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The nutritional implications of lactose intolerance Tolensky, Arlene Frances 1975

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THE NUTRITIONAL IMPLICATIONS OF LACTOSE INTOLERANCE i-*>y \ ARLENE FRANCES TOLENSKY B.Sc, McGill University, 1972 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the D i v i s i o n of Human N u t r i t i o n School of Home Economics We accept t h i s thesis as conforming to the required standard The University of B r i t i s h Columbia December, 197^ In presenting th is thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Un ivers i ty of B r i t i s h Columbia, I agree that the L ibrary shal l make it f ree ly ava i l ab le for reference and study. I fur ther agree that permission for extensive copying of th is thes is for scho la r ly purposes may be granted by the Head of my Department or by his representat ives . It is understood that copying or pub l i ca t ion of th is thes is fo r f inanc ia l gain shal l not be allowed without my wri t ten permission. Depa rtment The Univers i ty of B r i t i s h Columbia Vancouver 8, Canada i ABSTRACT Adult lactose intolerance due to low lactase l e v e l s i s often associated with varying degrees of abdominal d i s t r e s s ranging from bloating and distension to severe cramps and diarrhea. Recent studies have suggested that these gastro-i n t e s t i n a l disturbances may i n t e r f e r e with normal absorption of nutrients i n addition to lactose. In order to investigate t h i s p o s s i b i l i t y , both human and animal studies were conducted. Twenty-three healthy Caucasian adults were used to study the e f f e c t of lactose on the absorption of vitamin A, ascorbic a c i d and protein. Eight of the 2 3 subjects were lactose intolerant on the basis of a maximum r i s e of blood glucose of less than 2 0 mg/100 ml over the f a s t i n g blood glucose l e v e l a f t e r ingestion of 5 0 g of lactose i n 3 0 0 ml water. In each study, blood samples were drawn a f t e r an overnight f a s t and at intervals up to k hours a f t e r consuming 5 0 g lactose i n an aqueous s o l u t i o n or te s t meal containing g e l a t i n , vitamin C or vitamin A. Sucrose replaced lactose as a c o n t r o l . The r e s u l t s from the human studies f a i l e d to demon-strate that lactose had an e f f e c t on the absorption of ascorbic acid, vitamin A or protein i n lactose intolerant subjects. I t may be that the composition of the test drink which contained fat and protein, may have affected the rate of absorption of the nutrients tested through a delay i n g a s t r i c emptying time. However, the finding that absorption of vitamin C remained unaffected even when consumed with an aqueous s o l u t i o n of lactose, i s attributed to the p o s s i b i l i t y that the l e v e l of ascorbic acid given was too low to show measurable differences i n blood l e v e l s of that nutrient. To study the e f f e c t of lactose on the absorption of calcium, f a t and protein, balance studies were conducted using postweaning r a t s . The experimental groups received either 10?S, 20fo or 3 0 $ lactose d i e t s , while an equivalent amount of sucrose replaced the lactose i n the c o n t r o l d i e t s . In addition, postweaning rats were given vitamin A i n t r a g a s t r i c a l l y with either lactose or sucrose to investigate the e f f e c t of lactose on vitamin A absorption. From the balance studies with r a t s , the r e s u l t s indicate that f e c a l nitrogen and f a t excretion was s i g n i f i -cantly (p < 0 , 0 5 ) higher i n a l l the animals fed lactose as compared to the controls. However, f e c a l calcium excretion was found to be generally lower for each lactose group r e l a t i v e to the controls, but the difference was s t a t i s t i c a l l y s i g n i f i -cant ( p < 0 . 0 5 ) only at the 3 0 $ l e v e l of lactose intake. Improved calcium absorption may have important n u t r i t i o n a l implications where dietary calcium intake i s low. It appears though, that the l e v e l of dietary lactose would most l i k e l y have to exceed the l i m i t s of normal lactose consumption to have an e f f e c t on the absorption of nutrients. ACKNOWLEDGEMENT I would l i k e to thank my parents for the love, understanding and encouragement that they have always given me. This work i s dedicated to them. I also wish to thank Dr. J . Leichter for his assistance i n t h i s study, and Dr. M. Lee and Dr. J . Angel for serving on my committee. i v . TABLE OF CONTENTS PAGE I. INTRODUCTION 1 I I . LITERATURE REVIEW k A. Adult_Lactose_Intolerance 4 1. Diagnosis. 4 2. Pathogenesis of Symptoms 4 3. Etiology 5 a. Genetic Theory............. 5 b. Lactase Induction by Milk Consumption 7 c. Dietary I n h i b i t o r s . . . . , 8 d. Disease Hypothesis. 8 B. The_Effect_of_Intest £&2$2§§-lGt:2i§r.§52§» ••••••••••••• 9 1. The E f f e c t of I n t e s t i n a l M o t i l i t y on Nutrient  Absorption. 9 2. The E f f e c t of Gastric Emptying,on Nutrient  Absorption • • 14 3. The E f f e c t of Diet Composition on Symptoms of  Lactose Intolerance and Nutrient Absorption...... 16 I I I . MATERIALS AND METHODS 19 A. Human_Studies • 19 1, Experimental Procedures. 20 a. The E f f e c t of Lactose on the Absorption of Protein and Vitamin A 20 b. The E f f e c t of Lactose on the Absorption of Vitamins A and C 20 v. PAGE c. The E f f e c t of Lactose on the Absorption of Vitamins A and C 21 2. Methods 22 a. Plasma Glucose Determination 22 b. Plasma Urea Nitrogen Determination............ 22 c. Plasma Vitamin A Determination..... 23 d. Plasma Vitamin C Determination 23 3. S t a t i s t i c a l Analysis 23 B. Animal_Studies 2k 1. Experimental Procedures. 2^ a. The E f f e c t of Lactose on the Excretion of Fat, Nitrogen and Calcium. 2k b. The E f f e c t of Lactose on the Absorption of Vitamin A 26 2. Methods 27 a. Nitrogen Determination. 27 b. Calcium Determination. 27 c. Determination of Fat Content 27 d. Plasma Vitamin A Determination 27 3. S t a t i s t i c a l Analysis 27 IV. RESULTS 29 A. Human_Studies 29 1. The E f f e c t of Lactose on the Absorption of Protein.... 29 2. The E f f e c t of Lactose on the Absorption of  Ascorbic Acid • 29 3. The E f f e c t of Lactose on the Absorption of Vitamin A 33 v i . PAGE B. AnimalJ3tudies 33 1. The E f f e c t of Lactose on the Excretion of Fat. Nitrogen and Calcium. 33 a. Body Weight Gain and Food Consumption 33 b. The E f f e c t of Lactose oh Fecal Fat Excretion... 35 c. The E f f e c t of Lactose on Fecal and Urinary Nitrogen Excretion ,. 37 d. The E f f e c t of Lactose on Fecal and Urinary Calcium Excretion 37 2. The E f f e c t of Lactose on the Absorption of Vitamin A 41 V. DISCUSSION 45 A. HumanJStudies 4-5 B • Animal JStudies 48 1. The E f f e c t of Lactose on the Excretion of Nitrogen. Fat and Calcium 48 2. The E f f e c t of Lactose on the Absorption of Vitamin A. 52 VI. RECOMMENDATIONS 53 VII. SUMMARY 55 BIBLIOGRAPHY 58 APPENDIX 70 v i i . LIST OF TABLES PAGE I. Composition of Diets 2 5 I I . Mean Maximum Rise + S.D. i n Plasma Urea i n Lactose Tolerant and Intolerant Subjects Given 5 5 g Gel a t i n and 2 5 , 0 0 0 IU Vitamin A With Either 5 0 g Lactose or 5 0 g Sucrose 3 0 I I I . Mean Maximum Rise ± S.D. i n Plasma Ascorbic Acid i n Lactose Tolerant and Intolerant Subjects Given 5 0 0 mg Vitamin C and 2 5 , 0 0 0 IU vitamin A with Either 5 0 g Lactose or 5 0 g Sucrose 3 0 IV, Mean Maximum Rise ± S.D. i n Plasma Ascorbic Acid i n Lactose Intolerant Subjects Given 2 0 0 , 0 0 0 IU Vitamin A and 1 g Vitamin G with a Test Meal Containing 1 5 g Casilan, 2 5 ml Olive O i l and Ei t h e r 4 5 g Lactose or 4 5 g Sucrose 3 2 V. Mean Maximum Rise + S.D. i n Plasma Vitamin A i n Lactose Intolerant~Subjects Given 2 0 0 , 0 0 0 IU Vitamin A and 1 g Vitamin C with a Test Meal Containing 1 5 g Casilan, 2 5 ml Olive O i l , and Either 4 5 g Lactose or 4 5 g Sucrose 3 2 VI. Mean Weight Gain + S.D. of Experimental and Control Animals Over a Ten Day Period ( N = 6 ) . . . . . . . . . . 3 4 VII. Average Food Consumption + S.D. of Experimental and Control Animals Over a Ten Day Period (N=6).... 3 4 VIII. E f f e c t of Different Levels of Dietary Lactose on Fecal Excretion of Fat (N=6) 3 6 IX. E f f e c t of Different Levels of Dietary Lactose on Fecal Excretion of Nitrogen (N=*6) 3 8 X. E f f e c t of Dif f e r e n t Levels of Dietary Lactose on Urinary Excretion of Nitrogen (N=6) 3 9 XI. E f f e c t of Different Levels of Dietary Lactose on Fecal Excretion of Calcium (N=6) 4 0 XII. E f f e c t of Different Levels of Dietarv Lactose on Urinary Excretion of Calcium (N=6) 42 XIII. Mean Plasma Vitamin A Levels i n Postweaning Rats Af t e r Intragastric Administration of 2 5 0 0 IU of Vitamin A with E i t h e r 5 0 0 mg Lactose or 5 0 0 mg Sucrose ( 4 animals per subgroup) 4 3 1 . I. INTRODUCTION Adult lactose intolerance due to low l e v e l s of i n t e s t i n a l lactase a c t i v i t y i s common i n the majority of adults throughout the world. I t i s p a r t i c u l a r l y evident i n c e r t a i n races and ethnic groups ( 1 ) , a fact that accounts for i t s high incidence on a worldwide basis. In Eskimos ( 2 , 3 ) , Jews ( 4 - 7 ) , Asians ( 8 - 1 5 ) , Negroes ( 1 6 - 2 7 ) and North American Indians ( 3 , 2 1 , 2 8 - 2 9 ) i the incidence of lactose intolerance i s generally greater than 7 0 $ and may even be as high as 90%. On the other hand, i n some peoples, including northwestern Europeans, the incidence of lactose intolerance i s often below 2 0 $ ( 1 ) . In those individuals with low lactase l e v e l s , con-sumption of one or more glasses of milk w i l l induce various degrees of abdominal distress ranging from bloating and d i s -tension to severe cramps and diarrhea ( 3 0 , 3 1 ) . The symptom-a t i c response of a lactose intolerant i n d i v i d u a l i s associated with the accumulation of lactose i n the i n t e s t i n a l lumen. Since lactase l e v e l s are low, the a b i l i t y to hydrolyze lactose to i t s constituent monosaccharides, glucose and galactose, which are r e a d i l y absorbed, i s reduced. Consequently, lactose accumulates i n the lumen of the small i n t e s t i n e causing f l u i d and e l e c t r o l y t e changes which increase i n t e s t i n a l m o t i l i t y . In the colon, fermentation products r e s u l t i n g from b a c t e r i a l action on the unabsorbed lactose impair absorption of the f l u i d load and i n t e s t i n a l m o t i l i t y i s further enhanced. Therefore, the distension of the small intestine and the increased m o t i l i t y 2 . of both the small and large i n t e s t i n e are responsible for the abdominal discomfort seen i n lactose intolerance. Although the incidence and the etiology of adult lactose intolerance have been investigated extensively, l i t t l e i s known about the e f f e c t of lactose intolerance on the absorp-t i o n of nutrients other than lactose. Since rapid t r a n s i t of food through the g a s t r o i n t e s t i n a l t r a c t may not a f f o r d s u f f i c i e n t time for the absorption of dietary nutrients, a lactose i n t o l e r -ant i n d i v i d u a l may not be deriving f u l l n u t r i t i o n a l benefits when consuming only milk or other lactose-containing products. Recently, Paige and Graham ( 3 2 ) noted that lactose intolerant subjects receiving a lactose-based d i e t , showed an increase i n s t o o l water, f a t and nitrogen excretion as compared to values obtained on a sucrose-based d i e t . S i m i l a r l y , Calloway and Chenoweth ( 3 3 ) investigated nutrient absorption and retention i n lactose intolerant subjects. Their r e s u l t s indicated increased f e c a l energy losses that were lactose dose dependent i n four intolerant subjects each fed diets of varying lactose content over 1 2 day periods, as compared to the two c o n t r o l subjects. Both studies suggest that consumption of milk or other lactose-containing products might r e s u l t i n impaired , absorption of nutrients i n addition to lactose. The purpose of the present work was to examine the e f f e c t of dietary lactose on nutrient absorption i n lactose intolerant individuals as well as i n postweaning rats, which have low l e v e l s of i n t e s t i n a l lactase a c t i v i t y . 3. Human subjects were used to assess the effect of lactose on the absorption of vitamin A, ascorbic acid, and protein. Balance studies were carried out using postweaning rats to examine the effect of lactose on the absorption of fat, protein and calcium. In addition, postweaning rats were given vitamin A intragastrically with either lactose or sucrose to investigate the effect of lactose on vitamin A absorption. 4. I I . LITERATURE REVIEW A. Adult_Lactose_Intolerance 1 . Diagnosis Intolerance to lactose has been found i n many adults who were able to consume milk f r e e l y during infancy and c h i l d -hood ( 5 D . Most adults who are lactose intolerant are able to tolerate small quantities of milk, as i n coffee or tea. However, ingestion of one or more glasses of milk ( 3 0 , 3 1 ) may induce symptoms ranging from flatulence and bloating to severe cramps and diarrhea. I n t e s t i n a l lactase a c t i v i t y as low as 7 units/g protein may be found i n an intolerant i n d i v i d u a l as compared to approximately 7 0 units/g protein i n a lactose tolerant subject ( 3 0 , 3 4 ) . Because of the diminished l e v e l s of lactase a c t i v i t y i n the i n t e s t i n a l brush border c e l l s , a load of lactose w i l l not be s u f f i c i e n t l y hydrolyzed to i t s component units, glucose and galactose. C l i n i c a l l y , a f l a t lactose tolerance curve i s seen i n an intolerant subject as indicated by a, r i s e of blood glucose of less than 2 0 mg/100 ml over the f a s t i n g blood glucose l e v e l a f t e r a 5 0 g o r a l lactose load ( 3 5 ) . This low r i s e i n blood glucose may be accompanied by g a s t r o i n t e s t i n a l symptoms. 2 . Pathogenesis of Symptoms The symptoms associated with low lactase l e v e l s are caused by the accumulation of lactose i n the i n t e s t i n a l lumen. The unabsorbed lactose attracts a net osmotic movement of water 5 . out into the lumen ( 3 6 ) . This i s associated with changes i n the sodium gradient of the small i n t e s t i n e ( 3 7 ) so that absorption of water and e l e c t r o l y t e s i s impaired. Abdominal distension and bloating r e s u l t s causing an acceleration i n t r a n s i t time ( 3 7 - 3 9 ) . The osmotic e f f e c t of the accumulated disaccharide i n the small i n t e s t i n e i s enhanced i n the colon. Here the lactose i s subjected to b a c t e r i a l degradation to a number of organic acids, e s p e c i a l l y l a c t i c and acetic acid ( 3 8-41). These are not well absorbed i n the large intestine and i n t e r f e r e with absorption of the f l u i d load presented to the colon ( 3 8 , 4 0 ) . The symptoms seen then, are due to disten-sion of the small i n t e s t i n e (42) and the increased m o t i l i t y of both the small and large i n t e s t i n e (42) induced by the increased f l u i d load ( 3 8 ) . Diarrhea and occasionally steatorrhea may be seen i n lactose intolerance ( 4 0 , 4 3 - 4 5 ) . Fecal pH drops due to the presence of the organic acids (46), b a c t e r i a l counts may be increased (46), lactose as well as glucose and galactose may be found i n stools ( 4 7 ) . 3 . Etiology a. Genetic Theory One of the most widely accepted theories to explain the etiology of adult lactose intolerance i s the genetic theory ( 3 1 ) . I t would account for the equally high incidence of lactose intolerance i n those groups of people within t h e i r native environment and those same peoples who have l i v e d for generations i n countries of a t o t a l l y d i f f e r e n t environment than t h e i r native land. G i l a t et a l . (5) for example, found a high incidence of lactose intolerance among I s r a e l i Jews irrespect i v e of t h e i r o r i g i n , that i s , Ashkenazi, Sephardi, Yemenite, I r a q i and Oriental. I t has since been noted that there i s also a high incidence of intolerance among Canadian and American Jews (6,7). Investigation of the f a m i l i a l incidence of lactose intolerance also suggests a genetic etiology of adult lactose intolerance (8,40,48-51). In one study, Neale (50) found that a l l members of two generations of a Pakistani family i n B r i t a i n exhibited c l i n i c a l symptoms of lactose intolerance and/or had low l e v e l s of i n t e s t i n a l lactase a c t i v i t y . Other workers (8,40, 48-49,51) have noted that subjects who were lactose intolerant usually had a parent or s i b l i n g who had experienced intolerance to lactose. In addition, Cook and Kajubi (23) found a Bantu t r i b e i n East A f r i c a having a high incidence of lactose intolerance, the "Hamitic" Hima and Tussi t r i b e with a low incidence and the Hutu and Iru t r i b e s with an intermediate incidence who are believed to be of mixed Bantu/Hamitic o r i g i n . These studies suggest that lactose intolerance i s of genetic o r i g i n . I f t h i s i s so, then there should be no c o r r e l a t i o n between milk drinking habits and l e v e l s of lactase a c t i v i t y . The second hypothesis concerning the etiology of lactose intolerance disputes t h i s assumption. 7. b. Lactase Induction by Milk Consumption This theory states that the postweaning decline i n lactase a c t i v i t y i n most mammals i s a normal consequence of decreased milk consumption. I f the enzyme i s adaptive, as t h i s theory implies, then varying the lactose content of the die t should increase i n t e s t i n a l lactase a c t i v i t y . In lactose intolerant subjects, attempts at induction of the lactase enzyme by gradually increasing the lactose content of the d i e t have not been successful (52-56). Conversely, i n healthy adult subjects, denial of milk over a period of time did not reduce i n t e s t i n a l lactase a c t i v i t y (57-58). A c o r r e l a t i o n between the le v e l s of i n t e s t i n a l lactase a c t i v i t y and milk drinking habits has also been d i f f i c u l t to esta b l i s h (59,60-64). In man, therefore, ad-aptation of i n t e s t i n a l lactase a c t i v i t y to dietary lactose seems unl i k e l y as a causative factor i n adult lactose intolerance. Data from animal studies of the adaptation of i n t e s t i n a l lactase however, have been c o n f l i c t i n g (65)* A number of workers have found that lactase a c t i v i t y could be influenced by increasing the lactose content of the die t or by prolonged lactose feeding (66-75)« B o l i n et a l . (66 - 6 7 ) demonstrated the adaptive nature of i n t e s t i n a l lactase i n the adult r a t , when an increase i n lactase a c t i v i t y was produced a f t e r 5-8 weeks on a 30% lactose diet ( 6 6 ) , as well as on a 10% lactose d i e t ( 6 7 ) . However, the postweaning decline i n lactase a c t i v i t y could not be prevented by feeding a 10% lactose d i e t up to 5 weeks of age ( 6 7 ) . Jones et a l . (69) reported s i g n i f i c a n t l y higher le v e l s of lactase i n 40 day old r a t s fed a 6Q% lactose d i e t for one 8. to twelve weeks than i n r a t s fed glucose, sucrose or a lab chow. A number of other investigators have obtained s i m i l a r r e s u l t s (70-74), An equally large number of workers have been unsuccessful i n inducing the s p e c i f i c a c t i v i t y of lactase or preventing i t s decline a f t e r weaning (76-80). The discrepancies i n the findings are most l i k e l y due to differences i n methodol-ogy « length of experimental period, l e v e l of dietary lactose fed, and the enzyme assay method used. c. Dietary Inhibitors Proponents of another theory to explain the etiology of adult lactose intolerance, claim that c e r t a i n foods or drugs ingested are lactase antagonists or i n h i b i t o r s (81). As a r e s u l t , lactose intolerance may develop. Alte r a t i o n s i n the i n t e s t i n a l mucosa due to consumption of p a r t i c u l a r foods, for example highly spiced foods and betel nuts, may a f f e c t lactase a c t i v i t y (82). Also, drugs such as c o l c h i c i n e may cause a decreased lactase production which w i l l impair lactose absorption. However, further studies to investigate dietary habits and drug usage of those races and ethnic groups exhibi-t i n g a high incidence of lactose intolerance would determine the v a l i d i t y of t h i s theory. d. Disease Hypothesis This theory suggests that lactose intolerance i n c e r t a i n population groups may be a secondary manifestation of some s u b c l i n i c a l i n f e c t i o n indigenous to that p a r t i c u l a r area. 9. In other words, where the incidence of lactose intolerance i s high, for example i n t r o p i c a l countries, i n f e c t i o n (83-84) and/or malnutrition (85-86) may a l t e r the i n t e s t i n a l mucosa and i t s enzymes and thus impair i t s absorptive capacity. Bowie et a l . (87-89) have attempted to l i n k kwashiorkor i n A f r i c a n c h i l d r e n to adult lactose intolerance. They suggest that low lactase l e v e l s may r e s u l t from i n t e s t i n a l mucosa damage due to protein deprivation i n childhood. However, the c h i l d r e n i n Bowie's studies may have been lactose intolerant independent of the kwashiorkor, that is, before i t s onset. In addition, work with rat s revealed that protein deprivation did not a f f e c t i n t e s t i n a l lactase l e v e l s (90-91). I t appears that no single theory may account for the marked differences i n the occurence of adult lactose intolerance i n various population groups. Primary adult lactose intolerance i s probably a manifestation of genetic factors influencing lactase l e v e l s i n the i n t e s t i n e . Where disease and/or drugs or c e r t a i n foods have damaged the i n t e s t i n a l mucosa, lactase l e v e l s may also be affected r e s u l t i n g i n another, secondary type of adult lactose intolerance. B. The_Effect_of_Intestim 1. The E f f e c t of I n t e s t i n a l M o t i l i t y ori Nutrient  Absorption The parasympathetic nervous system i s l a r g e l y responsible for normal g a s t r o i n t e s t i n a l function (92,93). 10. Vagal stimulation of the cholinergic f i b e r s that are present within the i n t e s t i n a l wall tends to increase the o v e r a l l degree of a c t i v i t y by promoting p e r i s t a l s i s of the i n t e s t i n a l t r a c t . Distension, presence of food or s p e c i f i c chemical substances can stimulate the nerve endings and extreme i r r i t a t i o n can e l i c i t the " p e r i s t a l t i c rush". This begins i n the duodenum and passes down the entire length of small in t e s t i n e to the i l e o -cecal valve i n a matter of minutes. In thi s way, the small intestine i s r e l i e v e d of excessive i r r i t a t i o n or distension as i t s contents are swept into the colon. On the other hand, strong stimulation of the sympathetic nerve supply can t o t a l l y block movement of food through the g a s t r o i n t e s t i n a l t r a c t . The e f f e c t of e i t h e r extreme of i n t e s t i n a l m o t i l i t y on nutrient absorption i s discussed below. C l i n i c a l as well as experimental investigations have revealed that t r a n s i t time through the small in t e s t i n e i s a c r i t i c a l f actor i n optimal nutrient absorption (9**—108). In 1936, Wade (94) f i r s t noted the re l a t i o n s h i p between m o t i l i t y and absorption. He suggested that normal g a s t r o i n t e s t i n a l absorption i s dependent upon normal g a s t r o i n t e s t i n a l m o t i l i t y . In his treatment of two c e l i a c children, he administered a p e r i s t a l t i c stimulant to correct the reduced m o t i l i t y of the i n t e s t i n a l t r a c t and to cause a period of more rapid absorption of the chyme from the lumen. The r e s u l t was an increase i n body weight and height, the elevation of previously f l a t glucose tolerance curves and the eventual, return to normal i n t e s t i n a l p e r i s t a l s i s . In 19^0, May and McCreary (95) 1 1 . conducted an experiment to prove that low blood sugar i n c e l i a c disease was i n fact related to hypomotility of the small i n t e s -t i n e . They found a d e f i n i t e improvement i n glucose tolerance curves where a p e r i s t a l t i c stimulant had been administered intraduodenally with the glucose load. The authors concluded that the e f f i c i e n c y of absorption depends upon intimate contact of the mucosa with the i n t e s t i n a l contents and that t h i s may be accomplished by the constant segmenting a c t i v i t y of the i n t e s -t i n e . Therefore, they suggest that either a decrease,or increase i n p e r i s t a l t i c a c t i v i t y would l i k e l y r e s u l t i n a reduction i n nutrient absorption. Subsequent studies have since confirmed that altered i n t e s t i n a l m o t i l i t y , whether drug- or disease-induced, plays a d i r e c t r o l e i n the malabsorption of c e r t a i n nutrients ( 9 6 - 9 8 , 1 0 2 , 1 0 5 - 1 0 7 ) . Where hypomotility has been induced by adminis-t r a t i o n of a p e r i s t a l t i c i n h i b i t o r ( 9 6 - 1 0 2 ) absorption of vitamin A ( 9 6 ) , 2^sodium and water ( 9 7 - 9 8 ) , and f a t ( i n man) ( 1 0 2 ) have been found to be impaired. However, i n other studies, absorption appeared to be at least unaffected ( 9 9 » 1 0 1 ) or even improved ( 1 0 0 ) . The c o n f l i c t i n g r e s u l t s are probably due to the experimental procedure used to study absorption. Where absorption seemed to be unaffected ( 9 9 i l 0 1 ) or enhanced ( 1 0 0 ) , a slow intraduodenal infusion procedure of the t e s t substance had been used. Therefore, although the segmenting a c t i v i t y of the duodenum was reduced, the quantity of perfusate available to the mucosal surface per unit of time was s u f f i -c i e n t l y small to allow absorption to proceed normally. 12. Conversely, where nutrient absorption was impaired (96-98,102), the t e s t s o l u t i o n had been injected d i r e d t l y into the duodenum and l i k e the c l i n i c a l state of hypomotility ( c e l i a c disease), the load to the mucosal surface exceeded i t s p e r i s t a l t i c capacity. It appears then that absorption i s i n fact reduced where i n t e s t i n a l m o t i l i t y i s decreased. The reports concerning the e f f e c t of hypermotility on nutrient absorption have also been c o n f l i c t i n g (102-108). Reduced absorption of glucose (104), fat (102,105), and water, sodium and chloride (106-10?), have been c i t e d i n drug- or hormone-induced i n t e s t i n a l hypermotility i n man and animals. Similar studies have obtained contradictory r e s u l t s to those mentioned above (99.103.108). This may be due to differences i n the i n t e s t i n a l segment chosen for study. An apparent increase i n nutrient absorption may r e f l e c t the absorptive a c t i v i t y of that p a r t i c u l a r segment of the i n t e s t i n e . In fact, the t o t a l amount of material absorbed per unit of time, rather than per unit of length, may have ac t u a l l y been decreased. C l i n i c a l investigations of absorption i n a "natural" hypermotile state, such as i n thyrotoxicosis and congenital sucrose-isomaltose malabsorption syndrome, indicate that absorption of nutrients i s reduced. Steatorrhea i s common i n hyperthyroidism (104). Launiala (37-38) has reported a decrease i n palmitate, xylose and arginine absorption i n a c h i l d with congenital sucrose-isomaltose malabsorption. The accumulation of lactose i n the i n t e s t i n a l lumen of lactose 13. intolerant individuals may be considered analogous to the sucrose-isomaltose malabsorption seen i n CSIM. I t follows then, that the lactose-induced hypermotile state i n lactose i n t o l e r -ance might be i n t e r f e r i n g with absorption of dietary nutrients i n addition to lactose. Paige and Graham (32) recently conducted a balance study using four intolerant and two tolerant subjects between 22 months and 6 years of age. They noted that the lactose intolerant c h i l d r e n receiving a lactose-casein diet did not r e t a i n nutrients as well as they did on a sucrose-casein d i e t . Their findings include* a) a decrease i n apparent nitrogen absorption from 93% to 83% of intake b) a reduction i n nitrogen retention from 15% to 5% of intake c) a decrease i n fat absorption as indicated by an elevation i n s t o o l f a t from 3 g/day to 5 g/day d) an increase i n s t o o l weight from a mean of 38 g/day to 147 g/day. Nutrient absorption did not appear to be affected by either diet for the tolerant subjects. According to these r e s u l t s , i t appears that lactose intolerant subjects may be sustaining f e c a l losses of nutrients i n addition to lactose i t s e l f , Calloway and Chenoweth (33) have also examined t h i s p o s s i b i l i t y . Four intolerant and two tolerant subjects were confined to a metabolic ward for 48 days during which each subject received each of 4 diets for twelve day periods. The diets consisted ofs a) 1000 g of homogenized low-fat milk divided into four meals per day, supplying a t o t a l of 50 g lactose 1 4 . b) 1000 g of modified low-fat milk enzymatically processed so as to reduce lactose content by approximately 50% c) 1000 g simulated low-fat milk with glucose and galactose instead of lactose d) wheaten foods only because they a f f e c t nutrient absorption regardless of i n t e s t i n a l lactase l e v e l s . Calloway and Chenoweth (33) found that two of the intolerant subjects had increased hydrogen l e v e l s i n the breath as well as higher f e c a l losses of moisture, dry s o l i d s and energy, that were lactose dose dependent. These r e s u l t s concur with those of Paige and Graham ( 3 2 ) ,that lactose feeding may lead to n u t r i t i o n a l l y s i g n i f i c a n t f e c a l losses of nutrients i n subjects with low lactase l e v e l s . It should be noted that a l l these studies have purposefully eliminated the e f f e c t of gastric emptying time.in order to examine the e f f e c t of i n t e s t i n a l m o t i l i t y alone on nutrient absorption. Under normal conditions, gastric emptying time i n addition to the p e r i s t a l t i c a c t i v i t y of the small intestine determine the rate of i n t e s t i n a l absorption (109-113). 2. The E f f e c t of Gastric Emptying on Nutrient Absorption 1 The volume of gastric contents transferred to the duodenum i s generally under the i n h i b i t o r y influence of neural and hormonal factors o r i g i n a t i n g i n the duodenum (92,109,111). In decreasing order of potency» f a t t y acids, f a t s , proteoses, peptones, amino acids, sugars, other starch digestion products, and low pH present i n the duodenum w i l l stimulate the i n t r a -15. muscular p l e x i to transmit the enterogastric r e f l e x to the stomach and consequently i n h i b i t g a s t r i c evacuation. For example, the greater the concentration of solutes i n the small intestine, the stronger w i l l be the e x c i t a t i o n of the receptors and the smaller the volume of material pumped from the stomach into the duodenum. The presence of f a t i n the small intestine w i l l also delay gastric emptying v i a a hormone (enterogastrone) synthesized,in the i n t e s t i n a l w all. Gastric distension alone w i l l accelerate the rate of g a s t r i c emptying. I t i s not s u r p r i s i n g therefore, that large deviations i n the rate of t h i s transfer would influence nutrient absorption e s p e c i a l l y where the absorptive capacity of the mucosa of the small intestine i s impaired i n some way. Studies have shown that a decrease i n the rate of transfer of gastric contents i n healthy animals r e s u l t s i n a reduced rate of nutrient absorption (114-116). An increase i n the volume of g a s t r i c contents pumped per minute into the duodenum r e s u l t s i n decreased nutrient absorption only where the absorptive capacity of the small intestine i s impaired (117). For example where lactase lev e l s are low, an acceleration i n the rate of g a s t r i c emptying w i l l lead to a reduction i n absorption of nutrients (118-120). In other words, the lactose load presented to the intestine w i l l exceed the capacity of the i n t e s t i n a l lactase lev e l s to cleave the lactose molecule and i t s absorption w i l l be impaired. Consequently, a delay i n ga s t r i c emptying time i n these individuals i s b e n e f i c i a l to the absorption process. In t h e i r study of calcium absorption i n 1 6 . lactose intolerant individuals, Kocian et a l . ( 1 2 1 ) notei The slower supply of chyme protects the small intestine against lactose overloading although the lactase a c t i v i t y of the i n t e s t i n a l epithelium i s r e l a t i v e l y low and thus renders a better u t i l i z a t i o n of calcium possible. The slower supply of calcium reduces the amount offered per unit of time and thus also increases the percentage of absorbed calcium. Therefore, i f absorption i s improved through a delay i n gastric emptying time, the abdominal d i s t r e s s symptoms associated with lactose intolerance may be modified too, to some extent. The re l a t i o n s h i p of dietary modification of ga s t r i c emptying time and the appearance of c l i n i c a l symptoms of lactose intolerance i s discussed i n the proceeding section. 3 « The E f f e c t of Diet Composition on Symptoms of Lactose  Intolerance and Nutrient Absorption The symptomatic response of a lactose intolerant i n d i v i d u a l depends on the composition of the meal i n which the lactose i s given. A number of workers ( 1 2 2 - 1 2 7 ) ? ' have shown that the f a t and/or protein content of a meal or even the milk i t s e l f , may reduce the abdominal discomfort of an intolerant i n d i v i d u a l . Bayless and Paige ( 1 2 3 ) note that milk consumed alone seems to induce greater abdominal discomfort than i f taken with a meal. They suggest that the d i f f e r e n t components of a meal may delay g a s t r i c emptying time. In t h i s way the low l e v e l of i n t e s t i n a l lactase i s not "overloaded" with lactose and f l u i d and e l e c t r o l y t e balance i s not disturbed. Normal p e r i s t a l s i s can be maintained, thus avoiding or at least reducing the symptomatic response that would otherwise be seen i n lactose intolerance. 1 7 . Other investigators have shown (124 - 1 2 6 ) that the composition of the milk i t s e l f may be s u f f i c i e n t to modify symptoms of lactose intolerance also through a delay i n g a s t r i c emptying time. In one study ( 1 2 5 ) » symptomatic responses of 8 intolerant subjects were compared a f t e r r e c e i v i n g 5 0 0 ml skim milk and a f t e r receiving an equivalent amount of whole milk. Less discomfort was experienced a f t e r the whole milk was consumed. Therefore, the f a t and protein l e v e l s of a meal or milk may a l l e v i a t e the symptoms of lactose intolerance by delaying g a s t r i c emptying time and reducing i n t e s t i n a l m o t i l i t y (124). Whether or not nutrient absorption remains impaired i s less evident. Kocian et a l . ( 1 2 1 ) suggest that where low lactase l e v e l s are present, a delay i n g a s t r i c emptying time a f t e r a lactose load may be important for absorption to occur properly. However, Leiehter ( 1 2 5 ) showed that although the symptomatic response was less intense, the r i s e i n blood glucose did not improve i n lactose intolerant individuals who received whole milk as compared to skim or an aqueous lactose s o l u t i o n . L I t should be noted though, that the whole milk may have e f f e c -t i v e l y delayed gastric emptying so as to reduce the rate of lactose absorption, and eventually increase the absolute quantity of lactose absorbed. This might have been evident had absorption been followed for a longer period than the time of the lactose tolerance t e s t which lasted only one hour. Paige et a l . (127) found that feeding lower leve l s of lactose to intolerant subjects was also e f f e c t i v e i n 18. reducing t h e i r symptomatic response, however, lactose tolerance curves s t i l l did not improve. Bedine and Bayless (128) demon-strated that i n lactose intolerant subjects who were asymptom-a t i c , as l i t t l e as 3 and $ g of lactose i n 2G0 ml of e l e c t r o l y t e s o l u t i o n (21.7 mEq sodium/1, 3 7.1 mEq potassium/1),; resulted i n net f l u i d and sodium accumulation i n the small i n t e s t i n e . From these studies, i t appears that the fat and protein l e v e l s of a meal or milk ( 1 2 3 - 1 2 6 ) , or the lactose content i t s e l f ( 1 2 7 - 1 3 0 ) , may be altered so as to a l l e v i a t e the symptoms of lactose intolerance. However, i t i s s t i l l not c l e a r whether or not nutrient absorption i s concurrently improved. On the other hand, studies of the e f f e c t of altered i n t e s t i n a l m o t i l i t y on nutrient absorption (Section II.B.l) suggest that the symptomatic response induced when lactose i s consumed alone may int e r f e r e with absorption of nutrients i n a d d i t i o n to lactose. The present work i s concerned with i n v e s t i g a t i o n of t h i s l a t t e r p o s s i b i l i t y 1 that the lactose-induced state of,hypermotility i n a lactose intolerant i n d i v i d u a l may not afford s u f f i c i e n t time for absorption of dietary nutrients, Consequently, an i n d i v i d u a l with low lactase l e v e l s may not be deriving f u l l n u t r i -t i o n a l benefits when consuming only milk or other lactose-contain-ing products. 1 9 . I I I . MATERIALS AND METHODS A. Huraan_Studies In order to study the e f f e c t of lactose on the absorption of vitamin A, ascorbic acid and protein, twenty-three residents of Vancouver, B r i t i s h Columbia were used. A l l were Caucasians} nine females between 2 1 and 3 1 years of age, mean = 2 5 years, fourteen males between 2 2 and 3 3 years, mean = 2 8 years. Each subject was questioned about his general physical condition and on t h i s basis was considered to be healthy. None reported a family h i s t o r y of diabetes. Following an overnight f a s t , each subject received a lactose tolerance t e s t . Venous blood samples were drawn while the subjects were f a s t i n g and at 1 5 , 3 0 and 6 0 minute intervals a f t e r o r a l ingestion of 5 0 g l a c t o s e 1 dissolved i n 3 0 0 ml water. Development of any symptoms such as flatulence, bloating, gas, cramps or diarrhea were recorded. A maximum r i s e i n blood glucose of less than 2 0 mg/100 ml and gastro-i n t e s t i n a l symptoms were considered i n d i c a t i v e of lactose intolerance. On t h i s basis, eight of the subjects were lactose intolerant, and the remaining f i f t e e n were tolerant. The nutrients chosen for study were based on the following considerations! a) the drink or meal should be acceptable to the subjects 1 ) ffC-lactose, Fisher S c i e n t i f i c , N.J. 20. b) peak absorption of the nutrient should occur within a four hour period c) absorption of the nutrient should not be affected by the other nutrients present i n the t e s t s o l u t i o n d) absorption of the nutrient should vary proportionally with the quantity ingested. I t was decided that vitamins A and C seemed to meet the above considerations. Gelatin ;was also given i n order to measure changes i n blood urea l e v e l s as an indicator of protein absorption ( 1 3 D . The l e v e l s of vitamins A and C and protein ingested and the time inter v a l s at which blood samples were drawn were based on studies reported i n the l i t e r a t u r e ( 1 3 2 ) . The tolerant and intolerant subjects served as their,own controls. , Sucrose replaced the lactose i n the control studies. 1 . Experimental Procedures a. The E f f e c t of Lactose on the Absorption'of Protein and Vitamin A In order to study the e f f e c t of lactose on protein and vitamin A absorption, a preliminary study using 5 tolerant and 8 intolerant subjects was c a r r i e d out. After an overnight fa s t , venous blood samples were drawn, while the subjects were s t i l l f a s t i n g and at 6 0 , 1 2 0 , 180 and 240 minute in t e r v a l s a f t e r ingestion of a test drink. The drink consisted of 50 g lactose and 5 5 g g e l a t i n 1 dissolved i n 400 ml water. At the 2 same time each subject ingested 25»000 IU vitamin A i n capsule form. 1 ) Knox unflavored g e l a t i n , Knox Foods, Trenton, Ontario. 2 ) 2 5 , 0 0 0 IU vitamin A/capsule, Stanley Drug Products Ltd., Vancouver, B.C. 21. The following week, the procedure was repeated with the same subjects except that 50 g sucrose replaced the lactose i n the tes t drink. The volunteers were instructed to consume the f l u i d as quickly as possible because the g e l a t i n had a tendency to congeal. b. The E f f e c t of Lactose on the Absorption of Vitamins A and C Another preliminary experiment involving 9 subjects, 3 intolerant and 6 tolerant, was conducted to follow the eff e c t of lactose (without gelatin) on the absorption on vitamins A and C. The procedure was s i m i l a r to the f i r s t experiment except that each subject ingested 50 g lactose dissolved i n 400 ml water with 500 mg vitamin C 1 i n tablet form and 25.000 IU vitamin A i n capsule form. Blood samples were drawn while the subjects were fa s t i n g and at 60, 120, 180 and 240 minute intervals a f t e r ingestion of the test drink. This was repeated the following week with sucrose instead of lactose. c. The E f f e c t of Lactose on the Absorption of Vitamins A and C Since vitamin A i s fat soluble, i t was decided to give our subjects the vitamin with a t e s t meal, rather than a drink, to study the e f f e c t of lactose on i t s absorption. The meal, adopted from Barrowman et/;sPl). (133-) contained 45 g lactose, 1) 500 mg vitamin C/ tablet,;, Stanley Drug Products, Vancouver, B.C. 2 2 . 1 5 g c a s i l a n 1 and 2 5 ml olive o i l as well as 2 0 0 , 0 0 0 IU vitamin 2 A i n capsule form. Each subject also received 1 g vitamin C because the previous dose of 5 0 0 mg was thought to be too low to show measurable differences i n blood vitamin C l e v e l s . Venous blood samples were drawn af t e r an overnight fast and at 9 0 , 180 and 240 minute in t e r v a l s a f t e r ingestion of the meal. At a l a t e r date these same subjects received a s i m i l a r meal except sucrose replaced the lactose. 2 . Methods a. Plasma Glucose Determination Blood samples were drawn and transferred to test tubes containing potassium oxalate, centrifuged at 2 0 0 0 RPM for 2 0 minutes and plasma was removed and frozen. The glucose was determined within a few days by the glucose oxidase method ( 1 3 4 ) . b. Plasma Urea Nitrogen Determination Blood samples were drawn and transferred to heparin-ized test tubes and treated as above. Plasma urea nitrogefr l e v e l s were determined according to Hylandotest'"kit:;No. 0 3 0 - 0 1 0 (135.),.- ir^).-. 1 ) Casilan, Glaxo-Allenburys, Toronto, Ontario. 2 ) 5 0 , 0 0 0 IU vitamin A/capsule (Afaxin), Winthrop Lab., Div, of S t e r l i n g Drugs Ltd., Aurora, Ontario. 23. c. Plasma Vitamin A Determination Vitamin A was measured by the Carr Price ( 1 3 6 ) method with s l i g h t modifications. Instead of 2 ml plasma and 2 ml 9 6 % ethyl alcohol, 1 ml of each was used for the analysis. A f t e r evaporation under nitrogen 0 . 2 ml chloroform was added instead of 0 . 1 ml to each cuvette and 2 ml of chromogen reagent was used i n place of 1 ml. Optical density readings were taken i n a Coleman Junior Spectrophotometer, Model 6C at a wavelength of 6 2 0 mu. d. Plasma Vitamin C Determination Plasma was analysed for ascorbic acid using the dinitrophenylhydrazine method adapted from Roe and Kuether ( 1 3 7 ) . One ml of plasma was added to 9 ml of 5% t r i c h l o r o a c e t i c acid, instead of 2 ml plasma and 8 ml t r i c h l o r o a c e t i c a c i d . Blood samples drawn were frozen immediately a f t e r centrifugation and analysis was c a r r i e d out within 24 hours so as to avoid destruc-t i o n of vitamin G. Optical density readings for plasma glucose, urea nitrogen and ascorbic acid were taken i n a Coleman Hit a c h i Spectrophotometer, Model 1 0 1 at wavelengths of 4 5 0 mu, 6 3 0 mju, and 5 1 5 n»H» respectively. 3 . S t a t i s t i c a l Analysis The pafedst test was performed i n order to evaluate the r e s u l t s obtained when the d i f f e r e n t sugars were consumed 1 ) Vitamin A Standard was run using USP Vitamin A Reference Solution d i s t r i b u t e d by The United States Pharmacopeial Convention. 24. by the same group of subjects. The generalized t test was used to assess the responses of the controls and the intolerant subjects af t e r consuming the same sugar. S t a t i s t i c a l s i g n i f i -cance was assumed at or below the 5% l e v e l . B. Ariimal.Studigs 1. Experimental Procedures a. The E f f e c t of Lactose on the Excretion of Fat, Nitrogen and Calcium To investigate the e f f e c t of 10%, 20%, and 30% lactose diets on the absorption of protein, f a t and calcium, three balance studies were c a r r i e d out on postweaning rat s ( i n i t i a l weight = 164 g) for ten day periods. The procedure for each balance study was s i m i l a r i twelve male Sprague-Dawley r a t s 1 were housed sin g l y i n metabolic cages. Six served as controls and received the d i e t containing an amount of sucrose equivalent to the l e v e l of lactose i n the d i e t fed to the s i x experimental animals. The composition of the experimental d i e t i n each balance study i n shown i n Table I. Food and water were fed ad l i b . Weight gain and food consumption were recorded. D a i l y urine and feces c o l l e c t i o n started a f t e r the rats had been on the diets f o r 48 hours. For each animal, urine was c o l l e c t e d i n a 125 ml Erlenmeyer f l a s k containing 0.5 ml 6N HC1 and transferred d a i l y to a larger bottle for storage i n a freezer. After 10 days, the pooled volume of urine c o l l e c t e d was measured and 1) Obtained from Bio Breeding Laboratories, Ottawa, Canada. 25. Table I. Composition of Diets. 10% Lactose 20% Lactose 30% Lactose CORNSTARCH, % 53 43 33 VITAMIN FREE CASEIN, % 20 20 20 SALT MIXTURE, % X 5 5 5 VITAMIN MIXTURE, % 2 2 2 2 CORN OIL, % 10 10 10 1) Rogers-Harper S a l t Mix, purchased;from General Biochemicals, Chagrin F a l l s , Ohio. The s a l t mixture contained* CaCO^, 29.29%?CaHP0^.2H20, 0.43%} KHgPO^, 34.31%! NaCl, 25.06%i MgS0 i r7H 20, 9.98%} Fe(C6H5C>).6H20, 0.623%! CuSO^, 0.156%; MnSO^.HgO, 0.121%} ZnCl 2, 0.020%j KI, 0 .0005%i (NH^) 6M0 70 2^.4H 20, 0.0025%! Na 2Se0 3.5H 20, 0.0015%. 2) Vitamin Diet F o r t i f i c a t i o n Mix., purchased from N u t r i t i o n a l Biochemicals Corp., Cleveland, Ohio. The vitamin mixture contained i n g/kg« vitamin A concentrate, 4.5 (200,000 units/g)j vitamin D concentrate, 0.25 (400,000 units/g); alpha tocopherol, 5.0} ascorbic acid, 45.0} i n o s i t o l , 5.0} choline chloride, 75.0$ menadione, 2.25s p-aminobenzoic acid, 5.0} ni a c i n , 4 .5; r i b o f l a v i n , 1.0} pyridoxine hydrochloride, 1,0} thiamine hydrochloride, 1.0; calcium pantothenate, 3.0} and i n mg/kg» b i o t i n , 20; f o l i c acid, 90} vitamin B 1 2, 1.35. 2(5. made up to volume. To obtain a uniform sample, the bott l e containing the urine was well shaken p r i o r t o a i a l y s i s . Aliquots were taken d i r e c t l y for nitrogen determination. For calcium determination urine samples were f i l t e r e d through f i l t e r paper Whatman No. 41. Feces were c o l l e c t e d d a i l y and stored i n a freezer. After 1 0 days, the pooled feces for each r a t were weighed and then dried to a constant weight at 60°C i n a vacuum oven, so that moisture content could be determined. The dried feces were then ground to a powder and aliquots were taken d i r e c t l y for nitrogen and fat determination. In order to determine " calcium content, the dried feces were ashed overnight i n a muffle furnace at 6 0 0°C. The ash was dissolved i n concen-trated HC1, d i l u t e d to make a known volume, then f i l t e r e d (as urine samples) and aliquots were used for calcium determination by atomic absorption spectrophotometry. b. The E f f e c t of Lactose on the Absorption of Vitamin A Postweaning rats were used to study the e f f e c t of lactose on the absorption of vitamin A. In t h i s study, 72 male Sprague-Dawley rats (average weight = 2 6 3 g) were randomly divided into two groups. Each group was then subdivided into nine l o t s of four animals each. A f t e r an overnight fast, the experimental group received 5 0 0 mg lactose and 2 5 0 0 IU vitamin A 1) Trans Retinol Palmitate Type VII water dispersable, Sigma Chemical Co., St. Louis, Mo. 27. i n 2 ml water by stomach tube while the control group was given sucrose instead of lactose. Four rats from each group were s a c r i f i c e d and blood was drawn by heart puncture at the following time i n t e r v a l s : p r i o r to receiving the test s o l u t i o n and at 1, 2, 2 i , 3, 3 i . 4, and 5 hours a f t e r administration of the test s o l u t i o n . 2. Methods a. Nitrogen Determination Urinary and f e c a l nitrogen were determined by the Kjeldahl method (138). b. Calcium Determination Urinary (139) and f e c a l calcium (140) were determined by atomic absorption spectrophotometry. 1 c. Determination of Eat Content Fat content of feces was measured using the Goldfisch fat extraction apparatus ( l 4 l ) , d. Plasma Vitamin A Determination As i n Human Studies (III.A.2). 3. S t a t i s t i c a l Analysis The generalized t tes t was used to assess the signi f i c a n c e of mean values obtained for each experimental 1) Unicam Atomic Absorption Spectrophotometer, Model SP90; 28. group as compared to their controls for each parameter studied. Analysis of variance was also performed to test the significance of the differences between the type as well as the level of carbohydrate in each balance study and the possible interaction of both. S t a t i s t i c a l significance was assumed at or below the 5% level. 29. IV. RESULTS A. Hum§n_Studies 1. The E f f e c t of Lactose on the Absorption of Protein The mean maximum r i s e i n plasma urea above the fas t i n g plasma urea l e v e l a f t e r ingestion of 55 g g e l a t i n by the lactose tolerant and intolerant subjects i s shown i n Table I I . (The in d i v i d u a l values for each subject are i n Table I, Appendix.) There are no s t a t i s t i c a l l y s i g n i f i c a n t differences i n the maximum r i s e i n plasma urea i n either the tolerant or intolerant group whether lactose or sucrose was consumed. The plasma urea values obtained when the same sugar was consumed by either group of subjects also did not d i f f e r s i g n i f i c a n t l y . In addition, the mean plasma urea levels at each time i n t e r v a l were s i m i l a r for the intolerant subjects and the controls ( F i g . 1, Appendix), Consequently, peak plasma urea l e v e l s occurred at the same i n t e r v a l (240') for both groups. Symptoms of bloating, gas, cramps or diarrhea were not evident i n any of the subjects. 2. The E f f e c t of Lactose on the Absorption of Ascorbic  Acid The r e s u l t s for the mean maximum r i s e i n plasma ascorbic acid l e v e l s i n those subjects who received 500 mg of ascorbic acid are shown i n Table I I I . (The i n d i v i d u a l values are shown i n Table I I , Appendix.) There were no s i g n i f i c a n t differences i n the mean r i s e i n plasma ascorbic acid between the lactose intolerant and tolerant subjects whether vitamin C 3 0 . Table I I . Mean Maximum Rise + S. D. i n Plasma Urea i n Lactose Tolerant and Intolerant Subjects Given 5 5 g Gel a t i n and 2 5 , 0 0 0 IU Vitamin A with Either 5 0 . g Lactose or 5 0 g Sucrose. PLASMA UREA (mg urea / 1 0 0 ml) Lactose Sucrose P Tolerant (?) 1 1 . 7 ± 5 . 5 7 1 0 . 3 ± 2 . 7 8 > 0 . 0 5 Intolerant ( 5 ) 9.8 ± 3 . 1 6 1 0 . 5 + 5 . 0 3 > 0 . 0 5 P > 0 . 0 5 > 0 . 0 5 Table I I I . Mean Maximum Rise ± S. D. i n Plasma Ascorbic Acid i n Lactose Tolerant and Intolerant Subjects Given 5 0 0 mg Vitamin C and 2 5 , 0 0 0 IU Vitamin A with Either 5 0 g Lactose or 5 0 g Sucrose. PLASMA ASCORBIC ACID (mg vitamin C / 1 0 0 ml) Lactose Sucrose P Tolerant ( 6 ) 0 . 9 7 ± 0 . 3 1 1 . 0 2 + 0 . 2 8 > 0 . 0 5 Intolerant ( 3 ) 0 . 9 3 + 0 . 2 1 0 . 9 0 + 0.40 > 0 . 0 5 P > 0 . 0 5 > 0 . 0 5 was administered with sucrose or lactose. In the tolerant subjects, the peak i n absorption of vitamin C for 5 out of 6 subjects occurred at the 180 minute i n t e r v a l when the vitamin was consumed with lactose and at the 120 minute i n t e r v a l when consumed with sucrose (Fig. 2, Appendix). This difference i s not considered s t a t i s t i c a l l y s i g n i f i c a n t . The values for the maximum r i s e i n plasma vitamin C with sucrose or lactose are simi l a r i n the intolerant subjects. In addition, the ingestion of lactose or sucrose seemed to have no e f f e c t on the mean maximum r i s e i n plasma ascorbic acid when the subjects served as t h e i r own controls. Symptoms of gas and bloating, cramps and diarrhea were reported i n some of the intolerant subjects. The r e s u l t s i n Table IV show the maximum r i s e i n plasma ascorbic acid levels i n k intolerant subjects who received 1 g vitamin C with a test meal. (The i n d i v i d u a l values are shown i n Table I I I , Appendix.) The mean r i s e i n plasma ascorbic acid a f t e r the lactose meal, 1 . 0 5 mg vitamin C/100 ml plasma, does not d i f f e r s i g n i f i c a n t l y from that obtained when these subjects consumed the sucrose meal, 1 . 0 3 mg vitamin C/100 ml plasma. Absorption rates also remain unaffected ( F i g . 3 i Appendix). Because of the small sample size, one must always be c a r e f u l i n drawing conclusions from such data. In addition, the symptomatic response of our subjects i n t h i s experiment was reduced probably due to consumption of the lactose i n the form of a meal rather than a drink. 3 2 . Table IV. Mean Maximum Rise + S. D. i n Plasma Ascorbic Acid i n Lactose Intolerant Subjects Given 2 0 0 , 0 0 0 IU Vitamin A and 1 g Vitamin C with a Test Meal Containing 15 g Casilan, 2 5 ml Olive O i l and Ei t h e r 45 g Lactose or 45 g Sucrose. PLASMA ASCORBIC ACID (mg vitamin C/100 ml) Intolerant (4) Lactose 1 . 0 5 + 0.048 Sucrose 1 . 0 3 t 0 . 2 3 2 > 0 . 0 5 Table V. Mean Maximum Rise ± S. D. i n Plasma Vitamin A i n Lactose Intolerant Subjects Given 200,000 IU Vitamin A and 1 g Vitamin C with a Test Meal Containing 1$ g Casilan, 25 ml Olive O i l , and Ei t h e r 45 g Lactose or 453g Sucrose. PLASMA VITAMIN A (mg vitamin A / 1 0 0 ml) Intolerant (4) Lactose 0 . 0 1 2 ± 0 . 0 0 8 5 Sucrose 0 . 0 3 1 + 0 . 0 2 3 9 P > o . 0 5 3 3 . 3 . The E f f e c t of Lactose on the Absorption of Vitamin A The mean r i s e i n plasma vitamin A le v e l s when four lactose intolerant subjects consumed a meal with 2 0 0 , 0 0 0 IU vitamin A are shown i n Table V, (Values for each subject are shown i n Table IV, Appendix.) The mean maximum r i s e i n plasma vitamin A was s l i g h t l y lower a f t e r the lactose meal as compared to the value obtained a f t e r the sucrose meal. The difference however, between these two values i s not s t a t i s t i c a l l y s i g n i f -icant at the 5% l e v e l . In addition, the peak absorption for vitamin A was reached aft e r the same time i n t e r v a l whether or not lactose or sucrose was consumed with the vitamin. B. Animal_Studies 1. The E f f e c t of Lactose on the Excretion of Fat,  Nitrogen and Calcium a. : Body Weight G.ain and Food Consumption The mean cumulative weight gain and food consumption of each group of rats on the various diets are shown i n Tables VI and VII. Weight gain was s i g n i f i c a n t l y lower ( p < 0 . 0 5 ) i n the experimental animals fed the 2 0 % and 3 0 % lactose diets as compared to t h e i r corresponding controls. Food consumption was also lower for these same animals, although the difference between the controls and experimental animals i s s t a t i s t i c a l l y s i g n i f i c a n t (p < 0 . 0 5 ) only on the 3 0 % disaccharide d i e t s . This would suggest that feed e f f i c i e n c y i s reduced at the higher le v e l s of dietary lactose. 34. Table VI. Mean Weight Gain + S. D. of Experimental and Control Animals Over a Ten Day Period. (N = 6 ) DIET WEIGHT GAIN (g/ 1 0 days) P 1 0 % Lactose 1 0 % Sucrose 8 7 . 3 + 4 . 6 3 8 6 . 2 + 8 . 0 2 > 0 . 0 5 2 0 % Lactose 2 0 % Sucrose 7 3 . 8 + 5 . 9 3 8 3 . 8 + 8 . 9 0 < 0 . 0 5 3 0 % Lactose 3 0 % Sucrose 5 3 . 1 + 18 .83 7 4 . 4 + 6 . 7 1 < 0 . 0 5 Table VII. Average Food Consumption + S. D. of Experimental and Control Animals Over a Ten Day Period. ( N = 6 ) DIET FOOD CONSUMPTION (g/10 days) P 10% Lactose 20% Sucrose 174.0 ± 6.75 178.7 ± 16.77 > 0 . 0 5 20% Lactose 20% Sucrose 177.9 + 5.75 191.9 + 15.95 > 0 . 0 5 3 0 % Lactose 3 0 % Sucrose 142.0 + 26.57 173.7 + 14.42 < 0 . 0 5 3 5 . Loose stools were apparent i n the 3 ° % lactose group, indicating that diarrhea was induced by the high l e v e l of lactose intake. These rats, too, as a group, appeared to be s l i g h t l y more i r r i t a b l e than those i n any of the other groups. However, there were usually one or two animals i n the other dietary groups whose behavior was s l i g h t l y e r r a t i c . S p i l l a g e of food into excreta often occurred i n such cases and accounts for the large standard deviations i n the r e s u l t s . I t was also observed that the urine volume was consistently greater as dietary lactose l e v e l s increased, while the reverse was true as sucrose le v e l s increased. At the 3 0 % l e v e l of disaccharide intake, the difference i n urine volume between the controls (mean = 1 3 5 . 0 + 14.14 mls / 1 0 days) and the experimental group (mean = 2 5 5 . 8 + 79.08 mls / 1 0 days) i s s t a t i s t i c a l l y s i g n i f i c a n t at the 5% l e v e l . The reason for t h i s f i n d i n g i s not c l e a r . b. The.Effect of _Lacto.se on Fecal Fat Excretion The values for f e c a l fat excretion as per cent of f a t intake i n the control and experimental animals are shown i n Table VIII. S i g n i f i c a n t differences ( p < 0 . 0 5 ) i n f e c a l excretion of f a t are associated with both the type of carbo-hydrate and l e v e l of carbohydrate i n the d i e t s . In other words, f a t excretion was greater for>the experimental animals r e l a t i v e to t h e i r c o n t r o l s i also fat excretion was least for both groups on the 1 0 % disaccharide diets, as compared to the animals on the 2 0 % and 3 0 % disaccharide d i e t s . In addition there i s no i n t e r a c t i o n between the type of disaccharides and Table VIII. E f f e c t of Dif f e r e n t Levels of Dietary Lactose on Fecal Excretion of Fat.; (N = 6) DIET Mean Fecal Fat Excretion as % Fat Intake + S.D. 10% Lactose 10% Sucrose 3.75 ± 0.94 2 . 3 0 + 0.14 20% Lactose 20% Sucrose 6.54 + 2 . 3 6 3.42 ± 1 . 0 3 3 0 % Lactose 3 0 % Sucrose 4.43 + 0.72 3.51 ± 0.55 Source of V a r i a t i o n F* P** 1. Type of carbohydrate 21.5393 0.00006 2. Level of carbohydrate 8.2274 0.00142 3. Interaction of 2 and 3 2.824? 0.07526 * F = r a t i o of mean squares of treatment to mean squares of error ** P = p r o b a b i l i t y that e f f e c t of treatments i s due to chance 37. t h e i r l e v e l i n the d i e t j so that the presence of lactose alone would be s u f f i c i e n t to a f f e c t f e c a l excretion of f a t . c. The E f f e c t of Lactose on Fecal and Urinary Nitrogen Excretion The values for f e c a l nitrogen excretion as per cent of nitrogen intake are presented i n Table IX. Excretion of nitrogen i n feces i s £ s i g n i f i c a n t l y ( p < 0 . 0 5 ) affected by the type and l e v e l of dietary carbohydrate allhough there i s no inte r a c t i o n between the two. Those animals fed the lactose diets showed a greater excretion of f e c a l nitrogen r e l a t i v e to the sucrose-fed r a t s j as dietary lactose l e v e l s increased, f e c a l excretion of nitrogen was greater. As seen i n Table X; urinary nitrogen excretion as per cent of nitrogen intake i s s i g n i f i c a n t l y ( p < 0 . 0 5 ) affected only by the l e v e l of carbohydrate i n the d i e t . Therefore, either lactose or sucrose may increase nitrogen excretion i n urine, and t h i s e f f e c t i s more apparent as level s of these disaccharides i n the die t are increased. d. The E f f e c t of Lactose on Fecal and Urinary Calcium Excretion The results for f e c a l calcium excretion as per cent of calcium intake are shown i n Table XI. Fecal calcium excretion for each lactose group i s s i g n i f i c a n t l y lower ( p< 0 . 0 5 ) not only from i t s corresponding sucrose group but also from each sucrose group i n the two other balance studies. 3 8 . Table IX. E f f e c t of Dif f e r e n t Levels of Dietary Lactose on Fecal Excretion of Nitrogen. (N = 6 ) DIET Mean Fecal N Excretion as ? 1, % N Intake + S. D. 1 0 % Lactose 1 0 % Sucrose 5 . 0 2 + 0 . 9 1 3 . 7 1 + 0 . 5 5 ; 2 0 % Lactose 2 0 % Sucrose 5 . 2 3 ± 0 . 3 2 3.68 + 0 . 1 9 3 0 % Lactose 3 0 % Sucrose 6 . 1 1 + 0 . 9 2 4 . 2 2 + 0.48 Source of Va r i a t i o n F* P** 1 . Type of carbohydrate 5 7 . 4 2 5 7 0 . 0 0 0 0 0 2 . Level of carbohydrate 5 . 9 1 7 0 0 . 0 0 6 8 3 3 . Interaction of 2 and 3 0 . 6 3 4 3 0 . 5 3 7 9 5 * F = r a t i o of mean squares of treatment to mean squares of error ** P = p r o b a b i l i t y that e f f e c t of treatments i s due to chance 39. Table X. Ef fecit of Different Levels of Dietary Lactose on Urinary Excretion of Nitrogen. (N = 6) DIET Mean Urinary N Excretion as % N Intake + S.D. 10% Lactose 36.97 + 2 . 5 1 10% Sucrose 38.95 + 3 . 6 5 20% Lactose 42.6? ± 5.55 20% Sucrose 43.96 + 4.54 3 0 % Lactose 36.88 + 6.97 3 0 % Sucrose 42.06 + 4.18 Source of V a r i a t i o n F* }•'• 1. Type of carbohydrate 3.1281 0.08725 \ 2. Level of carbohydrate 4.0019 0.02884 3. Interaction of 2 and 3 0 . 5 6 5 1 0 . 5 7 4 9 6 * F = r a t i o of mean squares of treatment to mean squares of error ** P = p r o b a b i l i t y that e f f e c t of treatments i s due to chance Table XI. E f f e c t of Different Levels of Dietary Lactose on Fecal Excretion of Calcium. (N = 6 ) DIET Mean Fecal Calcium Excretion as % intake + S.D. 1 0 % Lactose 1 0 % Sucrose 4 5 . 1 2 + 1 3 . 1 5 51.42 + 4 . 1 0 2 0 % Lactose 2 0 % Lactose 38.14 + 7 . 0 0 4 4 . 0 5 i 3 . 5 0 3 0 % Lactose 3 0 % Sucrose 28 . 2 0 + 6 . 1 0 5 6 . 0 7 + 7 . 0 3 Source of Va r i a t i o n F* P** 1 . Type of carbohydrate 2 8 . 5 8 1 0 0 . 0 0 0 0 1 2 . Level of carbohydrate 3 . 2 0 5 5 0 . 0 5 4 8 1 3 . Interaction of 2 and 3 8 . 4 3 4 9 0.00124 * F = r a t i o of mean squares of treatment to mean squares of error ** P = p r o b a b i l i t y that e f f e c t of treatments i s due to chance 41. According to the re s u l t s i n Table XII, urinary calcium excretion i s s i g n i f i c a n t l y affected by the type and l e v e l of carbohydrate i n the diet, as well as the i n t e r a c t i o n of both. At the 1 0 % l e v e l of dietary lactose, calcium excre-t i o n i n urine i s lower than at the 2 0 % and 3 0 % dietary lactose l e v e l s . On the 2 0 % and 3 0 % lactose d i e t s , urinary calcium excretion i s not only higher r e l a t i v e to t h e i r corresponding controls, but also as compared to the controls i n the two other balance studies. This might be due to the finding that f e c a l calcium excretion i s lower (Table XI) when lactose i s present i n the d i e t . This indicates an increase i n calcium uptake, which might account for higher l e v e l s of calcium i n urine. 2 . The E f f e c t of Lactose on the Absorption of Vitamin A The mean plasma vitamin A levels reached a f t e r i n t r a g a s t r i c administration of 2 5 0 0 IU of r e t i n o l palmitate with either 5 0 0 mg lactose or sucrose to postweaning rats are shown i n Table XIII. Peak absorption occurred for both groups at the two hour time i n t e r v a l . Although t h i s value i s higher i n the lactose group, the difference i s not s t a t i s t i c a l l y s i g n i f i c a n t (p> 0 . 0 5 ) . The maximum mean plasma vitamin A r i s e (difference between the mean f a s t i n g plasma vitamin A value and the maximum mean plasma vitamin A r i s e ) i n the experimental group ( 0 . 1 9 3 6 mg vitamin A / t o t a l blood volume) i s s l i g h t l y higher as well r e l a t i v e to the controls ( 0 . 1 4 7 6 mg vitamin A/ t o t a l blood volume). The values between the corresponding Table XII. E f f e c t of Di f f e r e n t Levels of Dietary Lactose on Urinary Excretion of Calcium. (N = 6) DIET Mean Urinary Calcium Excretion as % Ca Intake + S. D. 10% Lactose 10% Sucrose 1.28 + 0.27 1.38 ± 0.71 20 % Lactose 20% Sucrose 1.64 ± 0.59 0.62 + 0.23 30% Lactose 30% Sucrose 2.87 + 0.48 1.34 + 0.84 Source of Va r i a t i o n F* P** 1. Type of carbohydrate 20.5826 0.00009 2. Level of carbohydrate 17.5576 0.00001 3. Interaction of 2 and 3 10.0167 0.00047 * F = r a t i o of mean squares of treatment to mean squares of error ** P = p r o b a b i l i t y that e f f e c t of treatments i s due to chance 43. Table XIII. Mean Plasma Vitamin A Levels i n Postweaning Rats Afte r Intragastric Administration of 2 5 0 0 IU of Vitamin A with E i t h e r 5 0 0 mg Lactose or 5 0 0 mg Sucrose ( 4 animals per subgroup). Time Interval (hrs) mg vitamin A / t o t a l blood volume* Lactose ± S.D. Sucrose ±S.D. P Fasting 0.0702 + 0 . 0 2 3 0 . 0 6 6 9 + 0.070 > . 0 5 1.0 0.1725 + 0.073 0.2082 + 0 . 0 9 0 > . 0 5 2.0 0.2638 + 0.124 0.2145 + 0.180 > . 0 5 2.5 0.2435 + 0.064 0.1686 + 0.040 > . 0 5 3.0 0.1249 + 0.027 0.1822 + 0 . 0 9 7 > . 0 5 3.5 0 . 0 9 3 2 + 0.020 0.1227 + 0 . 0 5 7 > . 0 5 4.0 0.1215 + 0.018 0.1273 ± 0.015 > . 0 5 4.5 0 . 1 5 0 6 + 0.046 0 . 1 1 5 3 ± 0.058 > . 0 5 5.0 0 . 1 3 9 9 + 0 . 0 1 6 0 . 0 9 1 6 + 0 . 0 1 6 < . 0 5 Maximum Mean Rise i n Plasma Vitamin A 0 . 1 9 3 6 0 . 1 4 7 6 * T o t a l blood volume = (mg vitamin A/ ml) x ( 4 . 3 % * * x body weight/rat) ** This figure represents the r a t i o of blood volume to body weight (4 . 3 ml/100 g) i n the rat. (Rowett, H.G.Q. The r a t as a smalL mammal. London. John Murray (Publishers) Ltd., I960, p.40.) 44. points on the vitamin A absorption curve (Fig. 5 . Appendix) differ significantly ( p < 0 . 0 5 ) for controls and the experimen-t a l animals only at the 5 hour interval. In addition, the rats that received the sucrose solution appeared to be more easily excitable and showed signs of diarrhea which sets certain limitations in interpretation of these findings. *5. V. DISCUSSION A. Human_Studies Results obtained i n t h i s study with human subjects do not indicate that lactose has any e f f e c t on the absorption of vitamin A, ascorbic acid or protein i n lactose tolerant and intolerant subject. The findings with regard to protein do not agree with those of Paige and Graham (32), or Calloway and Chenoweth (33). who found that lactose intolerant subjects had higher f e c a l losses of moisture, dry s o l i d s and energy which were r e l a t e d tqittiejlevel of dietary lactose. Because of d i f f e r -ences i n experimental procedure, i t i s d i f f i c u l t to compare t h e i r r e s u l t s with those of the present study. Paige and Graham (32), as well as Calloway and Chenoweth (33). conducted balance studies of nutrients over an extended period of time. In the present study, changes i n plasma urea l e v e l s only over a four hour period were used as a measure of protein absorption. Therefore the fact that lactose had no e f f e c t on plasma urea l e v e l s does not necessar-i l y mean that there were no differences i n the absolute absorption of the protein. The use of balance studies i s more suitable for assessing the n u t r i t i o n a l s i gnificance of the e f f e c t of lactose on protein absorption. Similar studies of the e f f e c t of lactose on the absorption of vitamin A and ascorbic acid have not been reported.Therefore, there i s no basis for comparison. 46. As pointed out i n the l i t e r a t u r e review (Section I I . B.3.) the fat and protein components of a meal, or the milk i t s e l f , may a l l e v i a t e the symptomatic response of a lactose intolerant i n d i v i d u a l , probably due to a delay i n g a s t r i c emptying time and a d i l u t i o n e f f e c t (122,123-127). In the present study, most of the intolerant subjects who consumed lactose i n the test drink containing g e l a t i n or i n a test meal, reported l i t t l e or no abdominal discomfort during the t e s t i n g period. The presence of the protein i n the t e s t drink, or the f a t and p r o t e i n contained i n the t e s t meal, may have delayed gas t r i c emptying and thus reduced the abdominal dis t r e s s symp-toms i n these subjects, as compared to the symptomatic response of those intolerant individuals who received the aqueous lactose s o l u t i o n alone. In addition, as Kocian et a l . (121) suggest, t h i s delay i n g a s t r i c emptying i s important for n u t r i -ent absorption to occur i n individuals with low lactase l e v e l s . This may also be the reason why the rate of absorption of vitamins A and C, and protein i n the intolerant subjects did not d i f f e r s i g n i f i c a n t l y whether lactose or sucrose was con-sumed i n the test drink containing protein or i n the test meal. However, when vitamin C was given with an an aqueous lactose s o l u t i o n (without g e l a t i n and vitamin A), plasma vitamin C l e v e l s did not d i f f e r from those a f t e r the sucrose drink i n lactose intolerant subjects. The explanation for t h i s finding i s not r e a l l y c l e a r . The test s o l u t i o n here did not contain any f a t or protein components that may have caused a 47. delay in gastric emptying and thus alleviated the symptomatic response and possibly improved absorption of acorbic acid. Perhaps 500 mg was too small an amount to show measurable difference in blood levels of vitamin C which might have been manifest with larger amounts of ascorbic acid. From these studies with human subjects, i t would appear that protein, ascorbic acid and vitamin A absorption is not affected by lactose intolerance. One may. conclude that under normal dietary conditions a lactose intolerant individual would probably not experience significant losses of nutrients,when consuming milk or lactose-containing products. 48. B. Animal_Studies 1. The E f f e c t of Lactose on the Excretion of Nitrogen,  Fat and Calcium The balance studies indicate that postweaning rats on lactose-containing diets show greater excretion of nitrogen, and f a t but not calcium, as compared to postweaning rat s on sucrose d i e t s . Furthermore, as dietary lactose le v e l s increased, feces were of s o f t e r consistency and f e c a l losses of nitrogen and fat increased. Medler et a l . (142) also noted that feeding an infant milk formula to weanling rats r e s u l t s i n diarrhea«iand a decrease i n net protein u t i l i z a t i o n from 88% to 67% as compared to feeding a formula that was treated with lactase. Our findings also agree with those of Paige and Graham (32) and Calloway and Chenoweth (33) who observed s i m i l a r losses with respect to f e c a l nitrogen and fat excretion i n lactose intolerant i n d i v i d u a l s . The e f f e c t of lactose on calcium excretion was not investigated by these workers. In the balance study by Paige and Graham (32), nitrogen excretion increased from 7% i n lactose intolerant c h i l d r e n who received sucrose-based diets to 17% when these same ch i l d r e n received lactose d i e t s . In the present balance study, f e c a l nitrogen excretion i n the controls was 3.71%, 3.68% and 4.22% of nitrogen intake on the 10%, 20% and 30% disaccharide diets respectively, while i n the experimental groups, mean f e c a l nitrogen excretion was 5.02%, 5.23% and 6.11% of nitrogen intake. Although these differences i n nitrogen losses are s t a t i s t i c a l l y s i g n i f i c a n t (p <0.05), i t i s doubtful 49. that they are of p r a c t i c a l s i g n i f i c a n c e . In terms of an average d a i l y loss of nitrogen, a loss of 1 or 2% of the nitrogen intake would not be serious. The n u t r i t i o n a l consequences of a 10% increase i n f e c a l nitrogen excretion, as reported by Paige and Graham (32), would be s i g n i f i c a n t i n an intolerant i n d i v i d u a l whose dietary protein was marginal. In addition, Paige and Graham (32) fed t h e i r subjects a d i e t containing almost 60% lactose as compared to the highest dietary l e v e l of lactose of 30% i n the present study. This may account for the more pro-nounced e f f e c t of lactose on f e c a l nitrogen excretion seen i n t h e i r study. Paige and Graham (32) also noted an increase i n s t o o l fat from 3 g to 5 g/day when lactose intolerant c h i l d r e n were given lactose diets a f t e r receiving sucrose-based d i e t s . The res u l t s from the present balance studies with rats indicate that f a t excretion expressed as per cent of f a t intake (Table VIII) was s i g n i f i c a n t l y greater i n the experimental groups than i n the controls. However, the figures reported i n Table VIII represent a maximum difference i n f e c a l f a t excretion of only 3.12% (at the 20% l e v e l of lactose intake) between the controls and the experimental animals. F i n a l l y , Paige and Graham (32) reported an increase i n d a i l y s t o o l weight from 38g/day to l4?g/day when the lactose childr e n intolerant^received a lactose d i e t as compared to a sucrose d i e t . I t i s l i k e l y that intense abdominal di s t r e s s symptoms, such as diarrhea, were present i n these c h i l d r e n due to the 50. high l e v e l of dietary lactose. In the present balance study, stoo l weight increased by approximately 23% i n the rats fed the lactose diets r e l a t i v e to the controls. As dietary lactose levels increased, looser stools and softer f e c a l consistency were evident. The rats fed the 20% lactose d i e t had softer feces than those fed the 10% lactose d i e t . Only the rats receiving the 30% lactose diet seemed to suffer from diarrhea. With respect to calcium absorption, the r e s u l t s from the present balance study indicate that lactose reduced f e c a l losses of calcium i n rats, p a r t i c u l a r l y at the 30% l e v e l of lactose intake. These findings are i n agreement with those of a number of workers (143-14?) who have repeatedly found that lactose stimulates calcium uptake from the rat i n t e s t i n e . One of the hypotheses proposed to explain t h i s phenomenon i s that l a c t i c acid produced by b a c t e r i a l action on the lactose i n the i n t e s t i n a l lumen lowers the pH, creating conditions more favourable to calcium uptake. Pansu and Chapuy (143) noted that i n humans as well, calcium absorption was improved by lactose consumption i n individuals with low lactase l e v e l s . They suggested that lactose w i l l cause» a hyperosmolar intraluminal e f f e c t , water secretion into the lumen and inverse transfer across the membrane. Conditions then, favoring lactose accumulation i n the i n t e s -t i n a l lumen would enhance calcium uptake. Such conditions existed i n the present work due to feeding large l e v e l s of dietary lactose. As the l e v e l of dietary lactose increased, the i n t e n s i t y of the g a s t r o i n t e s t i n a l disturbances increased. 5 1 . There was also a concomitant improvement i n calcium absorption. Therefore, the theories proposed above to explain the e f f e c t of lactose on calcium absorption seem to be supported by the re s u l t s obtained i n the present balance study. However, according to these same c r i t e r i a i t i s d i f f i c u l t to explain the r e s u l t s of Kocian et a l . ( 1 2 1 ) that lactose seemed to improve the rate of calcium uptake i n lactose tolerant subjects. In addition, these same investigators noted no difference i n calcium uptake i n lactose intolerant subjects who consumed milk and lactose free milk. The f i n d i n g of Kocian et a l . ( 1 2 1 ) that lactose had no ef f e c t on calcium absorption i n lactose intolerant subjects may be explained i n the following way. Because the milk solutions contained f a t and protein, g a s t r i c emptying time was probably de-layed and i n t h i s way, i n t e s t i n a l lactase was not overloaded with lactose. Consequently, there was l i t t l e change i n gastrointes-t i n a l m o t i l i t y and calcium absorption was not improved. However, i t may also be argued that calcium absorption was i n fact i n -creased a f t e r the milk was consumed because the probable delay i n g a s t r i c emptying allowed s u f f i c i e n t time f o r calcium absorption to occur. I f one accepts the l a t t e r explanation, i t then becomes possible to account for the r e s u l t s obtained by Kocian et a l . ( 1 2 1 ) with tolerant subjects. . This suggests that lactose enhances calcium absorption i n tolerant and intolerant i n d i v i d -uals, however, the theories proposed to explain t h i s phenomenon which are based on the accumulation of lactose, must be rejected. 52. I f lactose enhances t o t a l calcium absorption, as the r e s u l t s from the present balance studies indicate, and. t h i s e f f e c t i s proportional to the l e v e l of lactose i n the d i e t , such an e f f e c t may have important n u t r i t i o n a l implication where dietary calcium intake i s low. However, the p r a c t i c a l s i g n i f -icance of the e f f e c t of lactose on fat and protein absorption i s doubtful. I t appears not only from the present study but also from the work of Paige and Graham (32) that the l e v e l of dietary lactose necessary to i n t e r f e r e with nutrient absorption would far, exceed the l i m i t s of normal dietary consumption. 2. The E f f e c t of Lactose on the Absorption of Vitamin A The r e s u l t s from the vitamin A absorption study i n rats indicate that lactose did not impair vitamin A absorption and even seemed to improve i t . However, as compared to the lactose group, the rats that received the sucrose s o l u t i o n appeared to be more excitable, which may have contributed to the observation that they were also s u f f e r i n g from diarrhea. These g a s t r o i n t e s t i n a l disturbances which were evident i n the sucrose group may have n u l l i f i e d the e f f e c t of lactose on vitamin A absorption i n the lactose group. x'Mii 53. VI. RECOMMENDATIONS In Canada, i t i s estimated that some 6.5 m i l l i o n people, or approximately 30% of the t o t a l Canadian population, are lactose i n t o l e r a n t 1 . I f a l l these individuals are sustain-ing losses of important nutrients due to lactose consumption, as suggested by recent studies.(32,33) then t h i s might become an area of public health concern i n Canada. The r e s u l t s of the present work suggest that under normal dietary conditions, absorption of nutrients may not be affected by lactose intolerance. However, future research i s needed to determine the v a l i d i t y of th i s suggestion. Attention should be focused on the dietary modifi-cation of the symptomatic response of a lactose intolerant individual, and what e f f e c t t h i s modification has on absorption. I t should be established whether or not a l l e v i a t i o n of gastro-i n t e s t i n a l symptoms by consuming lactose with a meal, i s r e l a t e d to improved nutrient absorption i n individuals with low lactase l e v e l s . A larger number of subjects should be used to study the e f f e c t of lactose on the absorption of various nutrients i n order to obtain s i g n i f i c a n t r e s u l t s . In addition, conducting balance studies with humans, besides measuring blood levels of the various nutrients, would aid i n the in t e r p r e t a t i o n of the 1) These figures are based on calculations derived from (1)19?1 S t a t i s t i c s Canada figures for the d i f f e r e n t ethnic popula-tions i n Canada and (2) the values for the incidence of lactose intolerance for these ethnic groups that have been reported i n the l i t e r a t u r e . 54. findings. In other words, where the rate of absorption does not appear to be affected by lactose, changes i n the absolute amount of nutrient absorption could be detected. The n u t r i t i o n a l implications that can be drawn from the balance studies with rats are not as s t r i k i n g as would be suggested by Paige and Graham (92) and Calloway and Chenoweth (33). Of course, one must exercise caution r.in extrapolating from animal studies to humans. F i n a l l y , i n any future studies, the l e v e l of lactose administered to subjects should be maintained within the l i m i t s of normal lactose consumption. This would avoid undue concern over apparent nutrient losses due to exaggerated levels of dietary lactose. 5 5 . VII. SUMMARY Adult lactose intolerance due to low lactase l e v e l s i s often associated with varying degrees of abdominal d i s t r e s s ranging from bloating and distension to severe cramps and diarrhea. Recent studies have suggested that these gastro-i n t e s t i n a l disturbances may i n t e r f e r e with normal absorption of nutrients i n addition to lactose. In order to investigate th i s p o s s i b i l i t y , both human and animal studies were conducted. Twenty-three Caucasianst nine females between 2 1 and 3 1 years of age, mean = 2 5 years and fourteen males between 2 2 and 3 3 years of age, mean * 28 years were used to study the ef f e c t of lactose on the absorption of vitamin A, ascorbic acid and protein. Lactose tolerance tests revealed that 8 of the subjects were lactose intolerant on the basis of a maximal blood glucose r i s e of less than 2 0 mg/ 1 0 0 ml over the f a s t i n g blood glucose l e v e l and the presence of g a s t r o i n t e s t i n a l symptoms a f t e r a lactose tolerance t e s t . In each study, blood samples were drawn a f t e r an overnight fast and at int e r v a l s up to 4 hours a f t e r consuming 5 0 g of lactose i n an aqueous so l u t i o n or t e s t meal containing g e l a t i n , vitamin C or vitamin A. Sucrose replaced lactose as a c o n t r o l . The r e s u l t s of the human studies f a i l e d to demon-strate that lactose had an ef f e c t on the absorption of ascorbic acid, vitamin A or protein i n lactose intolerant subjects. The mean maximum r i s e i n plasma urea ( 9.8 mg/100 ml), plasma 5 6 . ascorbic a c i d ( 0 . 9 3 mg/100 ml) and plasma vitamin A ( 0 . 0 1 2 mg/ 1 0 0 ml) a f t e r lactose ingestion did not d i f f e r s i g n i f i c a n t l y (p> 0 , 0 5 ) from the values obtained a f t e r consumption of sucrose ( 1 0 . 5 mg urea / 1 0 0 ml, 0.90 mg ascorbic a c i d / 1 0 0 ml, 0 . 0 3 1 mg vitamin A / 1 0 0 ml). I t may be that the composition of the test drink which contained f a t and protein, may have affected the rate of absorption of those nutrients through a delay i n ga s t r i c emptying time. However, the finding that absorption of vitamin C remained unaffected even when consumed with an aqueous s o l u t i o n of lactose (without g e l a t i n ) , i s attributed to the p o s s i b i l i t y that,the l e v e l of ascorbic acid given was too low to show measurable differences i n blood l e v e l s of that nutrient. In order to study the e f f e c t of lactose on the absorption of calcium, f a t and protein, balance studies were conducted using postweaning r a t s . The experimental groups received either 1 0 % , 2 0 % or 3 0 % lactose d i e t s , while an equiv-alent amount of sucrose replaced the lactose i n the c o n t r o l d i e t s . In addition, postweaning rats were given vitamin A i n t r a g a s t r i c a l l y with either lactose or sucrose to investigate the e f f e c t of lactose on vitamin A absorption. From the balance studies with r a t s , the r e s u l t s indicate that f e c a l nitrogen and f a t excretion was s i g n i f i -cantly ( p < 0 . 0 5 ) higher i n a l l the animals fed lactose as compared to the controls. Mean f e c a l f a t excretion expressed as percent f a t intake was 3 . 7 5 % . 6 . 5 4 % and 4 . 4 3 % for those 5 7 . animals that received the 1 0 % , 2 0 % and 3 0 % lactose diets respectively, while the values for the corresponding controls were 2 . 3 0 % , 3.42% and 3 . 5 1 % . S i m i l a r l y , mean f e c a l nitrogen excretion expressed as percent nitrogen intake was 5 . 0 2 % , 5 . 2 3 % and 6 . 1 1 % for the lactose groups and 3 . 7 1 % . 3 . 6 8 % and 4 . 2 2 % for the controls on 1 0 % , 2 0 % and 3 0 % sucrose d i e t s , r e s p e c t i v e l y . However, f e c a l calcium excretion was found to be generally lower for each lactose group r e l a t i v e to the controls, but the difference was s t a t i s t i c a l l y s i g n i f i c a n t ( p < 0 . 0 5 ) only at the 3 0 % l e v e l of lactose intake. The values f o r mean f e c a l calcium excretion as percent calcium intake were 4 5 . 1 2 % , 3 8.14% and 28 . 2 0 % f o r each group on the 1 0 % , 2 0 % and 3 0 % lactose d i e t respectively, and 51.42%, 4 4 . 0 5 % and 5 6 . 0 7 % for the correspon-ding controls. I t appears that lactose impairs nitrogen and f a t absorption, but enhances calcium absorption i n postweaning r a t s . Improved calcium absorption may have important n u t r i -t i o n a l implications where dietary calcium intake i s low. I t appears though, that the l e v e l of dietary lactose would most l i k e l y have to exceed the l i m i t s of normal lactose consumption to have an e f f e c t on the absorption of nutrients. 5 8 . BIBLIOGRAPHY 1 . 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The simultaneous measurement of absorption and transit in the gastro-intestinal tract of the rat. J. Physiol. 1 3 1 * 4 5 2 -4 6 2 , 1 9 5 6 . 1 1 8 . Pirk, F., I. Skala and M. Vulterinova. Milk intolerance after gastrectomy. Digestion 9 » 1 3 0 - 1 3 7 , 1 9 7 3 . 1 1 9 . Kocian,J.» M. Vulterinova, 0 . Bejblova and I. Skala. Influence of lactose intolerance on the bones of patients after partial gastrectomy. Digestion 8 i 3 2 4 - 3 3 5 . 1 9 7 3 . 1 2 0 . Wapnick, S. Milk and lactose intolerance following d i s t a l small bowel resection. Amer. J. Clin. Nutr. 2 5 i 6 5 5 - 6 6 0 , 1 9 7 2 . 1 2 1 . Kocian, J., I. Skala and K. Bakos. Calcium absorption from milk and lactose free milk in healthy subjects and patients with lactose intolerance. Digestion 9 * 3 1 7 - 3 2 4 , 1 9 7 3 . 1 2 2 . Stephenson, L.S., and M.C Latham. Lactose intolerance and milk consumption* the relation of tolerance to symptoms. Amer. J. Clin. Nutr. 2 7 * 2 9 6 - 3 0 3 , 1974, 1 2 3 . Bayless, T.M., and D.M. Paige. Disaccharide intolerance in feeding programs. In* Proc. Western Hemisphere Nutr. Congr. III.r. ed. P.L. White. Mount Kisco, N.Y. Futura, 1 9 7 2 . p. 188 -196. 124. Reddy, V., and J. Pershad, Lactase deficiency in Indians. Amer. J. Clin. Nutr. 2 5 »114 - 1 1 9 , 1 9 7 2 . 1 2 5 . Leichter, J. Comparison of whole milk and skim milk with aqueous lactose solution in lactose tolerance testing. Amer. J. Clin. Nutr. 2 6 * 3 9 3 - 3 9 6 , 1 9 7 3 . 1 2 6 . Bedine, M.S., and T.M. Bayless. Modification of lactose • 1 tolerance by glucose or a meal. Cli n . Res. 20*448, 1 9 7 2 . (Abstract) 68. 127* Paige, D.M., £. Leonardo, J . Nakashima, B. AdrianzenT. and G.G. Graham, Response of lactose intolerant c h i l d r e n to d i f f e r e n t lactose l e v e l s . Amer. J . C l i n . Nutr. 25i467-469, 1972. 128. Bedine, M.S., and T.M. Bayless. Intolerance of small amounts of lactose by individuals with low lactase l e v e l s . Gastroenterology 65i735-743, 1973. 129. Garza, C., Y, Garza, C. 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Nutr. 71*10-14, i 9 6 0 . 147. Wasserman, R.H., and F.W. Lengemann, Further observations on lactose stimulation of the gastrointestinal absorp-tion of calcium and strontium in the rat. J. Nutr. 7 0 * 3 7 7 - 3 8 3 . I960. 70. A P P E N D I X Table I. Maximum r i s e i n plasma urea i n lactose tolerant and intolerant subjects given 5 5 g g e l a t i n and 2 5 , 0 0 0 IU vitamin A with either 5 0 g lactose or 5 0 g sucrose. Subject (mg urea / 1 0 0 ml) No. Lactose sucrose 1 . 9 . 6 9 . 9 Lactose 2 . 1 6 . 1 1 2 . 2 Tolerant 3 . 7 . 5 1 1 . 1 4. 8 . 2 1 2 . 9 5 . 2 0 . 6 1 2 . 6 6 . 1 3 . 5 7 . 9 1 7 . 6 . 2 5.4 Mean + S.D. 1 1 . 7 + 5 . 5 7 1 0 . 3 ± 2 . 7 8 8 . 9.4 8.4 9 . 6 . 5 6.4 Lactose Intolerant 1 0 . 7 . 5 5 . 8 1 1 . 1 1 . 0 16.4 1 2 . 14.5 1 5 . 3 Mean + S.D. 9 . 8 + 3 . 1 6 1 0 . 5 + 5 . 0 3 72. Table I I . Maximum r i s e i n plasma ascorbic acid i n lactose tolerant and intolerant subjects given 5 0 0 mg vitamin G and 2 5 . 0 0 0 IU vitamin A with either 5 0 g lactose or 5 0 g sucrose. Subject (mg vitamin C / 100ml) • No. Lactose Sucrose 1 0 . 7 5 0 . 9 3 2 0 . 9 6 0.98 Lactose 3 1 . 3 ? 0.82 Tolerant 4 1.17 1.49 5 1.14 1.18 6 0.49 0 . 7 0 Mean + S.D. 0 . 9 7 + 0.31 1.02 + 0.28 7 1.00 1.29 Lactose Intolerant 8 0 . 6 9 0 . 4 9 9 1.09 0 . 9 3 Mean + S.D. 0 . 9 3 + 0.21 0.90 + 0.40 Table I I I . Maximum r i s e i n plasma ascorbic acid i n lactose intolerant subjects given 200,000 IU vitamin A, 1 g vitamin C and a tes t meal containing 15 g ca s i l a n , 25 ml o l i v e o i l with either 45 g lactose or 45 g sucrose. Subject No. mg vitamin C / 100 ml Lactose Sucrose 1 0.98 1.13 2 1.05 0.71 3 1.07 1 . 2 5 4 1 . 0 9 1 . 0 3 Mean + S.D. 1 . 0 5 + 0.048 1 . 0 3 + 0.232 7 4 . Table IV. Maximum r i s e i n plasma vitamin A i n lactose intolerant subjects given 2 0 0 , 0 0 0 IU vitamin A, 1 g vitamin C and a t e s t meal containing 1 5 g c a s i l a n , 2 5 ml o l i v e o i l with; either 4 5 g lactose or 4 5 g sucrose. Subject No. mg vitamin A / 1 0 0 ml Lactose Sucrose 1 0.009 0.048 2 0.014 0.012 3 0 . 0 2 3 0 . 0 5 5 4 0 . 0 0 3 0 . 0 0 9 Mean + S.D, 0 . 0 1 2 + 0 . 0 0 8 5 5 0 . 0 3 1 + 0 . 0 2 3 9 20 Time (minutes) u FIGURE 1. Mean Plasma Urea L e v e l s i m L a c t o s e T o l e r a n t (LT) and S I n t o l e r a n t (LI) Subjects Given 55 g G e l a t i n With E i t h e r 50 g Lactose (L) or 50 g Sucrose (S). LT (S) LT (L) LI (L) LI (S) Time (minutes) FIGURE 2 Mean Plasma A s c o r b i c A c i d L e v e l s infcLactose T o l e r a n t (LT) and 3 I n t o l e r a n t (LI) Subjects Given 500 mg Vitamin C and 25,000 IU Vitamin A With E i t h e r 50 g Lactose (L) or 50 g Sucrose (S). 3.00 e o o Time (minutes) Mean Plasma A s c o r b i c A c i d L e v e l s i n Lactose I n t o l e r a n t fa) S u b j e c t s Given 2 00,000 IU Vitamin A and 1 g Vitamin C With a Test Meal C o n t a i n i n g 15 g C a s i l a n , 25 ml O l i v e O i l and E i t h e r 45, g ' Lactose or 45 g Sucrose. o o •ri e -p •ri > e 0.07 0.06 + 0.05 4 0.04 0.03 FIGURE' 4, Sucrose Lactose 240 Time (minutes) Mean Plasma Vi t a m i n A L e v e l s i n Lactose I n t o l e r a n t S u b j e c t s (4) Given 200,000 IU Vitamin A and 1 g Vitamin C With a T e s t Meal C o n t a i n i n g 15 g C a s i l a n and 25 ml O l i v e O i l and E i t h e r 45 g Lactose or 45 g Sucrose. 00 .300. Time (hours) FIGURE 5. Mean Plasma V i t a m i n A L e v e l s i n Rats A f t e r I n t r a g a s t r i c A d m i n i s t r a t i o n of 500 mg La c t o s e or 500 mg Sucrose, and 2500 IU Vitamin A. (M « 3 0 

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