Lactulose, Disaccharides and Colonic Flora Clinical Consequences
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Drugs 1997 Ju n: 53 (6): 930-942 REVIEW ARTICLE 00 12-6667/97/rJ:XJO-O<I3O/S13.00/0 © Ad isInterna tional lim ited . AUrights reserved . Lactulose, Disaccharides and Colonic Flora Clinical Consequences Mette Rye Clausen and PerBrebech Mortensen Department of Medicine CA, Division of Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Contents Summary . 930 1. Dietary Carbohydrate . 931 1.1 Lactulose . 931 2. Colonic Fermentation and Producti on of Short-Chain Fatty Acids (SCFA) 931 2.1 Fermentation of Lactulose . 932 3. Lactulose in the Management of Constipation ........ 933 3.1 Colonic Compensation in Car bohydrate Malabsorption 933 3.2 Fermentation Capac ity Threshold: Individual Variability . 934 3.3 Does Lactulose Exert Its Laxative Effect Through the Osmotic Activity of Unferme nted Carbohydrate? . 935 3.4 Capac ity of the Colon to Absorb Fluid . 936 3.5 Possible Me chanisms of Action of Lactulose in the Treatment of Constipation. 936 4. Lac tulose in the Management of Hepatic Encephalopathy . 937 4.1 Effects of Lac tulose on Ammonia and Nitrogen Metabolism . 937 4.2 Role of Short- and Medium-Chain Fatty Acids in Hepatic Encephalopathy . 938 4.3 Effect of Lactulose on Colon ic SCFA Production in Hepatic Encephalopathy 939 4.4 Possible Mechanisms of Action of Lactulose in the Treatment of Hepatic Encephalopathy 940 5. Conclusions.................................. 940 Summary Lactulose is one of the mos t freq uently utilised age nts in the treatment of constipation and hepatic ence pha lopathy because of its efficacy and good safe ty profile. The key to understanding the possible modes ofaction by which lactulose ac hieves its therapeutic effects in these diso rders lies in certain pharmacological phe nomena: (a) lactulose is a sy nthetic disaccharide that does not occur naturally; (b) there is no disaccharidase on the microvillus membrane of enterocytes in the human small intesti ne that hydrolyses lactulose; and (c) lactulose is not absorbed from the small intestine. Thus, the primary site of action is the colon in which lactulose is readi ly fermented by the co lonic bacterial tlora with the produ ction ofshort-chain fatty acid s and various gases. T he purpose ofthis review is to focu s on some pertinent basic aspects of the clinical pharmacology of lactulose and to discuss the possible mec hanisms by which lactulose benefits patients with co n stipation and hepatic encephalopat hy. Disaccharides and Colonic Flora 931 1. Dietary Carbohydrate human small intestine.Pv' Once in the caecum, lactulose is a fully fermentable carbohydrate. Dietary carbohydrates may be divided into Lactulose is widely considered to be an effective monosaccharides, disaccharides, oligosaccharides agent in the management of constipation and he and polysaccharides. Their physiological proper patic encephalopathy. It is the purpose of this re ties and health benefits depend on the site, rate and view to discuss the interaction of lactulose with the extent of their digestion or fermentation in the hu bacterial flora of the colon and the possible modes man gastrointestinal tract. The polysaccharide ofaction by which it achieves its therapeutic effects fraction of plant cell walls (dietary fibre) and some in patients with constipation and hepatic encepha forms of starch (resistant starch) are resistant to lopathy. The review deals almost exclusively with hydrolysis in the small intestine. These carbohy lactulose. The principles expressed, however, are drate polymers as well as indigestible oligosaccha applicable to any malabsorbed and fermentable di rides, e.g. stacchyose and raffinose, enter the colon saccharide, e.g. lactitol, a disaccharide analogue of through the ileocaecal valve to be fermented by the lactulose for which there is also no disaccharidase colonic bacterial flora. Monosaccharide and disac on the microvillus membrane of enterocytes, or charide sugars are absorbed as they pass through lactose when it is administered to lactase-deficient the healthy small intestine and only become avail individuals. able to the colonic flora as a consequence of defi ciencies in the transport system, or, more usually, specific disaccharidase deficiencies, e.g. lactase 2. Colonic Fermentation and Production deficiency. Physiological carbohydrate malabsorp ofShort-Chain Fatty Acids (SCFA) tion, that is, the fermentable carbohydrate entering Fermentation, the process whereby the micro the colon in healthy individuals, is in the range of bial population that inhabits the human colon 30-60 g/day in Western communities.l!l This load breaks down carbohydrates in order to obtain en is normally fermented by the vast numbers of co ergy for maintenance of cellular function and lonic bacteria. growth, is an important component of normal colonic activity (fig. I). Short-chain fatty acids 1.1 Lactulose (SCFA) and the gases H2, CO 2 and, in some indi Lactulose is a synthetic disaccharide composed viduals, CH4, are the principal end products of car of the monosaccharides galactose and fructose [p bohydrate fermentation.l!' The major SCFA found ( 1-4)-galactosido-fructose]. The disaccharidases in the human colon are the C2 (acetate), C3 (pro that split naturally occurring disaccharides into pionate) and C4 (butyrate) members of the ali their hexose moieties do not include a lactulase, phatic monocarboxylic acid series. Formate (C I), and lactulose is not metabolised or absorbed in the valerate (C5), hexanoate (C6), and the branched- Dietary mono·, di- and oligosaccharides Bacterial enzymes IPolysaccharides 1-- - - --ICarbohydrates Ir---- SCFA,H2,C02,CH.and increased bacterial mass Fig. 1. Bacterial fermentation in the human colon . Abbrevialion: SCFA = short-chain fatty acids . <0Adis International Limited. Ail rights reserved. Drugs 1997 Jun; 53 (6) 932 Clausell & Mor!('//s('// chain fatty acids isobutyrate (iC4) and isovalerate 3-fo ld by the additio n of 100 mmol/L lactulose or (iC5) , whi ch are produced during amino acid fer its mon osacch ari de co nstituents, ga lac tose and ment ation,14's1are also present in the colon, though fructose, during inc ubation for 6 hours, secondary in smaller quantities. Oth er orga nic ac ids such as to an isolated 4- to 6-fo ld increase in the synthes is lactate and succ inate are ferment ation intermedi of acetate. In patient s undergoing elective chole ates. Th ey can be further metaboli sed to SC FA, and cystectomy, caecal insti llatio n of lactulose ca used do not usually accumulate to any extent, except an immediate increa se in portal plasma SCFA during rapid carbohydrate breakd own. P"! co nce ntrations, principally acetate; peak co ncen Th e SCFA are weak acid s and their pKa values trations were achieve d in 15 to 45 minutes, co n are very similar, rangin g from 4.76 to 4.87. Thu s, firming efficient fermen tatio n of lactulose and ab more than 95% of the SCFA are present in their sorption of the resultant SCFAP ol di ssociated form at the phy siological pH of the co Th e various gases ge nerated in the co lon are ei lon (pH 6-8) . Total co ncentrations of SCFA are low ther absorbed and ex pired in breath or expelled as in the small intestine, but in the co lon and faeces flatu s, and excess gas production may ca use bor SCFAco nstitute the predominant ani ons at concen borygm i and flatul ence. Sin ce H2 produced in the tration s ranging from about 80 to 130 mmol/Lp ·IOI human bod y deri ves entirely from bacter ial fer Concentrati ons are highest in the caecum, where ment ation of nonabsorbed carb oh ydrate, breath H2 substra te avai lability is grea tes t, and fall progres exc retion in the abse nce of small intestinal bacte sive ly towards the distal co lon. By co ntras t, pH is rial ove rgrowth ca n be used as a marker of carbo lowest in the right colon and rises in the distal hydrate rnalabsorpt ion .F! ' Th e extent of malab bowel.l?' SC FA are avidly abso rbed by the co lonic sorption may be quantified by co mparing breath H2 epithelium,II I.1 21 and used as a source of energy, excretion following a test dose of lactulose with either locall y (co lonic mucosa)113.151 or syste mi tha t after ingestion of a different carbohydrate.l->' ca lly (liver, peripheral tissues).' 161 In the colon, ab Fermentation of a readily fermen tab le carbohy sorpt ion ofSCFA is accompanied by luminal bicar drate result s in acidification of co lonic co ntent s. bon ate acc umulatio n and increased sodium and Using a pH-sensitive rad iotelem etry de vice, Bown wate r absorption.t'I -P!Thu s, the micro bia l process et aL/231 showed that lactul ose 30 to 40g daily de co nve rts unabsorb able materi al to rapidly absorbed creased the pH of the right co lon fro m control lev SCFA, thereby redu cing the effective osmo tic pres els of 6.0 to 4.8 5. As the intes tinal co ntent reached sure of the colonic co ntents, enhanci ng water and the left co lon and rectum, the median pH rose, electrolyte abso rption, and sa lvaging calories whi ch wo uld otherwise be lost in the faeca l strea m. probably as a res ult of SCFA absorpt ion and bicar bonate sec retion. Th e effect of lactulose on faeca l pH depend s on the dose employed, and the drop in 2.1 Fermentation of Lactu lose pH is usually maint ain ed throughout the co lon and Lactul ose, after arriving in the colon, is digested the stool when larger doses of lactul ose are ad min by bacteri al disaccharidases and metabolised to or istered.124.261 ga nic aci ds, mainl y acetate and lactate, H2 and Alth ough co nsistent changes in the relative pro C02.1 61 A variety of studies have show n that lactu portion s or in the abso lute numbers of differe nt lose is usuall y vigorously fermented .