See discussions, stats, and author profiles for this publication at: archgate/publication/13439119 Functional food science of gastrointestinal physiology and function
ARTICLE in BRITISH JOURNAL OF NUTRITION · SEPTEMBER 1998
Impact Factor: 3.34 · DOI: 10.1079/BJN19980108 · Source: PubMed
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Functional food science and gastrointestinal physiology and function
S.Salminen 1,C.Bouley 2,M.-C.Boutron-Ruault 3,J.H.Cummings 4¬,A.Franck 5,G.R.Gibson 6,
E.Isolauri 7,M.-C.Moreau 8,M.Roberfroid 9and I.Rowland 10
1
Department of Biochemistry and Food Chemistry,University of Turku,SF-20500Turku,Finland
2
Groupe Danone,15,Av.Galile
´e,F-92350Le Plessis-Robinson,France 3
U290INSERM,Ho
ˆpital St Lazare,107,rue du Faubourg Saint-Denis,F-75010Paris,France 4
Dunn Clinical Nutrition Centre,Hills Road,Cambridge CB22DH,UK 5
Raffinerie Tirlemontoi –ORAFTI,Aandorenstraat 1,B-3300Tienen,Belgium 6
u盘raw
Institute of Food Rearch,Reading Laboratory,Earley Gate,Reading RG66BZ,UK 7
University of Tampere Medical School,PO Box 607,SF-33101Tampere,Finland 8
INRA –Unite
´d’Ecologie et de Physiologie du Syste `me Digestif,Ba ˆtiment 440R-2,Domaine de Vilvert,F-78352Jouy-en-Josas Cedex,France
9
UCL,Ecole de Pharmacie,Tour Van Helmont,Avenue E.Mounier,73,B-1200Brusls,Belgium
10
University of Ulster,Coleraine BT521SA,UK愚昧什么意思
British Journal of Nutrition (1998),80,Suppl.1,S147–S171S147
Abbreviations:GALT,gut-associated lymphoid tissue;IBS,irritable bowel syndrome;Ig,immunoglobulin;ILSI,International Life Sciences Institute;IQ,2-amino-3-methyl-7H-imidazo[4,5-f ]quinoline;MTT,3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide;7-OHIQ,7-hydroxy-2-amino-3,6-dihydro-3-methyl-7H-imidazo[4,5-f ]quinoline-7-one;rRNA,ribosomal RNA;SCFA,short-chain fatty acids.
*Corresponding author:Dr J.H.Cummings,fax þ44(0)1223413763,email john.cummings@mrc-dunn.cam.ac.uk
Contents
1.Introduction
S1482.Intestinal microflora:physiology and functions S1482.1.The normal flora
S1482.2.Fermentation and short-chain fatty acids
S1492.2.1.Physiology and health S1492.2.2.Acetate S1492.2.3.Propionate S1492.2.4.Butyrate
S1492.3.Interactions between the intestinal microflora and
epithelial cells
S1512.4.The concept of healthy microflora S1513.The gastrointestinal immune system
S1523.1.Gut-associated lymphoid tissue (GALT)S1523.2.The structure of GALT and cell distribution S1523.3.Immunophysiological regulation S1523.4.Regulation of antigen transfer
S1533.5.Interactions between the intestinal microflora and
the GALT
S1534.Mucosal cell proliferation and differentiation S1544.1.Cell proliferation S1544.2.Differentiation S1544.3.Apoptosis
S1544.4.Mucosal enzymes
S1545.Gastrointestinal function and dia S1545.1.Gastrointestinal infections S1545.2.Normal bowel habit S1555.3.Constipation
S1555.4.Irritable bowel syndrome (IBS)S1555.5.Inflammatory bowel dia
S1555.5.1.Crohn’s dia S1555.5.2.Ulcerative colitis S1565.6.Food allergy
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5.7.Colorectal cancer S156
6.Methodology
S1566.1.Human intestinal microflora
S1566.2.Functional analysis of the gut microflora
S1576.2.1.Bacterial enzymes
S1586.2.2.Bacterial metabolites in faeces
S1586.2.3.Asssment of cytotoxicity,genotoxicity and
mutagenicity of faeces
S1586.2.4.Susceptibility of functional markers to
dietary change
S1586.3.Digestibility and bioavailability of foods S1586.4.Large-bowel function
S1586.5.Gut-associated lymphoid tissue
S1596.6.Epithelial cell proliferation and colon
carcinogenesis
S1606.6.1.Biological markers for colorectal
carcinogenesis S1606.6.2.Cell proliferation S1606.6.3.Differentiation S1616.6.4.Apoptosis
S1616.6.5.Products ud in experimental
carcinogenesis S1616.6.6.Types of lesion
S1616.6.7.Transgenic mou models for colon cancer
studies
S1616.6.8.Limits of experimental models
S1627.Human studies on the effects of food and food components S1627.1.Prebiotics S1627.2.Probiotics
S1637.2.1.Alleviation of lacto intolerance symptoms S1637.2.2.Immune enhancement
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Abstract
The gut is an obvious target for the development of functional foods,acting as it does as the interface between diet and the metabolic events which sustain life.The key process in digestive physiology which can be regulated by modifying diet are satiety,the rate and extent of macronutrient breakdown and absorption from the small bowel,sterol metabolism,the colonic microflora,fermentation,mucosal function and bowel habit,and the gut immune system.The intestinal microflora is the main focus of many current functional foods.Probiotics are foods which contain live bacteria which are beneficial to health whilst prebiotics,such as certain non-digestible oligosaccharides which lectively stimulate the growth of bifidobacteria in the colon, are already on the market.Their claimed benefits are to alle
viate lacto maldigestion,increa resistance to invasion by pathogenic species of bacteria in the gut,stimulate the immune system and possibly protect against cancer.There are very few reports of well-designed human intervention studies with prebiotics as yet.Certain probiotic species have been shown to shorten the duration of rotavirus diarrhoea in children but much more work is needed on the mechanism of immunomodulation and of competitive exclusion and microflora modification.The develop-ment of functional foods for the gut is in its infancy and will be successful only if more fundamental rearch is done on digestive physiology,the gut microflora,immune system and mucosal function.
Gastrointestinal function:Microflora:Immune system
1.Introduction
One of the most promising areas for the development of functional foods lies in modification of the activity of the gastrointestinal tract by u of probiotics,prebiotics and synbiotics.To understand the potential value of the functional foods and to be able to develop new approaches it is necessary to study the normal human intestinalflora, fermentation,the gut immune system,mucosal function and the principal gut-related dias.
2.Intestinal microflora:physiology and functions
2.1.The normalflora(Gibson&Macfarlane,1995) Bacterial numbers and composition vary considerably along the human gastrointestinal tract.The total bacterial count in gastric contents is usually below103/g,with numbers being kept low due to the acid lumen pH.In the small intestine, numbers range from approximately104/ml contents to about 106–107/ml at the ileocaecal region.The main factors limiting growth in the small bowel are the rapid transit of contents and cretion of bile and pancreatic juice.
西湖的水The human large intestine is an intenly populated micro-bial ecosystem.Several hundred species of bacteria are usually prent,with typical numbers of about1011–1012/g. The majority of the bacteria are strict anaerobes.
Table1lists bacteria commonly isolated from the human colon.Bacterial counts of individual species range over veral orders of magnitude,and the nutrition and metabolic products of different bacterial groups vary considerably. Mostbacteria growingin the colon are non-sporing anaerobes and include members of the genera Bacteroides,Bifido-bacterium and Eubacterium among many others.Clostridia are also reprented,although they are outnumbered by the non-sporing anaerobes,
as are facultative anaerobes such as streptococci and enterobacteria.Quantitatively,the most important genera of intestinal bacteria in animals and man are the bacteroides and bifidobacteria,which can account for30%and25%of the total anaerobic counts respectively. The Gram-negative Bacteroides Bacteroides ovatus,Bacteroides fragilis,Bacteroides thetaiotaomicron) are thought to be numerically predominant.The genus contains both proteolytic and saccharolytic species. Amongst the Gram-positive,non-sporing rods,veral genera are numerically significant.Obligate anaerobes include eubacteria and bifidobacteria,such as Bifido-bacterium bifidum and Bifidobacterium infantis,which are prominent in the faeces of breast-fed infants.The genus Lactobacillus contains many species that occur in the gut of most warm-blooded animals.Although numerically import-ant in the alimentary tract,their ecological significance has not been conclusively determined.
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7.2.3.Acute gastroenteritis S163
7.2.4.Faecal mutagenicity and enzymes S163
7.3.Diet and colon cancer S163
7.3.1.Dietary protective factors S163
8.Safety issues S164
8.1.Prebiotics S164
8.2.Probiotics S164
9.Critical evaluation of prent knowledge S164
9.1.Intestinal microflora S164
9.2.Mucosal function S164
9.3.Gastrointestinal physiology S165
9.4.Methodology S165
9.5.Human studies on health benefits S165
9.5.1.Prebiotics S165
9.5.2.Probiotics S165
9.5.3.Diet and colon cancer S165
9.6.Safety S165
10.Recommendations for future rearch priorities S165
10.1.Intestinal microflora S166
10.2.Short-chain fatty acids and intestinal microflora S166
10.3.Diet and cancer S166
10.4.Immune system S166
10.5.Gut mucosa S166
Several types of spore-forming rods and cocci are also inhabitants of the gut.The genus Clostridium is probably the most common:C.perfringens,C.bifermentans ani are regularly isolated,albeit in relatively low numbers, and are of significance in human and veterinary medicine. Facultative and
obligately anaerobic Gram-positive cocci are also numerically important.The strict anaerobes include Peptostreptococcus,Ruminoccus,Megasphaera elsdenii and Sarcina ventriculi.The facultatively anaerobic strepto-cocci are well reprented by many species from Lancefield group D,including S.faecalis,S.bovis and S.equinus,and some from group K,such as S.salivarius,which is usually associated with the mouth.Gram-negative anaerobic cocci include Veillonella and Acidaminococcus.
自我介绍的英文Although not numerous,the Gram-negative facultative anaerobic rods include a number of important patho-gens.For example,members of the Enterobacteriaceae, particularly Escherichia coli,are usually thought of as characteristic intestinal bacteria.
The large-gut microflora is acquired at birth.Initially, facultatively anaerobic strains dominate.Thereafter,differ-ences exist in the species composition that develops and this is largely controlled by the type of diet.The faecalflora of breast-fed infants is dominated by bifidobacteria.In contrast, formula-fed infants have a more complex microbiota with bifidobacteria,bacteroides,clostridia and streptococci all being prevalent.After weaning,a pattern that rembles the adultflora becomes established(Ducluzeau,1993).
The principal role of the intestinal microflora is to salvage energy from carbohydrates not digested in
the upper gut, through fermentation.The major substrates for fermentation are dietary carbohydrates that have escaped digestion in the upper gastrointestinal tract.The include starch that enters the colon(resistant starch),as well as llulo, hemicellulos,pectins and gums.Other carbohydrate sources available for fermentation are non-digestible oligosac-charides,various sugars and sugar alcohols(Cummings et al. 1997).In addition,proteins and amino acids can be effective as growth substrates for colonic bacteria.The include elastin, collagen and albumin,as well as bacterial protein relead following cell lysis.Pancreatic enzymes reprent a source of N.Bacterial cretions,lysis products,sloughed epithelial cells and mucins may also make a contribution as fermentation substrates.Total substrate availability in the human adult colon is20–60g carbohydrate and5–20g protein/d(Cummings& Englyst,1987;Cummings et al.1989).
Significant regional differences occur in bacterial activity in the colon.The right(proximal)colon is characterized by a high substrate availability(due to dietary input),low pH (from acids produced in fermentation)and rapid transit.The left,or distal,colon has a lower concentration of available substrate,the pH is approximately neutral and bacteria grow more slowly.The proximal region tends to be a more saccharolytic environment than the distal gut,the latter having higher bacterial proteolysis.
In addition to its role in fermentation the large-intestinal microflora contributes towards health in a number of other ways.The development of the intestinal microflora provides the basis for a barrier that prevents pathogenic bacteria from invading the gastrointestinal tract.The composition of the intestinal microflora together with the gut immune system allows resident bacteria to exert a protective function.In addition gut bacteria are involved in vitamin synthesis(espe-cially vitamins B and K)and in the metabolism of xenobiotics. Thus,modification of theflora by dietary means offers one of the most effective opportunities for development of functional foods.
2.2.Fermentation and short-chain fatty acids
(Binder et al.1994;Cummings,1995;隐隐
Cummings et al.1995)
Through fermentation,bacterial growth is stimulated(bio-mass),and short-chain fatty acids(SCFA)and the gas H2, CO2and CH4are produced.过年放假有工资吗
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Gastrointestinal physiology and function
Table1.Bacteria,their substrates and products in the human large intestine(From Macfarlane et al.1995)
Concentration
(log10/g dry wt faeces)
Fermentation Bacteria Description Mean Range Substrate products Bacteroides G¹rods11·39·2–13·5Saccharolytic A,P,S Eubacteria Gþrods10·75·0–13·3Saccharolytic,some amino acid fermenting
species
A,B,L
Bifidobacteria Gþrods10·24·9–13·4Saccharolytic A,L,f,e Clostridia Gþrods9·83·3–13·1Saccharolytic and amino acid fermenting
species
A,P,B,L,e
Lactobacilli Gþrods9·63·6–12·5Saccharolytic L Ruminococci Gþcocci10·24·6–12·8Saccharolytic A Peptostreptococci Gþcocci10·13·8–12·6As for the clostridia A,L Peptococci Gþcocci10·05·1–12·9Amino acid fermenters A,B,L Methanobrevibacter Gþcocco bacilli8·87·0–10·5Chemolithotrophic CH4 Desulfovibrios G¹rods8·45·2–10·9Various A Propionibacteria Gþrods9·44·3–12·0Saccharolytic,lactate fermenting A,P Actinomyces Gþrods9·25·7–11·1Saccharolytic A,L,S Streptococci Gþcocci8·93·9–12·9Carbohydrate and amino acid fermenting L,A Fusobacteria G¹rods8·45·1–11·0Amino acid fermentation,carbohydrate
also assimilated
B,A,L Escherichia G¹rods8·63·9–12·3As for streptococci Mixed acids Gþ,Gram-positive;G¹,Gram-negative;A,acetate;P,propionate;B,butyrate;L,lactate;S,succinate;f,formate;e,ethanol.
SCFA are the major end-products of bacterial ferment-ative reactions in the colon and are the principal anions in the hindgut of man and all other mammals.The SCFA are acetate,propionate and butyrate but other significant end-products of carbohydrate fermentation include lactate, ethanol,succinate,formate,valerate and caproate(Table 1).Branched-chain fatty acids such as isobutyrate,2-methyl-butyrate and isovalerate may be formed from the fermenta-tion of amino acids t
我要再来一次hat originate in proteolysis.The other end-products from bacterial metabolism of proteins include NH3,phenols,indoles and amines,some of which have toxic properties(Macfarlane&Macfarlane,1995).
The amount of SCFA,which is usually in excess of 100mmol/kg contents,and the molar ratios of the three principal acids produced by fermentation,vary substan-tially,depending on the substrate.This has been studied extensively in vitro using single-chamber chemostat models of the gut inoculated with intestinal micro-organisms. Yields vary from40–60%(g SCFA/100g substrate util-ized),with molar ratios of acetate from60–80,propionate 14–22and butyrate8–23(Cummings,1995).Whilst acetate is produced in all fermentation systems in vitro,it is the major product of pectin breakdown.Similarly,the highest molar ratios of propionate are en characteristically with arabinogalactan and guar gum as substrate.Amounts of butyrate vary perhaps more than any other according to substrate but the polysaccharide that is associated with the highest relative amounts is starch.In animal studies,wheat bran ems to give ri to high concentrations of SCFA in the gut,despite the fact that it is relatively poorly fermented, especially in human subjects(Cheng et al.1987;McIntyre et al.1991).Studies in human subjects to determine amounts of SCFA in the gut are difficult,but evidence suggests that caecal concentrations of SCFA are approxim-ately double tho in the recto-sigmoid area(Cummings et al.1987).
The amount of SCFA produced in human subjects is very difficult to determine.Studies of arterio–venous differences across the gut indicate that300–500mmol are produced each day,whilst in individual cas this may reach1–2mol. Few dynamic studies have been carried out in man becau of problems accessing the portal vein and differential metabolism of SCFA by individual tissues.The situation is complicated by endogenous production of acetate by the liver.Future stable-isotope studies may give more information in this area.
SCFA production in the large intestine can be obrved qualitatively by measuring levels in blood.However,only acetate appears in significant amounts in peripheral blood, although this responds in both time and amount to sub-strate fermentation in the large intestine(Pomare et al. 1985;Lifschitz et al.1995).
2.2.1.Physiology and health.All SCFA are rapidly absorbed from the hindgut and stimulate salt and water absorption.They are then metabolized principally by the gut epithelium,liver and muscle,with virtually none appearing in urine and only small amounts in faeces.
One of the most important properties of SCFA is their trophic effect on the intestinal epithelium.All three major SCFA are trophic when infud into the large intestine, although butyrate ems to be th
e most effective and propionate the least.What is perhaps more interesting is that infusion of SCFA into the hindgut leads to trophic effects in the small intestine(Sakata,1987;Frankel et al. 1994)although the mechanisms for this are not fully determined.The trophic properties of SCFA have import-ant implications,particularly for patients receiving enteral or parenteral nutrition,and in maintaining the mucosal defence barrier against invading organisms.
2.2.2.Acetate.Acetate is the principal SCFA in the gut. It is taken up by the epithelium,appears in portal blood and eventually pass through the liver to peripheral tissues where it is metabolized by muscle.In animal studies,the liver cretes free acetate when levels in portal blood fall below a critical level.Uptake and utilization of acetate by many tissues has been shown and is the principal route whereby the body obtains energy from carbohydrates not digested and absorbed in the small intestine.Current evidence suggests that the energy value of fermented carbohydrate is6·3–8·4kJ/g(1·5–2kcal/g)(Livey, 1990;Roberfroid et al.1993).
2.2.
3.Propionate.In ruminant species,propionate is a major gluco precursor but this is not an important role in hindgut fermenting species such as man.Propionate is largely cleared by the liver and has not
been shown consistently to have significant effects on carbohydrate metabolism in human subjects.In vitro,propionate inhibits uptake of acetate into the cholesterol synthesis pathway,and in both rats and pigs propionate supplementation of the diet reduces cholesterol levels in blood.In human feeding studies of propionate only one out of three currently reported shows any change in blood cholesterol levels (Venter et al.1989;Todesco et al.1991;Stephen,1994).
2.2.4.Butyrate.Butyrate is the most interesting of the SCFA,since in addition to its trophic effect on the mucosa it is an important energy source for the colonic epithelium and regulates cell growth and differentiation.Butyrate is almost entirely cleared by the colonic epithelium and is the principal energy source for the epithelial cells(Bugaut& Bentejac,1993;Cummings,1995).A defect in butyrate metabolism has been identified in ulcerative colitis patients and may be induced by S compounds generated in the large-bowel lumen(Roediger et al.1993;Pitcher&Cummings, 1995).
The effect of butyrate on cell growth and differentiation is of great importance and has been the subject of a number of studies(Boffa et al.1992;McIntyre et al.1993).Butyrate brings about a concentration-dependent slowing of the rate of transformed cell growth and promotes expression of differentiation markers in vitro,thus leading to reversion of cells from a neoplastic to a non-neoplastic phenotype (Kim et al.1980,1994;Whitehead et al.1986;Gibson et al. 1992).In vitro studies with colon
ocytes suggest an interac-tion between long-chain fatty acids,which result in decread viability and differentiation of the cells,and butyrate,which has the opposite effect(Awad et al. 1991).In carcinogen-induced animal models of large-bowel cancer,however,butyrate,either from fermentable carbohydrate sources such as resistant starch or purified NSP such as pectin,leads to incread cell turnover and in some studies incread tumour formation(Sakamoto et al. 1996;Young et al.1996).The proliferative effects of
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