This page intentionally left blank vip persianss.irNutrition, Digestion, & Absorption David A. Bender, PhD & Peter A. Mayes , PhD, DSc = Describe the digestion and absorption of carbohydrates, ipids, proteins, vitamins, and minerals '= Explain how energy requirements can be measured and estimated and how ‘measuring the respiratory quotient permits estimation of the mix of metabolic fuels being oxidized. = Describe the consequences of undernutrition: marasmus, cachexia, and kwashiorkor. = Explain how protein requirements are determined and why more of some proteins than others are required to maintain nitrogen balance, BIOMEDICAL IMPORTANCE In addition to water, the diet must provide metabolic fuels (mainly carbohydrates and lipids), protein (for growth and turnover of tissue proteins, as well as a source of metabolic fuel), fiber (for bulk in the intestinal Iumen), minerals (containing elements with specific metabolic functions), and vilamins and essential fatty acids (organic compounds needed in smaller amounts for other metabolic and physi- ‘logic functions). The polysaccharides, triacylglycerols, and proteins that make up the bulk of the diet must be hydrolyzed to their constituent monosaccharides, fatty acids, and amino acids, respectively, before absorption and utilization. Minerals and vitamins must be released from the complex matrix of food before they can be absorbed and utilized Globally, undernutrition is widespread, leading to impaired growth, defective immune system, and reduced ‘work capacity. By contrast, in developed countries, and increas. ingly in developing countries, there is excessive food con- sumption (especially of fat), leading to obesity, and the development of diabetes, cardiovascular disease, and some cancers. Worldwide, there are more overweight and obese people than underaourished people, Deficiencies of vita ‘min A, ron, and iodine pose major health concerns in many countries, and deficiencies of other vitamins and minerals are a major cause of ill health, In developed countries nutri cent deficiency is rare, although there are vulnerable sections of the population at risk Intakes of minerals and vitamins that are adequate to prevent deficiency may be inadequate to promote optimum health and longevity. Excessive secretion of gastric acid, associated with, Helicobacter pylor infection, can result in the development of gastricand duodenal ulcers; small changes in the composition of bile can result in crystallization of cholesterol as gallstones; failure of exocrine pancreatic secretion (as in cystic fibrosis) leads to undernutrition and steatorthea, Lactose intolerance is the result oflactase deficiency, leading to diarshea and intes- tinal discomfort when lactose is consumed. Absorption of intact peptides that stimulate antibody responses causes aller- sic reactions; celiac disease is an allergic reaction to wheat gluten.538 SECTION SpecalTopes A) DIGESTION & ABSORPTION OF CARBOHYDRATES ‘The digestion of carbohydrates is by hydrolysis to liberate oli gosaccharides, then free mono- and disaccharides, The increase in blood glucose after atest dose ofa carbohydrate compared with that after an equivalent amount of glucose (as glucose or from a reference starchy food) is known as the glycemic index. Glucose and galactose have an index of 1 (or 100%), as do lactose, maltose, isomaltose, and trehalose, which give rise to these monosaccharides on hydrolysis. Fructose and the sugar alcohols are absorbed less rapidly and have a lower slycemic index, as does sucrose. The glycemic index of starch varies between near 1 (or 100%) and near 0 asa result of va able rates of hydrolysis, and that of nonstarch polysaccharides (see Figure 15-13) is 0. Foods that have a low glycemic index are considered to be more beneficial since they cause less fluc- tuation in insulin secretion. Resistant starch and nonstarch polysaccharides provide substrates for bacterial fermenta tion in the large intestine, and the resultant butyrate and other short chain fatty acids provide a significant source of fuel for intestinal enterocytes. There is evidence that butyrate also has antiprolferative activity, and so provides protection against colorectal cancer. Amylases Catalyze the Hydrolysis of Starch ‘The hydrolysis of starch is catalyzed by salivary and pancre- atic amylases, which catalyze random hydrolysis of al 4) slycoside bonds, yielding dextrins, then a mixture of glucose, maltose, and maltotriose and small branched dextrins (irom the branchpoints in amylopectin, Figure 15-12) Disaccharidases Are Brush Border Enzymes "The disaccharidases, maltase, sucrase-isomaltase (a bifune- tional enzyme catalyzing hydrolysis of sucrose and isomaltose), lactase, and trehalase are located on the brush border of the intestinal mucosal cells, where the resultant monosaccharides and those arising from the diet are absorbed. Congenital de ciency of lactase occurs rarely in infants, leading to lactose intolerance and failure to thrive when fed on breast milk oF normal infant formula. Congenital deficiency of sucrase- isomaltase occurs among the Inuit, leading to sucrose intolex- ance, with persistent diarthea and failure to thrive when the dict contains sucrose. In most mammals, and most human beings, lactase activ- ty begins to fall alter weaning and is almost completely lost by late adolescence, lading to lactose intolerance. Lactose remains in the intestinal lumen, where it is a substrate for bacterial fermentation to lactate, resulting in abdominal dis- comfort and diarrhea after consumption of relatively large amounts. In two population groups, people of north European, origin and nomadic tribes of sub-Saharan Africa and Arabia, lactase persists ater weaning and into adult life, Marine mammals secrete high-fat milk that contains no carbohydrate, and their pups lack lactase. There Are Two Separate Mechanisms for the Absorption of Monosaccharides in the Small Intestine Glucose and galactose ae absorbed by a sodium-dependent process, They are cazried by the ssme transport protein (SGLT 1) and compete with each other for intestinal absorp- tion (Figure 43-1). Other monosaccharides are absorbed by carrier-mediated diffusion, Because they are not actively transported, fructose and sugar alcohols are only absorbed down their concentration gradient, and alter a moderately high intake, some may remain in the intestinal lamen, acting asa substrate for bacterial fermentation. Large intakes of frue- tose and sugar alcohols can lead to osmatic diarthea DIGESTION & ABSORPTION OF LIPIDS ‘The major lipids in the diet are triacylglycerols and, to a lesser extent, phospholipids. These are hydrophobic molecules and have to be hydrolyzed and emulsified to very small droplets Balseose Glucose Frictose” Galeloce ‘cure FIGURE 43-1 Transport of glicose, fructose, and galactose across the intestinal epithelium. The SGLT 1 transporters coupled to the Na-K" puma, allowing glucose and galactose to be wansported against hel concentravion gradients, The GLUT 5 No~indepencent faciitative vansporte allows Fuctose 3: well as glucose and galac- ‘tose tobe transported dovin ther concentration gradients. Fxt from ‘the cel fo al sugars is via the GLUT 2facltative transporter.(enicelles, 4-6 nm in diameter) before they can be absorbed ‘The fat-soluble vitamins, A,D,E, and K, and a variety of other lipids (including cholesterol and carotenes) aze absorbed dissolved in the lipid micelles. Absorption of carotenes and fat-soluble vitamins is impaired on a very low fat diet. Hydeolysis of triacylglycerols is initiated by lingual and gastric lipases, which attack the 5-3 ester bond forming 1 2-diacyglycerols and fre fatty acids, which at as emulsify: ing agents: Pancreatic lipase ie secreted into the small intestine and requires a further pancreatic protein, colipase, fr activity. Itis specific for the primary ester links—ie, postions 1 and 3 in teiacylglycerols—resulting in 2-monoacyllycerols and five fatty acids asthe major end products of luminal triacyl- lycerol digestion, Inhibitors of pancreatic lipase are used to vglycerol hydrolysis in the treatment of severe ‘obesity. Pancreatic esterase in the intestinal lumen hydrolyzes ‘monoacylglyceros, but they are poor substrates, and only -25% of ingested triacylglycerol is completely hydrolyzed to glycerol and faty acids before absorption (Figure 43-2) Bile salts, formed in the liver and secreted inthe bil, permit emulsifiation of the products of lipid digestion into micelles together with dietary phospholipids and cholesterol secreted {nthe bile (about 2 gid) as well as dietary cholesterol (about 015 gd). Micelles are less than 1 ym in diameter, and soluble, so they allow the product of digestion, snchuding the fat-soluble vitamins, to be transported through the aqueous environ. rent of the intestinal lumen to come into close contact with the brush border of the mucosa cells, allowing uptake into the epithelium, The bie salts remain in the intestinal lumen, where most ae absorbed from the eum into the enterohepatic ueLody 61d Z-€¥ FUNDA Tanai ORTOP 540«ells, where they ae hydrolyzed to free amino acids, which are then transported ino the hepatic portal vein. Relatively large peptides may be absorbed intact, either by uptake into mucosal epithelial cells (ransclluat) or by passing between epithe lial cells (paracellular). Many such peptides are large enough to stimolate antibody formation—this is the basis of allergic reactions to foods DIGESTION & ABSORPTION OF VITAMINS & MINERALS ‘Vitamins end minerals are released from food during diges- tion, although this is not complete, and the availability of vitamins and minerals depends on the type of food and, espe- Fe Duodenal mucosel ee Bloodstream Feroportn| ownrequated by hepeicin FIGURE 43-3 Absorption of iron. Hepcidin secreted by the lve dowregulatessyathess ‘of ferropoctn and limits iron absorption. ‘A more recent technique permits estimation of total energy expenditure over a period of 1 to 2.weeks, using dual ‘isotopically labeled water,’H,""0.°H is lost from the body oniy in water, while "O is lost in both water and carbon dioxide; the difference in the rate of los ofthe two labels permits esti mation of total carbon dioxide production, and hence oxygen. consumption and energy expenditure (Figure 43—4) Basal metabolic rate (BMR) is the energy expenditure by the body when at rest, but not asleep, under controlled conditions of thermal neutrality, measured about 12 hours after the last meal, and depends on weight, age, and gender. ‘Total energy expenditure depends on the BMR, the energy required for physical activity, and the energy cost of synthe- sizing reserves in the fed state I is therefore possible to esti- mate an individual’ energy requirement from body weight, age, gender, and level of physical activity, Body weight affects 100) 0] «0| 40| | 20| 3 10 5 20 25 Days since ingesting duaHiabeted water FIGURE 43-4 Dual isotopically labeled water for estimation of energy expenditure, BMR because there is a greater amount of active tissue in a larger body. The decrease in BMR with increasing age, even when body weight remains constant, is the result of muscle ts- sue replacement by adipose tissue, whichis metabolically less active. Similarly, women have a significantly lower BMR than, do men of the same body weight and age because womerts bodies contain proportionally more adipose tissue Energy Requirements Increase With Activity ‘The most useful way of expressing the energy cost of physical activities is at a multiple of BMR. This is known as the physi- cal activity ratio (PAR) or metabolic equivalent of the task (MET), Sedentary activities use only about 1.1 to 1.2.x BMR, By contrast, vigorous exertion, such as climbing stairs, ross- country walking uphill, etc, may use 6 to 8x BMR, The overall physical activity level (PAL) isthe sum of the PAR of different activities, multiplied by the time taken for that activity, divided by 24 hours, Ten Percent of the Energy Yield of a Meal May Be Expended in Forming Reserves ‘There is a considerable increase in metabolic rate after a meal (dietinduced thermogenesis). A small part of this is the energy cost of secreting digestive enzymes and of active trans- ‘port of the products of digestion; the major partis the result of synthesizing reserves of glycogen, tiacyiglycerl, and protein, There Are Two Extreme Forms of Undernutrition Marasmus can occur in both adults and children and occurs in vulnerable groups of all populations. Kwashiorkor affects vip.persianss.ironly children and has been reported only in developing coun- tries. The distinguishing feature of kwashiorkor is that there is fluid retention, leading to edema, and fatty infiltration of, the liver. Marasmus is a state of extreme emaciation; itis the ‘outcome of prolonged negative energy balance. Not only have the body's fat reserves been exhausted, but there is wastage of muscle as well, and asthe condition progresses there is loss of | protein from the heart, liver, and kidneys. The amino acids released by the catabolisin of tissue proteins are used as a metabolic fuel and as substrates for gluconeogenesis to maintain a supply of glucose for the brain and red blood cells (See Chapter 20). As a result of the reduced synthesis of proteins, there is impaired immune response and more risk from infections, Impairment of cell proliferation in the intesti- ‘nal mucosa occurs, resulting in reduction in the surface area of the intestinal mucosa, and reduction in the absorption of such ‘nutrients as are available. Patients With Advanced Cancer and AIDS Are Malnourished Patients with advanced cancer, HIV infection and AIDS, and 4 number of other chronic diseases are frequently undernour- ished, a condition called cachexia, Physically, they show all the signs of marasmus, but there is considerably more loss of ody protein than that occurs in starvation. The secretion of ‘eytokines in response to infection and cancer increases the catabolism of tissue protein by the ATP-dependent ubiquitin- proteasome pathway, so increasing energy expenditure. This differs from marasmus, in which protein synthesis i reduced, but catabolism in unaffected. Patients are hypermetaboli¢ i, they havea considerably increased BMR. In addition to activa- tion of the ubiquitin-proteasome pathway of protein catabo: lism, three other factors are involved, Many tumors metabolize glucose anaerobically to release lactate, This is then used for gluconeogenesis in the liver, which is energy consuming with a net cost of six ATP for each mol of glucose cycled (eee Figure 19-4). There is increased stimulation of mitochondrial ‘uncoupling proteins by cytokines leading to thermogenesis and increased oxidation of metabolic fuels, Futile cycling of lipids occurs because hormone sensitive lipase is activated by a proteoglycan secreted by tumors, resulting in liberation of fatty acids from adipose tissue and ATP-expensivereesteification to Uuiacylglycerols in the liver, which are exported in VLDL. Kwashiorkor Affects Undernourished Children In addition to the wasting of muscle tissue, loss of intestinal ‘mucosa and impaired immune responses seen in marasmus, children with kwashiorkor show a number of characteris: luc features. The defining feature is edema, associated with a decreased concentration of plasma proteins. In addition, there is enlargement of the liver as a result of accumulation of fat, It was formerly believed that the cause of kwashiorkor vwas a lack of protein, with a more or less adequate energy. inlake; however, analysis of the diets of affected children CHAPTERS Nation Ogetin, Abortion 543 shows that this is not so. Protein deficiency leads to stunting of growth, and children with kwashiorkor are less stunted than those with marasmus, Furthermore, the edema begins to improve early in treatment, when the child is still receiv ing alow protein diet. Very commonly, an infection precipitates kwashiorkor. Superimposed on general food deficiency, there is probably a deficiency of antioxidant nutrients such as zinc, copper, caro ene, and vitamins C and E, The respiratory burst in response to infection leads to the production of oxygen and halogen free radicals as part ofthe cytotoxic action of stimulated mac rophages, This added oxidant stress triggers the development of kwashiorkor, PROTEIN & AMINO ACID REQUIREMENTS Protein Requirements Can Be Determined by Measuring Nitrogen Balance ‘The state of protein nutrition can be determined by measuring the dietary intake and output of nitrogenous compounds from the body. Although nucleic acids also contain nitrogen, protein is the major dietary source of nitrogen and measurement of total nitrogen intake gives a good estimate of protein intake (mg N x 625 = mg protein, as N is 16% of most proteins). The output ‘of N from the body is mainly in urea and smaller quantities of ‘other compounds in urine, undigested protein in feces; signifi ‘cant amounts may also be lost in sweat and shed skin. The dif- {ference between intake and output of nitrogenous compounds is known as nitrogen balance. Three states can be defined. In a healthy adult, nitrogen balance is in equilibrium, when intake equals output, and there is no change in the total body content of protein, Ina growing child, a pregnant woman, or a person in recovery from protein loss, the excretion of nitrog: ‘enous compounds is less than the dietary intake and there is net relention of nitrogen in the body as protein—positive nitrogen balance. In response to trauma or infection, or ifthe intake of protein is inadequate to meet requizements, there is ret loss of protein nitrogen from the body—negative nitro- agen balance. Except when replacing protein losses, nitrogen ‘equilibrium can be maintained at any level of protein intake above requirements. A high intake of protein docs not lead to positive nitrogen balance; although it increases the rate of protein synthesis, it also increases the rate of protein catabo lism, so that nitrogen equilibrium is maintained, albeit with a higher rate of protein turnover, Both protein synthesis and catabolism are ATP expensive, and this increased rate of pro tein turnover explains the increased diet-induced thermogen- esis seen in people consuming a high protein diel ‘The continual catabolism of Ustue proteins creates the requitement for dietary protein, even in an adult who is not ‘growing: although some of the amino acids released can be re utilized, much is used for gluconeogenesis inthe fasting state. [Nitrogen balance studies show thatthe average daly requirement vip.pe!544 skeTION IX. Specialist) is 0.66 g of protein per kg body weight (giving a reference intake of 0.825 g of protein/kg body weight, allowing for indi vidual variation); 55 g/d, or 0.825% of energy intake. Average intakes of protein in developed countries are of the order of £80 to 100 g/d. ie, 14% to 15% of energy intake. Because grow ing children are increasing the protein in the body, they have a proportionally greater requirement than adults and should be in positive nitrogen balance. Even so, the need is relatively small compared with the requirement for protein turnover, In some counlsies, protein intake is inadequate to meet these requirements, resulting in stunting of growth. There is ite or no evidence that athletes and body builders require large amounts of protein; simply consuming more of a normal diet providing about 14% of energy from protein will provide more than enough protein for increased muscle protein synthesis—the ‘main requirement is for an increased energy intake to permit increased protein synthesis. There Is a Loss of Body Protein in Response to Trauma & Infection One of the metabolic reactions to a major trauma, such as a burn, a broken limb, or surgery, ian increase inthe net catab- olism of tissue proteins, both in response to cytokines and lucocorticoid hormones, and asa result of excessive uiiza tion of threonine and cysteine in the synthesis of acute-phase proteins. As much as 6% to 7% of the total body protein may be lost over 10 days. Prolonged bed rest results n considerable loss of protein because of atrophy of muscles. Protein catabo lism may be increased in response to cytokines, and without the stimulus of exercise itis not completely replaced. Lost pro tein is replaced during convalescence, when there is positive nitrogen balance. Again, as in the case of athletes, a normal diets adequate to permit tis replacement protein synthesis The Requirement Is Not Just for Protein, but for Specific Amino Acids Not all proteins ae nutritionally equivalent. More of some is needed to maintain nitrogen balance than others because dit: ferent proteins contain different amounts of the various amino acids. The body's requirement is for amino acids n the correct proportions to replace tise proteins, The amino acids ean be divided into two groups: tential and nonessential. There ate nine essential or indispensable amino acids, which can not be synthesized inthe body: histidine, isoleucine, lecine, Iysin, methionine, phenylalanine, threonine tryptophan and valine. fone ofthese is lacking or inadequate then regardless ofthe total intake of protein, it will mot be possible to maintain bitrogen balance since there will not be enough of tht amino acid for protein synthesis: Twoamino aids, cysteine and tyrosine, canbe synthesized in the body, but only from essential amino acid precursors— cysteine from methionine and tyrosine from phenylalanine The dietary intakes of cysteine and tyrosine thus aflect the recpireneot for methionine and pheaplanioe, The rcuining 11 amino acids in proteins are considered to be nonessential or dispensable since they can be synthesized as long az there fs enough tolal protein in the diet. If one of these amino acids is omitted from the diet, nitrogen balance can still be main tained. However, only three amino acids, alanine, aspartate, and glutamate, can be considered to be truly dispensable; they are synthesized by transamination of common meta- bolic intermediates (pyruvate, oxaloacetate, and keloglutarate, respectively). The remaining amino acids are considered as nonessential, but under some circumstances the requirement may outstrip the capacity for their synthesis SUMMARY 1 Digestion involves hydrolyzing food molecules into smaller molecules for absorption through the gastrointestinal epithelium. Polysaccharides ate absorbed as monosacchatides, swiacyelycerole a2 2-monoacyiglycerol, fatty acids and lycerl, and proteins ae amino acide and small peptides, 1 Digestive disorders atise sea nesult of (1) enzyme deficiency, cg lctae and suctase; (2) malabsorption, ef, of glucose and galactose a a result of defects in the Na'-glucore cotransporter (SGT 2); (8) absorption of unkydolyzed polypeptides leading to smmiune responses, ef, a in celine diteas; and (4) precipitation of cholesterol fom bie ae gallstones 1 In addition to water, the dit must provide metabolic fuels (carbobydrate and ft) for body growth and activity, protein for synthesis of tise proteins, ber for bulk in the sternal contents, minerals fo specific metabolic functions (Chapter 4), polyunsaturated fay acids of the n-3 and n=6 famies, and ‘vitamins organic compounds needed in small amounts for other essential functions (see Chapter 44) = Undernutrtion occurs in two extreme forms: marasmus, in adults and children, and kwaehiorkor in children. Chronic illness can also lead to undernutrition (cachexia) asa result of bbypermetaholism. = Overnuttition leads to excess energy intake and i associated with chronie noncommunicable diseases such as obesity, type 2 diabetes, atherosclerosis, cancer and hypertension = “Twenty different amino acide are required for protein synthesis, ‘of which nine ae essential n the human diet. The quantity ‘of protein required can be determined by studies of nitrogen balance and is afected by protein quality—the amounts of ‘extential amino ack present in dietary proteins compared. ‘with the amounts required fr teeue protein synthetis. REFERENCES Bender DA: Inroduction to Nutrition and Metabaliom, Sth CRC Press, 2014 Bender DA, Bender AE: Nutrition: A Reference Handbook. Oxford University Pret, 1997 Fuller ME, Gullick Pf; Human amino acid requirements can the controversy be resolved? Ann Rev Nutr 1994:14217 Geisler C, Powers HI (editors Human Nuttion, 2th ed. Hever, 2010. Gibney MY, Lanham-New S, Cassidy A, etal Introduction to Human Nutrition, The Nutrition Society Textbook Series, 2nd ed, ‘Wiley-Blackwell, 2009. vip.pe!Institute of Medicine: Dietary Reference Intakes for Energy, Carbohydrate, Fiber Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) National Academies Press, 2002 Penchare PB, Ball RO: Different approaches to define individual ‘amino acid requirements, Ann Rev Nutr 200323101, Royal College of Physicians: Nutrition and Patients—A Doctor’ Responsibility. Royal College of Physicians, 2002. ‘Swallow DM: Genetic influences on eazbohydrate digestion, [Nutr Res Rev 200331637, CHAPTERS: Nation Ogetin, Abortion 545 ‘World Health Organization Technical Report Series 894: ‘Obesity —Preventing and Managing the Global Epidemic, WHO, 2000, World Health Organization Technical Report Series 916: Diet and the Prevention of Chronic Disease. WHO, 2003, ‘World Health Organization Technieal report Series 935: Protein and “Aniino Acid Requirements in Human Nutrition, WHO, 2007. vip.persianss.ir