters contributing to intestinal sugar transport are associated with human diseases, such as glucose-galactose malabsorption and Fanconi-Bickel syndrome caused by mutations in SGLT1 SLC5A1 and GLUT2 SLC2A2 , respectively Martin et al.

Particularly, fructose uptake gained increasing attention, as fructose consumption is rising over the last decades and is associated with developing cardiovascular diseases and type 2 diabetes Johnson et al.

Furthermore, the molecular basis of fructose malabsorption still remains elusive, but defective absorption is most likely. Hence, intestinal organoids which can be directly derived from patients and allow to picture the complex interaction of transporters might considerably advance science in this field.

Previously, we established a straightforward approach to assess nutrient and drug transport in murine intestinal organoids Zietek et al. By using fluorescently FITC labeled dextrans, we were able to show that molecules of a size of 4 kDa rapidly reach the luminal compartment of murine organoids.

Hence, radiolabeled substrates were simply added to the culture plates, keeping the organoids in their 3-dimensional environment a dome of laminin-rich gel Zietek et al.

As species-specific differences might result in misleading outcomes Youhanna and Lauschke, , we validated experimental procedures for human intestinal organoids, allowing for tackling human-specific research questions.

After confirming translocation of 4 kDa FITC-dextrans also into the lumen of human organoids Supplementary Figure 2A , we applied the experimental procedures established in murine intestinal organoids Supplementary Figure 2B to human organoids.

First investigating uptake of glucose and fructose, we used different inhibitors for functional characterization of monosaccharide transport, the SGLT1 inhibitor phloridzin, the GLUT inhibitor phloretin and rubusoside, inhibiting fructose transport by GLUT5 Figure 2A.

Figure 2. Nutrient and drug transport in human intestinal organoids. A Schematic illustration of the transporters investigated and inhibitors used. B Uptake of radiolabeled glucose in human organoids derived from different small intestinal segments.

C Uptake of radiolabeled fructose in human duodenal organoids. E Left: comparison of detected counts per sample for both approaches using the same amout of radiolabeled substrates and right: reduction of radiolabeled Gly-Sar uptake by the competitive inhibitor Gly-Gly depicted for both approaches.

F Chemical structures and formulas of the peptidomimetics used. G Assessment of transport of peptidomimetics in a competition assay using radiolabeled Gly-Sar in murine small intestinal organoids derived from wild type and Pept1 knockout mice.

H Similar approach to G using human duodenal organoids. I Reduction of radiolabeled Gly-Sar uptake using the antibiotic Cefadroxil as competitive inhibitor. E,I Unpaired t tests. Glucose is a substrate for both, apical and basolateral GLUT transporters, with the electrogenic solute carrier SGLT1 as the main apical glucose transporter in the small intestine.

GLUT5 represents an exception, transporting exclusively fructose at the apical membrane. Opposing, the uniporter GLUT2 mediates glucose and fructose fluxes at the basolateral membrane via facilitated diffusion, providing import as well as export capacities Thorens and Mueckler, ; Roder et al.

Due to the experimental setup, substrates first reach the outside, i. Therefore, it is not possible to target apical or basolateral transporters separately, yet the use of inhibitors enables to illustrate contributions of certain transporters.

Thus, using glucose as substrate in combination with either phloridzin or phloretin in human organoids derived from different regions of the small intestine, resulted in the expected pattern of blunted glucose uptake, which was more pronounced with the pan-GLUT inhibitor phloretin as compared to the SGLT1 inhibitor phloridzin Figure 2B.

In line, fructose transport could be diminished by phloretin, and to a lesser extent, by the GLUT5-inhibitor rubusoside Figure 2C as well as glucose Supplementary Figure 2C in human duodenal organoids.

In this case, human duodenal organoids were exposed to the radiolabeled dipeptide glycyl-sarcosin Gly-Sar , a hydrolysis-resistant model substrate of the peptide transporter PEPT1.

Peptide transport over the plasma membrane occurs in cotransport with protons and allows transport of di- and tripeptides against a substrate gradient[24].

Next to PEPT1-mediated substrate fluxes at the apical membrane, a not yet genetically identified system for basolateral peptide uptake with similar features to PEPT1 has been described Berthelsen et al. Although radiolabeled transport assays are very sensitive, costs of labeled substrates are a major drawback.

Hence, reducing the amount of substrates needed for experiments is desirable. As mentioned before, peptide transporters also play a role in drug uptake, including peptidomimetics.

Peptidomimetics are compounds mimicking a peptide or protein, which possess the ability to interact with a biological target to exert agonistic or antagonistic effects Giannis and Kolter, ; Marshall and Ballante, Hence, they have a great potential in drug discovery, exerting drug-like properties Rader et al.

For example, peptidomimetics have been designed for cancer therapy, e. Primary goals in the development of orally available peptides are improving their intestinal transport and enhancing their stability to enzymatic degradation. Common strategies comprise the use of cyclic peptides, as well as D - instead of L -amino acids and N -methylation to increase metabolic stability Rader et al.

For example, Cilengitide, a cyclic pentapeptide with one D -amino acid and one N -methylation is completely stable in humans and is excreted with a half-life of 4 h without any metabolization Becker et al.

Yet, intestinal permeation from the lumen into the bloodstream remains a major challenge. Structural changes affect intestinal and cellular permeability, and a change in one methyl position already can greatly impact permeability properties Ovadia et al.

Oral availability crossing the gastrointestinal wall to reach the circulation can be mediated via paracellular or transcellular mechanisms, including active transporters Rader et al.

Common tools to evaluate permeability properties of peptide drugs include Caco-2 monolayers and the side-by-side diffusion chamber Ussing chamber , however, both systems are poorly correlative Jezyk et al.

Caco-2 cells, even though known to possess a rather small intestinal phenotype Yee, , were originally derived from a colon carcinoma, and phenotypic as well as functional characteristics highly differ from native human enterocytes Harwood et al.

For example, Caco-2 cells exhibit tighter junctions compared to the small intestine of human Matsson et al.

In contrast, Ussing chamber approaches, mainly using excised rat tissue better reflect physiology but suffer from potential species differences and large numbers of animals needed for screening. Hence, we tested the applicability of intestinal organoids as a new tool to evaluate the absorption properties of peptidomimetics.

Three different cyclic hexapeptides P1, P2, P3 Figure 2F were tested that were originally developed via a stepwise library approach: First a library of more than 55 different N -methylated alanine peptides of the general structure cyclo D -Ala- L -Ala 5 were synthesized and investigated in a Caco-2 assay Ovadia et al.

Peptides identified as highly permeable including P3 were subsequently functionalized by substitution of neutral Ala residues with the integrin-binding tripeptide sequence RGD.

Among them, one compound P2 , has been identified with similar high activity and selectivity as Cilengitide sub-nanomolar affinity for integrin αvβ3, high selectivity against other integrins Weinmuller et al. However, P2 lacked permeability due to charges in the cyclic N -methylated alanine-peptides.

To overcome this limitation, charged residues were protected with lipophilic protecting moieties two hexyloxycarbonyl Hoc groups and conversion of the carboxylic side chain of Asp into a neutrally charged methyl ester. The resulting compound P1 showed both, permeability in the Caco-2 assay and biological activity after oral administration in mice Weinmuller et al.

To test the involvement of active peptide transporter-mediated uptake in the permeability properties of P1-P3 , we evaluated the ability of the three cyclic hexapeptides to competitively inhibit the uptake of radiolabeled Gly-Sar in murine small intestinal organoids derived from wild type and Pept1-deficient mice.

In this assay, we identified P1 as a potential substrate for active transport mediated by Pept1, P2 to be actively transported independently of Pept1, and in contrast, P3 showed no signs of peptide transporter-mediated uptake in murine organoids Figure 2G.

Subsequently testing P1 and P3 in human duodenal organoids, both peptides were able to significantly reduce radiolabeled Gly-Sar uptake, indicating P1 and P3 to be substrates for peptide transporter-mediated uptake in humans Figure 2H.

These data highlight the suitability of intestinal organoids to screen for transporter-mediated uptake of drug candidates, a process that might have been underappreciated in Caco-2 assays due to lack of physiological transporter expression, but contributes to oral availability.

Additionally, efflux processes that limit drug absorption might be evaluated in detail in organoid systems Schumacher-Klinger et al.

Concomitantly, these data point toward potential species-specific transport phenotypes as already described for PEPT1 Kottra et al. Accordingly, we could also confirm transport of the peptide-like β-lactam antibiotic cefadroxil, that has been previously described as PEPT1 substrate Ganapathy et al.

In conclusion, these results underline the superior properties of human intestinal organoids for studying nutrient and drug uptake. Since organoids retain location-specific properties of their site of origin, absorption could even be determined at an intestinal region-specific resolution.

It has been reported that fluorophore-conjugated dipeptides with a high-affinity for PEPT1 were able to block transport of Gly-Sar, however, they failed to be transported Abe et al.

To exclude similar effects, either specific inhibitors can be applied for example Lys-z-NO2-Val, a specific PEPT1-inhibitor or downstream effects of transport processes can be investigated.

Thus, we extended our previously established protocol for visualization of intracellular signaling by life-cell imaging of murine intestinal organoids Zietek et al. As mentioned before, peptide transport over the plasma membrane occurs in cotransport with protons, leading to cytosolic acidification of enterocytes Chen et al.

Hence, intracellular changes immediately reflect transport activities and provide direct evidence for substrate fluxes. A drop in pH can be visualized by live-cell imaging using fluorescent probes Chen et al. Employing the pH-indicator BCECF-AM, intracellular acidification was demonstrated in human duodenal organoids upon exposure to Gly-Sar, Gly-Gly as well as cefadroxil and the carbonyl cyanide m-chlorophenyl hydrazine CCCP, an ionophore used as a positive control Figures 3A—D.

Stimulating organoids with CCCP subsequent to administration of Gly-Sar, Gly-Gly, and cefadroxil caused an additional decline in intracellular pH, indicating the physiological range of observed responses Supplementary Figure 3A.

As expected, neither glucose nor fructose used as negative controls led to an intracellular acidification of enterocytes Supplementary Figure 3B.

In accordance to literature, robust signals were obtained upon ATP-mediated increases in intracellular calcium Figure 3E. For both dyes, BCECF-AM and FuraAM, excellent dye-loading efficiency was observed Supplementary Figure 3C. Figure 3. Visualization of intestinal peptide transport processes.

Intracellular acidification visualized by BCECF-AM induced by transport of peptide-transporter substrates A Gly-Sar and B Gly-Gly, C by the antibiotic Cefadroxil and D the protonophore CCCP. E Calcium responses to ATP stimulation visualized by Fura Intracellular acidification induced by the antibiotic Cefadroxil.

F Schematic illustration of the transporters investigated and inhibitors used. G Course of intracellular acidification induced by Gly-Sar exposure for an extended time frame left with and middle without the NHE-inhibitor Amilorid; right: overlay of both curves giving relative BCECF ratios.

H Similar approach to G using the NHE3-inhibitor S A—E human duodenal organoids, G,H murine small intestinal organoids. For data analysis, whole organoids were selected and no background correction was applied.

Analyses were performed on several organoids derived from independent cultures and representative measurements are shown. For continuous peptide uptake, IECs need to maintain the transmembrane ionic gradients and furthermore, augmented or prolonged acidification of the cell by proton symport of peptide transporters has to be avoided.

In enterocytes, several types of NHEs are expressed, and NHE3 specifically has been shown to be required for proper PEPT1-mediated transport Chen et al. Importantly, NHE-function is targeted by both, clinically relevant drugs as well as bacterial toxins.

To illustrate the function of NHEs in general and NHE3 in particular in the context of active peptide transport in organoids, we used two different inhibitors: Amiloride, an FDA-approved inhibitor of NHEs, and S, which predominantly acts on NHE3 Wiemann et al. As expected, both inhibitors prevented the recovery of intracellular pH to basal levels as observed in non-treated murine organoids following exposure to Gly-Sar Figures 3G,H left.

In accordance to their specific inhibitory spectrum, amiloride led to a continuous influx of protons in the observed time span Figure 3G , while S treatment resulted in a stable intracellular pH level below base line Figure 3H.

To decipher biology and functional characteristics of intestinal transporters it is very important not only to quantify transport of substrates, but also to take intracellular downstream effects and signaling into account, as presented above. These data highlight the high-resolution measurements possible in intestinal organoids.

Metabolism in IECs has gained increasing attention, not only due to the expression of key drug metabolizing enzymes, including cytochrome P 3A4 CYP3A4 , in small intestinal epithelial cells, that are prone to diet-drug interactions Lown et al.

IEC and whole body metabolism are tightly interrelated via production of incretine hormones Zietek and Rath, and factors like Fgf15 Kliewer and Mangelsdorf, by enteroendocrine cells and enterocytes, respectively, and vice versa, IECs are targets of remote-tissue metabolic signals such as insulin and leptin signaling Yilmaz et al.

In the gastrointestinal tract, carbohydrates, peptides and lipids are broken down and absorbed by enterocytes. Subsequently, they serve as substrates for cellular energy generation or for interconversions and distribution to the whole organism via transfer into the circulation.

Hence, IEC metabolism also profoundly impacts availability and quality of nutrients, constituting an initial check point between diet and host. In this context, the intestinal microbiota plays an additional key role, as a source of bacterial metabolites such as short chain fatty acids SCFAs including butyrate.

IEC metabolism and exposure to certain nutrients furthermore relates to diseases, for example high-fat diets were shown to enhance tumorigenicity of intestinal progenitors Beyaz et al. Despite the fact that general metabolic functions of enterocytes are understood, many open questions remain, including whether the small intestine can act as a site for gluconeogenesis, which seems to be species-dependent Sinha et al.

Metabolomic approaches are key technologies allowing to tackle such questions by enabling analysis of metabolic events in a large scale and high throughput manner. First, we determined the effect of insulin on amino acid AA and acylcarnitine levels in small intestinal organoids.

All proteinogenic amino acids could be detected in small intestinal organoids at concentration ranges given in Figure 4B. Insulin is known to promote anabolism, affecting both, processes of protein synthesis and proteolysis.

Enterocytes respond to insulin signals and develop insulin resistance under conditions of obesity-related inflammation Monteiro-Sepulveda et al.

In line, concentrations of valine and alanine responded fast to insulin stimulation showing maximal reduction 30 min after addition of insulin Figure 4C , consistently with most other AAs data not shown , indicating a shift in protein turnover toward an enhanced net incorporation of AAs in proteins.

In parallel, tau-methylhistidine, a marker compound for proteolysis and propionylcarnitine C3 , a typical intermediate in the breakdown of valine, isoleucine, methionine and threonine were diminished with lowest levels observed 60 min after insulin stimulation Figure 4D , confirming also the inhibitory effect of insulin on proteolysis in intestinal organoids.

Figure 4. Metabolite analysis in intestinal organoids. A Schematic representation of the experimental setup from which samples were derived for analyses shown in panel B,C.

B Range of amino acid AA concentrations detected in organoids. C Concentration of valine and alanine at different time points after insulin stimulation. D Concentration of tau-methylhistidine, a marker compound for proteolysis, and propionylcarnitine C3 , a typical intermediate in the breakdown of valine, at different time points after insulin stimulation.

E Schematic representation of the experimental setup from which samples were derived for analyses shown in panel F. F Concentration of the acylcarnitine species Acetylcarnitine C2 , Butyrylcarnitine C4 , and Palmitoylcarnitine C16 at different time points after addition of butyrate.

G Proposed mode of action for the effect of butyrate on beta-oxidation. H Schematic representation of the experimental setup from which samples were derived for analyses shown in panel I. I Appearance of deuterium-labeled acylcarnitines at different time points after addition of deuterium-labeled dpalmitate.

J Schematic illustration of carnitine acyltransferases involved in the generation of the acylcarnitine species detected. B,C,F,I Representative results from three independent organoid cultures.

ASCL, long-chain acyl-CoA synthetase; CPT, carnitine palmitoyltransferase; CAT, carnitine acetyltransferase; CACT, carnitine-acylcarnitine translocase. Next, we depict the effect of butyrate on acylcarnitine profiles in murine large intestinal organoids.

In this approach, 1mM butyrate was added and shifts in acylcarnitines were measured 0, 5, 10, 30, and 60 min afterward Figure 4E. Butyrate has been shown to broadly affect colonocyte metabolism, including glucose utilization Donohoe et al. In accordance to literature, a clear effect of butyrate on saturated acylcarnitines, comprising short-, medium- and long-chain acylcarnitines was observed, with acetylcarnitine, butyrylcarnitine and palmitoylcarnitine increasing to maximal concentrations 60 min after butyrate addition Figure 4F.

A proposed mechanism explaining the effect of butyrate involves the butyrate transporter SLC5A8 and the butyrate receptor GPRA expressed by coloncytes Cresci et al. Last but not least, we followed the breakdown of dlabeled palmitic acid, in which all 31 hydrogen atoms are replaced by deuterium atoms, in small intestinal organoids.

Stable isotope labeling enables following the fate of the labeled fatty acid within the enterocyte, being either subjected to chain-shortening during beta-oxidation and conversion to the respective acylcarnitine species for energy generation, or being reesterified, and incorporated into chylomicrons for systemic supply.

Importantly, sensing dietary fat via fatty acid oxidation in enterocytes has been implicated in the control of eating Langhans et al. Appearance of deuterium-labeled acylcarnitines were determined 0, 10, 30, and 60 min after addition of dpalmitic acid Figure 4H. Indicating beta-oxidation, we could detect chain-shortened, deuterium-labeled acylcarnitine species Figure 4I.

The conversion of the long-chain fatty acids to their acylcarnitine species is known to be mediated by carnitine palmitoyltransferase 1 and 2 CPT1 and CPT2 , while short-chain acylcarnitine species are formed by carnitine acetyltransferase CAT Figure 4J.

Carnitine octanoyltransferase COT located in peroxisomes is responsible for the conversion of medium-chain fatty acids Violante et al. Contrarily, CPT1 is located in the outer mitochondrial membrane and thus may convert the added dpalmitic acid directly to dpalmitoylcarnitine Bonnefont et al.

Shorter fatty acid intermediates are formed within the mitochondria and their respective acylcarnitine species are generated by CPT2 and CAT, located in the inner mitochondrial membrane. Consistent with the sequential removal of 2-carbon units during beta-oxidation, dmyristoylcarnitine dC and to a lesser extent ddodecanoylcarnitine dC could already be seen after 10 min of incubation, whereas ddecanoyl-, doctanoyl- and dhexanoylcarnitine appeared 30 min after addition of dpalmitic acid.

Of note, the larger peaks of dC6, as compared to dC10 and dC8 after 30 and 60 min might be explained by a higher preference of CAT for short-chain fatty acid substrates C2 to C6. In summary, intestinal organoids are an excellent model system close to physiology to explore cellular metabolism and the applied metabolic readouts could be adapted easily to the 3D culture.

Human organoids, constituting the most relevant model, are superior to animal rodent -derived organoids and cancer cell lines, especially in the context of metabolism and diseases, since metabolic properties differ between species and alterations in the cellular metabolism are part of many pathologies.

Thus, human organoids hold great potential to answer remaining questions on intestinal metabolism and to identify drug targets to improve overall metabolic health. Taken together, our results demonstrate that intestinal organoids cultured in 3D, embedded in a laminin-rich gel dome, the most basic and probably least cost and labor extensive culture protocol, is suitable for a broad range of measurements in the field of intestinal transport and metabolic studies.

Beyond these applications, many other readouts are possible in this setup, for example assessment of proteasome activity Supplementary Figure 2D , which is of interest in the context of proteasome inhibitors, an important class of drugs in the treatment of different types of cancer Fricker, Implementing other culture protocols like organoids with reversed polarity in which the apical side faces outward Co et al.

Paracellular transport of fluorescein, transcellular transport of propranolol, and basolateral efflux of rhodamin, a substrate of p-glycoprotein MDR1 have been measured in a model in which human organoid-derived cells are seeded as a 2D monolayer on a porcine small intestinal scaffold Schweinlin et al.

The field of applications for organoids is still rapidly growing, and there is a trend toward more complex and sophisticated organoid-based model systems. For example, co-cultures with bacterial and viral pathogens and immune cells Yin et al. These systems provide a microenvironment to study the impact of oxygenation, mechanical stress, and tissue communication via soluble factors and will further advance intestinal research.

Yet, to date they remain very expensive tools in highly specialized laboratories not suitable for broad applications Almeqdadi et al. In contrast, the intestinal organoid culture protocols and methods presented here represent in vitro models that already now allow for partly replacement and reduction of animal numbers needed for research and testing.

Although the methodologies that we have established are applicable to mouse and human organoids, the human organoid technology should be focused when targeting human-related issues. Drug development success rates are particularly low in widespread diseases such as diabetes Ali et al.

Only 5 to 10 percent of drugs proven as safe and effective in preclinical animal studies make it to the market Arrowsmith, ; Thomas et al. Species-specific differences and hence poor transferability from animal models to humans is the main reason for this high failure rate Arrowsmith and Miller, ; Cook et al.

In light of this, we provide innovative approaches for physiologically relevant in vitro testing in the field of intestinal research and metabolomics. In particular, the use of human organoids in this context is a highly valuable tool for drug discovery and testing as well as for human-relevant disease modeling.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Medical Faculty of TUM. The animal study was reviewed and approved by the Committee on Animal Health and Care of the local government body of the state of Upper Bavaria Regierung von Oberbayern.

TZ contributed to study conception and design, human organoid culture, data acquisition, analysis and interpretation, and drafting and revising the article.

PG contributed to data acquisition, analysis and interpretation, and drafting and revising the article. ME contributed to data acquisition, organoid culture, and analysis and interpretation. FR and MW contributed to synthesis of peptidomimetics.

EU contributed to organoid culture and analysis of protein expression. DH contributed to critically revising the article. ID and GC provided material for organoid preparation. HK contributed to study conception and critically revising the article.

ER contributed to study conception and design, murine and human organoid culture, data acquisition, analysis and interpretation, and drafting and revising the article. All authors contributed to the article and approved the submitted version. ID and GC were funded by the Deutsche Forschungsgemeinschaft DFG, German Research Foundation — Project number — SFB The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors gratefully acknowledge the Bavarian NMR Center BNMRZ for covering publication costs. We thank Beate Rauscher for excellent technical support. Abe, H. Conjugation of dipeptide to fluorescent dyes enhances its affinity for a dipeptide transporter PEPT1 in human intestinal Caco-2 cells.

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Nutrient absorption and metabolism

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