for health care professionals - Danone

Edition 2004
Danone 672 039 971 RCS NANTERRE
ACTIVIA BY DANONE
CONTAINING ACTIVE BIFIDUS ESSENSIS
MONOGRAPH
FOR HEALTH CARE PROFESSIONALS

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M O N O G R A P H F O R H E A L T H C A R E P R O F E S S I O N A L S
CONTENTS INTRODUCTION
1 THE GASTROINTESTINAL TRACT: GENERAL DATA P. 4
2 ENDOGENOUS INTESTINAL FLORA AND CHARACTERISTICS P. 5
A COMPOSITION AND DEVELOPMENT
B INTERACTIONS BETWEEN THE ENDOGENOUS FLORA AND THE HOST
1 Role of intestinal flora in colonic digestion
2 Protection against infection and toxic agents
3 Interactions between flora and transit
C PARAMETERS THAT MODIFY THE MICROBIAL ECOLOGY
1 Physiological parameters
2 Iatrogenic parameters
3 Nutritional parameters
3 PROBIOTICS THE SPECIAL CASE OF BIFIDOBACTERIA P. 8
A PROBIOTICS
B THE SPECIAL CASE OF BIFIDOBACTERIA
1 Characteristics
2 General beneficial effects
4 INTESTINAL TRANSIT P. 10
A INTESTINAL TRANSIT: THE PROCESS
B INTESTINAL TRANSIT: MECHANISMS OF REGULATION
C CONSEQUENCES OF RETARDED INTESTINAL TRANSIT
1 Consequences for everyday life
2 Potential pathological consequences
5 INTERACTION BETWEEN FLORA AND TRANSIT P. 14
6 ACTIVIA AND BIFIDOBACTERIUM ANIMALIS DN-173 010 P. 15
A STUDIES PERFORMED WITH ACTIVIA AND BIFIDOBACTERIUM ANIMALIS DN–173 010
1 Survival of Bifidobacterium animalis DN-173 010
2 Effects of Activa and/or Bifidobacterium animalis DN-173 010 on transit
B CONCLUSION ON ALL OF THE ABOVE STUDIES
5 GENERAL CONCLUSION P. 21
BIBLIOGRAPHY P. 22
The colon was long considered as simply an organ for
elimination of the remains of the food bolus, in contrast
with the stomach or the small intestine, in which enzymatic
and hormonal secretions take place allowing digestion
and absorption of nutrients.
The colon now appears to be responsible for regulation
of intestinal well-being, particularly through its complex
bacterial flora and maintenance of intestinal equilibrium.
Among the species present in flora, the lactic-acidproducing
bacteria (LAB: Lactic Acid Bacteria) have
fascinated researchers for several decades now due to their beneficial effects on human health.
Many studies, some of which are still ongoing, have examined the interaction between intestinal
flora and the functions of the digestive tract, in particular, between the endogenous intestinal flora
and intestinal transit. Based on these studies, the beneficial effects on health of the exogenous
flora have been investigated and the concept of “probiotics” has been described and developed.
The present dossier is concerned with the properties of certain probiotics strains and with the foods
in which they are found, in relation to health in general and to gastro-intestinal transit in particular.
One probiotic strain is particularly well represented: Bifidobacterium animalis DN-173 010 (also
known as Bifidus Essensis ® ), a proprietary strain found in ACTIVIA by Danone, a fermented milk
product. Specialists at the Groupe DANONE Research Centre, Danone Vitapole Daniel Carasso
Research Centre and independent researchers have investigated the effects of this probiotic on
intestinal transit.
This monograph presents an overview of the effects of starters of ACTIVIA by Danone on the
intestinal ecosystem and on gastrointestinal transit in the light of the latest advances in research
into probiotics and their relationship with human health.
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THE GASTROINTESTINAL TRACT:
GENERAL DATA
Adequate digestion is a necessary prerequisite of good health. In the absence of good digestion and absorption,
even the most balanced diet cannot be considered optimal for the body.
The primary function of the gastrointestinal tract is to permit digestion and absorption of nutrients. While food is
generally consumed in the form of polymers (starches, triglycerides, proteins), the nutrients absorbed and transported
from the intestine to the tissues where they are utilised in the form of monomers or oligomers.
Among other things, the gastrointestinal tract exerts two essential functions that may appear paradoxical:
• First, absorption of nutrients,
• Second, presentation of a selective physical, microbiological and immunological barrier with regard to
agents potentially harmful for the body.
The area of exchange (over 200 m2 ) is considerable due to the intestinal folds and the villosities and microvillosities
that increase the surface area over 600-fold in relation to a simple cylinder of comparable length.
The small intestine (a particularly active structure) is often described as being quite the opposite of the colon (a
structure designed for storage but devoid of any metabolic function). However, there is no logical basis for this description,
since both parts of the intestine play host to complex and specific functions.
The small intestine in fact acts as the main site of enzymatic digestion of foods and absorption of nutrients.
The colon absorbs large quantities of water and electrolytes and allows evacuation of waste matter and toxic substances,
but it also plays host to many bacterial species. The latter have an extremely important role in the metabolism of
substrates not digested in the small intestine, with breakdown of these substrates resulting in the production of short-chain
fatty acids1 (SCFA), which form substrates for the epithelial cells of the colon.
Approximately 400 to 500 bacterial species2 exist in the colon within an abundant bacterial flora: there are 10
times more bacteria than cells in the body. Most of these species exert a beneficial role on the colon. However,
others are potentially pathogenic (Clostridium difficile, Clostridium perfringens etc.) but since they are too small in
number and are subject to competition from other saprophytic bacteria, their pathogenicity remains only latent.
The intestinal microflora of each individual is highly specific. It develops in stages throughout the individual’s lifetime
as a result of diet, host health status and environmental conditions. However, the flora within an adult individual
remains remarkably stable over time3 .
2
ENDOGENOUS INTESTINAL FLORA
AND CHARACTERISTICS
A COMPOSITION AND DEVELOPMENT
Within a few hours of birth 4 , the gastrointestinal tract in humans is colonised by a specific microbial population.
During this colonisation process, the microorganisms organise into populations in a state of equilibrium. The stomach
is the site of very low levels of colonisation due to the presence of oxygen and hydrochloric acid. In the small intestine,
the number of bacteria remains very low in the duodenum, but gradually increases towards the terminal ileum.
The highest numbers of microorganisms are found in the caecum and colon due to slower digestive transit and a
more favourable physicochemical environment (less oxygen, more acidic pH than the distal small intestine).
The intestinal tract of an adult human contains flora comprising approximately 10 11 microorganisms (or colony forming
units cfu/g) per gram of stool containing approximately 400 to 500 different bacterial species.
The dominant population consists of strict anaerobic bacteria: Bacteroides, Bifidobacterium, Eubacterium and
Peptostreptoccocus. These four types of organism are found in all individuals at concentrations of 10 8 to 10 11 cfu/g.
Of these four organisms, Bacteroides (Gram-negative) is the most numerous, followed closely by the bifidobacteria
(Gram-positive).
The sub-dominant flora comprises bacteria belonging to the Streptococcus and Lactobacillus families and to a lesser
extent, Enterococcus, Clostridium and yeasts, which are found in concentrations 10 4 to 10 8 cfu/g. It is important
to note that not all bacteria present in the intestinal tract have been identified to date.
The intestinal flora is thus a complex entity that contains dominant populations including bifidobacteria.
B INTERACTIONS BETWEEN THE ENDOGENOUS FLORA AND THE HOST
The intestinal flora may be the source of beneficial effects for the health of the host but it can also be harmful in
the event of disequilibrium.
Many studies have provided a better understanding of these positive and negative effects. They have been performed
mainly in animal models and have compared animals with known flora to animals without any flora (axenic animals);
they have provided evidence of the protective role of the intestinal flora against specific infections and toxic agents
and of its contribution to optimal functioning of the intestine (colonic digestion, synthesis of essential substances
such as vitamins and certain amino acids, etc.).
1 Role of intestinal flora in colonic digestion 1
The colonic flora facilitates the digestion and absorption of various nutrients not digested in the small intestine.
a Carbohydrate metabolism
Degradation of complex polysaccharides not digested in the small intestine (xylanes, pectin, micro-polysaccharides,
glycoprotein) is performed principally in the colon by the intestinal flora. This process allows the colonocytes to
recover energy provided by these elements.
b Protein metabolism
The flora is involved in degradation of undigested nitrogen-containing matter and can also synthesise amino acids
that may subsequently be used by the host.
c Lipid metabolism
The intestinal flora exerts indirect action by modifying metabolism of cholesterol and bile salts; certain bacterial
species are able to deconjugate bile salts and thus modify absorption.
d Mineral and vitamin metabolism
Certain bacteria are able to synthesise vitamins, including vitamin K (the intestinal flora comprises an essential source
of this substance), vitamin B12, folic acid (B9), biotin (B8) riboflavin (B2) and pantothenic acid (B5).
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ENDOGENOUS INTESTINAL FLORA AND CHARACTERISTICS
2 Protection against infection and toxic agents 5
This is without doubt one of the most important actions performed by the intestinal flora. It ensures protection against
infections and colonisation of the digestive tract by pathogenic organisms entering the intestine through food. One
of the body’s defence mechanisms is based on the barrier effect of the intestinal flora. Undesirable bacteria may
be completely eliminated or may subsist in the gastrointestinal tract at population levels insufficient to threaten
pathogenic effects.
However, where imbalance occurs in the intestinal flora, exogenous pathogens, but also endogenous pathogens
(i.e. potentially pathogenic organisms) may develop and contribute to the onset of infections. In addition, certain
bacteria in the flora may have negative effects on the health of the host as a result of various enzymatic activities.
Thus, in the case of imbalance of the flora the beta-glucuronidase activity of certain bacteria may be increased
with release of potentially carcinogenic substances.
Certain enzymes involved in nitrogen metabolism may degrade tryptophan, indoles, nitrates and secondary amines
for example to derivatives having carcinogenic potential.
3 Interactions between flora and transit
The intestinal flora exerts an effect on transit as a result of direct and indirect actions that involve the production of
volatile fatty acids, changes in local pH and other mechanisms, many of which are still hypothetical. Evidence of
the reality of such interaction is provided by experiments in animal models, particularly axenic models and/or
models with retarded transit.
There are thus indications of both positive and negative effects of the flora with regard to the health of the host,
depending on the different species that make up the flora.
A balanced flora rich in bifidobacteria helps ensure optimal functioning of the intestine. It facilitates colonic
digestion and absorption of certain nutrients and helps eliminate toxic wastes (by means of regular transit); it
also protects the body against pathogenic bacteria.
C PARAMETERS THAT MODIFY THE MICROBIAL ECOLOGY
The stability of the intestinal flora is dependent on the following three types of parameter:
• Physiological parameters,
• Environmental parameters,
• Nutritional parameters.
1 Physiological parameters
Age: during the first two years of life, the flora establishes itself and gradually develops. It becomes richer particularly
at the time children’s’ diets become more diversified. Subsequently, studies suggest that changes (which are nevertheless
moderate) in the faecal flora occur with age 6 . Most of these studies were performed comparing the flora of groups
of people of different ages. To date, there are no longitudinal studies providing data concerning change in bacterial
flora in a single individual over time. In elderly subjects, certain elements tend to suggest an increase in flora having
a negative effect, particularly Clostridium or Pseudomonas. In addition, the incidence of subjects presenting
decreased bifidobacteria population rises.
Modifications in the intestinal flora associated with age could account for the decreased resistance of endogenous
bacteria to colonisation by other organisms.
This decrease in resistance to colonisation by other organisms is probably the result of the intestinal physicochemical
medium 7 and impairment of the intestinal mucosa due to age.
Menopause : Differences have been noted in the composition of intestinal flora between women of procreational
age and menopausal women. In menopausal women, there appears to be a moderate increase in gram-negative
enterobacteria, yeasts and Clostridia. These differences have been ascribed to changes in the female hormonal profile.
Le stress : In many situations involving physical or psychological stress, the balance of the intestinal flora may be
modified8 .
2 Iatrogenic parameters 9
a Diseases
Certain diseases modify the distribution of the flora profoundly due to the structural alteration that ensues in the
intestinal mucosa. Each intestinal disease affects microbial distribution in the intestine in a specific way:
• Diarrhoea is accompanied by a reduction in lactobacilli, bacteroides and bifidobacteria, as well as
an increase in facultative anaerobes.
• Pseudo-membranous colitis is associated with an increase in Clostridium difficile, which secretes toxins.
• In the context of Crohn’s disease, enterococcal concentrations fall while streptococcal populations rise.
• Finally, in constipation, levels of lactic acid bacteria fall.
In vitro studies suggest that certain diseases induce structural changes in the intestinal mucosa. These phenomena
could increase bacterial translocation or proliferation.
b Certain medicines
The administration of certain medicines, particularly antibiotics, is the most common and significant reason for
change in the intestinal flora.
Certain medicines can alter the intestinal pH, which in turn may affect the equilibrium of the flora. Thus, a clinical
study has shown that an increase in pH during treatment for duodenal ulcer results in a significant increase in
growth of gram-negative germs in these patients. Reduced pH on the other hand can change the metabolic activity
of bacteria.
3 Nutritional parameters
Diet plays an important role in the equilibrium of the flora, both through the nutritional elements it provides (fibres,
prebiotics, protein, etc.) and through probiotics.
a Probiotics
A probiotic is a living microorganism that when ingested in sufficient quantities exerts beneficial effects on the host that
go beyond the primary nutritional effect.
A probiotic must possess the following principle characteristics:
• It must be of food grade.
• It must be present in the form of live cells, preferably in large quantities prior to ingestion,
• It must be stable and remain viable throughout the entire shelf life of the food in which it is found,
• It must exert beneficial effects on the health of the host.
It is consequently of value to evaluate survival in the gastrointestinal tract.
A probiotic food is a food that contains live probiotics in sufficient quantities and which exerts a beneficial effect
on the health of the host, throughout the entire shelf life of the food in which it is found.
Probiotics are usually selected from lactic bacteria, the most common of which are Lactobacillus, Bifidobacterium
or Streptococcus10 families. The first probiotics consisted of strains of Lactobacillus (particularly in the case of
yoghurts). More recently, the Bifidobacterium genus has been used and in particular B. adolescentis, B. bifidum,
B. infantis, B. longum and B. animalis. Ingestion of probiotics can increase the number of bacteria present in the
intestine throughout the entire period of their consumption. Thus, it has been shown that administration of
Lactobacillus causes a 10- to 100-fold increase not only in the number of Lactobacillus in the intestine, but also in
the number of Streptococcus present11 .
b Prebiotics
Prebiotics are substances that are not digested in the small intestine and are utilised in the colon as specific substrates
for certain bacterial species whose development they favour.
Among the non-digestible carbohydrates, oligosaccharides (FOS, GOS, inulin, etc.) extracted from various foodstuffs
such as chicory, garlic, onion and artichoke generally present all the criteria allowing them to be classified as prebiotics.
Many of these substances increase the growth of certain endogenous bifidobacteria12 .
In conclusion, the intestinal flora plays an important functional role. It maintains a very precise relationship with
the host and confers benefits on the latter. The composition of the intestinal flora changes with age and is sensitive
to environmental variations, as is the case during the menopause and during drug treatment. It is profoundly
altered in the event of acute and chronic and intestinal diseases. Equilibrium is temporarily restored to the flora
by ingestion of probiotics.
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PROBIOTICS
THE SPECIAL CASE OF BIFIDOBACTERIA
A PROBIOTICS
Probiotics exert beneficial effects on their host by means of various mechanisms of action that are currently under
study. Certain of these mechanisms contribute to inhibition of growth of pathogenic bacteria or neutralisation of
toxic products 5 , or they may act on the body’s natural defence mechanisms. Others effectively participate in the
digestive process by improving the digestibility of certain components found in our diet. For instance, beta-galactosidase,
which is secreted by certain probiotics, facilitates digestion of lactose 13 .
A number of probiotics also stimulate enzymatic activity such as the activity of lactases, invertases and maltases in
epithelial cells within the gastrointestinal tract.
The use of probiotics in food opens up interesting perspectives for health and requires careful selection of the most
effective strains. In vitro and in vivo testing is vital to determine the potential effects of these probiotics on the body
and to allow optimal utilisation of the specific properties of each strain.
B THE SPECIAL CASE OF BIFIDOBACTERIA
1 Characteristics
Whether exogenous or endogenous, bifidobacteria are in all cases anaerobic, Gram-positive bacteria.
They belong to the group of lactic bacteria, which also encompasses lactobacilli and streptococci.
• Bifidobacteria produce acetic acid and lactic acid through metabolism of glucose. Other carbohydrate
substrates may be utilised (e.g. lactose, galactose and sucrose),
• Ammonia is the only available source of nitrogen for bifidobacteria,
• Certain bifidobacteria are able to resist gastric acid and bile salts,
• Certain strains of bifidobacteria are able to synthesise group B vitamins and vitamin K.
Lactobacillus bulgaricus
Clichés Danone Vitapole Recherche / INRA Massy
Bifidobacterium animalis DN-173 010
Streptococcus thermophilus
2 General beneficial effects 14
a Contribution to protein and vitamin metabolism
In the newborn, bifidobacteria exert a phosphatase activity
that appears to improve absorption of protein from breast milk.
In addition, certain strains of bifidobacteria are able to produce
vitamins such as B1, B2, B12, C, PP and folic acid.
In addition, in a standard diet, vitamin production by these
bifidobacteria may allow improvement in the nutritional
properties of fermented milks.
b Antimicrobial action
In vitro, bifidobacteria have demonstrated antibacterial activity
with regard to a certain number of pathogenic micro-organisms
such as Escherichia coli, Staphylococcus aureus, Salmonella
typhi, Schigella dysenteriae and Candida albicans.
The antimicrobial action exhibited by these bifidobacteria is
due in part to the production of substances such as bacteriocins
and peroxides, but also to the production of organic acids
such as lactic acid and acetic acid. The latter, by reducing the
pH within the intestinal medium, antagonises the growth of
certain microorganisms.
c Action on immunity
Beneficial action of bifidobacteria on cellular immunity has
been widely demonstrated in vitro, but there are as yet relatively
few positive results in vivo. A number of studies performed in
animals and in man suggest that ingestion of certain strains of
bifidobacteria improves non-specific anti-infectious defence
mechanisms.
d Reduction of risk of colonic cancer?
Many studies have concentrated on the potential role of bifidobacteria in the prevention of colonic cancer in recent
years 15 . A number of these studies performed in animal models demonstrate retarded regression of certain experimental
cancers. In man, bifidobacteria have shown their ability to reduce the activity of enzymes involved in conversion
of pro-carcinogens to carcinogens such as nitrosamines and secondary amines 16 . Nevertheless, the mechanisms
responsible and the long-term effects of these changes have not yet been fully elucidated. Considerable research
is currently being carried out in this domain.
e Action on intestinal transit
Among the data concerning the effects of ACTIVIA by Danone and its specific proprietary strain on intestinal transit,
there are currently relatively few results available concerning the relationship between intestinal transit and
bifidobacteria. It nevertheless would appear that production of organic acids and reduction of pH contribute
among other things to accelerated transit.
Furthermore, there appears to be a correlation between improved colonic movement and simultaneous in the quantity
of bifidobacteria present in faeces.
In conclusion, probiotics, and in particular certain bifidobacteria play a major role in the intestinal ecosystem;
they contribute to vitamin metabolism, exert anti-microbial activity and immune effects and are active upon
intestinal transit. They may help to reduce the risk of colonic cancer.
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INTESTINAL TRANSIT
Through fermentation of substrates not digested in the small intestine and effective re-absorption of water and
electrolytes, the colon limits energy and water-electrolyte loss.
These functions require slow transit of the colonic contents, which occurs physiologically in less than 72 hours
according to age and lifestyle, in contrast with the transit time for the stomach and small intestine, which is only
several hours. This capacity to retain material in the colon is made possible by a different type of motility from that
seen in the other segments of the gastrointestinal tract.
In addition, the intraluminal contents are progressively concentrated into solid faecal mass, which is then slowly
transported to the rectum, where faeces are stored until the time of elimination.
In an adult in good health, the transit time from mouth to anus takes under 72 hours and most of this transit time
is spent in the colon.
There are numerous factors that determine the transit time within the colon in healthy subjects and not all have yet
been elucidated.
Transit time varies significantly between individuals in spite of identical diet and also varies within specific individuals.
Thus, in ten women in whom transit time was measured 5 times over a period of several successive weeks, the
coefficient of variation was close to 28% 17 .
Certain of these variations may be explained partly by psychological factors. In addition, it appears to be accepted
that transit time is longer in women than in men and increases with age.
Thus, a total transit time in excess of 72 hours is considered abnormally long and normally gives rise to a
diagnosis of constipation.
In the narrowest sense constipation is defined as slowing of oral-anal transit, although in clinical terms, a patient
may complain of constipation where effort at stool is greater than normal. Patients producing two stools or less per
week are considered as constipated. Delayed transit in certain or all segments of the colon in fact results in hard
faecal mass that is eliminated irregularly and often with great difficulty.
Constipation affects a large percentage of the population in western countries, with a high predominance among
elderly subjects.
A recent French epidemiological study 18 indicates that the prevalence of constipation is around 10%.
However, when patients are questioned directly, 40% of the French population report that they are constipated
or have been constipated and half of these have seen a doctor about this problem.
Differences between slow transit and constipation.
Slow transit is not necessarily pathological: it corresponds to the upper limit of normal transit time and is between
48 and 72 hours.
Constipation involves a combination of pathologically long transit time, of over 72 hours, and excessive dehydration
of stools. Clinically, the frequency of stools must be below 3 per week.
A INTESTINAL TRANSIT: THE PROCESS
The food bolus passes through the small intestine. This organ is a long tube measuring approximately six and a
half metres and is divided into three sections, the duodenum, the jejunum and the ileum. Passage through the small
intestine allows absorption of the majority of water, electrolytes, nutrients and micro-nutrients present.
In the duodenum, the pancreatic digestive enzymes release monoglycerides and fatty acids from lipids, sugars from
digestible carbohydrates and amino acids from proteins.
The gall bladder secrets bile, which allows emulsification of the fatty acids, thereby facilitating their absorption. At
the end of the ileum, whatever is not absorbed passes into the large intestine and is referred to as chyme. The
colon represents the last stage in which the gastrointestinal tube may reduce the faecal volume and shape faecal
matter in such a way as to facilitate defecation.
In this way, nutrients in the food bolus are utilised by the body and all waste evacuated.
B INTESTINAL TRANSIT: MECHANISMS OF REGULATION 19
Intestinal transit is based on motility of the gastrointestinal tract and particularly of the colon. Colonic motility, which
results in slow progress of the food bolus, differs from the proximal colon to the distal colon. These regional
variations may be explained by embryological differences in innervation and vascularisation between the proximal
and distal colon.
• Regulation of colonic motility through ingestion of food
The volume of meals consumed certainly plays a role in colonic response to eating. Gastric distension by means
of an intragastric balloon is in itself sufficient to stimulate phasal and rectal-sigmoid motility and gives rise to tonic
contraction. The degree of response depends on the volume of gastric distension.
A minimal calorie load (greater than 800 calories) is nevertheless necessary to induce a significant response.
Colonic motility is also affected by the type of food eaten. Thus, intra-duodenal infusion of lipids stimulates phasal
colonic motility while intravenous infusion of lipids has no effect. Inclusion of carbohydrates in a meal containing
lipids does not affect the myoelectrical response of the colon to meals.
Nevertheless, increased blood glucose levels inhibit tonic colonic contraction produced by gastric distension.
• Nervous control of colonic motility
Colonic motility is controlled by a complex nervous network20 .
The multiple functions of this network include:
_
transmission of sensory information to adjacent or distant gastrointestinal segments,
_
stimulation or inhibition of activity of colonic smooth muscle,
_
control over certain colonic and sphincter functions such as defecation.
The nerves controlling these functions belong to the central nervous system, the autonomic peripheral nervous and
the enteric nervous system. The modulator effect of the central nervous system comes into play principally in the
event of stress, emotion or danger and is probably not permanent. The autonomic peripheral nervous system comprises
the parasympathetic system (vagal and pelvic nerves) and the sympathetic system (splanchnic, lumbar, colonic and
hypogastric nerves) 21,22 .
Finally, the enteric nervous system is composed primarily of two interconnected plexuses located between the
longitudinal and circular layers of colonic muscle and in the submucosa. This enteric nervous system is modulated
by the autonomic nervous system, the key mediator of which is acetylcholine and by a group of other factors (colonic
distension, neurotransmitters, hormones, including cholecystokinin (CCK)).
• Hormonal regulation
Many hormones are released following ingestion of a meal and they exert an inhibitory or stimulatory effect on
gastrointestinal motility.
Whether CCK23 or serotonin, their mechanism of action may occasionally be inhibitory and occasionally stimulatory.
• Role of bacterial fermentation in regulation of colonic transit
The bacteria present in the colon transform non-digested carbohydrates in the small intestine to SCFA, which are
then released into the colon. Part of these fatty acids are absorbed by the intestinal mucosa while the other part
is used and serves as substrates for the colonic flora, increasing the weight of the latter.
In addition, SCFA reduce colonic pH and increase the osmolarity of the medium. These two mechanisms, found
essentially in the proximal colon, permit increase in the stool volume and weight of while reducing stool
consistency. Conversely, retardation of the transit time effects fermentation and stool formation. It is likely that transit
within the colon depends partly on transit within the small intestine. If the latter is retarded, there is more time
available for absorption of the contents of the small intestine, resulting in a reduction in chyme within the colon.
This reduction in nutrient substrate results in a fall in bacterial mass and therefore a reduction in stool weight.
In addition, the decrease in bacterial mass leads to lower production of SCFA, leading to harder stools.
Other mechanisms have been suggested (see Chapter 5).
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C CONSEQUENCES OF RETARDED INTESTINAL TRANSIT
Retarded intestinal transit is responsible for metabolic changes that may be partly responsible for various diseases;
various hypotheses have been evoked and many studies are currently being conducted in an attempt to validate them.
1 Consequences for everyday life 24
Retardation of intestinal transit is a source of real discomfort for a large proportion of the population and results in
daily discomfort whose physical and psychological consequences on the quality of life should not be underestimated.
Bloating, heaviness, difficult and painful defecation are all troublesome symptoms when they become chronic.
Reduction in elimination of waste and toxic materials by the body due to slow transit very probably contributes to
non-optimal functioning of the body.
In addition, the imbalance to which the intestinal flora is subjected during slowing of intestinal transit and constipation
enhances production of secondary amines, the toxic role of which is well known. In the long term, slow transit may
lead to real pathological problems.
2 Potential pathological consequences
a Short chain fatty acids and colonic cancer
In 1969, Walker et al 25 formulated the hypothesis that colonic cancer could be related to slow colonic transit. Few
epidemiologiocal studies exist on this subject, but it has nevertheless been shown that in the study population, there
is a relationship between risk of colonic cancer and faecal volume or weight 26 .
These findings are consistent with the protective role of SCFA on risk of colonic cancer. In effect, there is an inverse
correlation between intestinal transit time and concentration of SCFA (butyrate, acetate and propionate) in the
colon. This action of SCFA may be direct (butyrate) or indirect through decreased colonic pH. A low or neutral pH
is associated with low risk of colonic cancer 27 .
During transit through the colon, concentrations of SCFA decrease (they are absorbed and utilised by the intestinal
mucosa) and the intraluminal pH increases gradually towards neutral values. Furthermore, colonic cancer is more
commonly found in the distal colon.
Transit time could therefore be a decisive factor in colonic cancer, independently of diet. However, it can not be
the sole factor since the incidence of colonic cancer is no higher in women, who generally have a longer transit
time than men. This apparent contradiction could be due to a protective effect exerted by oestrogens.
b Biliary acids and gall stones
Slowing of intestinal transit increases levels of deoxycholate and biliary cholesterol, thereby facilitating the formation
of gallstones 28 .
In the normal population, constipation is associated with a higher instance of gall stones, particularly in non-obese
women.
c Intestinal flora, oestrogens and breast cancer
Oestrogens are excreted in urine and bile.
In the intestine, these excreted oestrogens are largely reabsorbed following deconjugation by bacterial betaglucuronidases,
before being reconjugated and recycled.
The intestinal bacteria increased the biological activity of the absorbed oestrogens by transforming reduced oestrone
to active oestradiol 29 . Slowing of intestinal transit also appears to increase the oestrogenic environment, thereby
favouring hormone-dependent breast cancer. Although a diet rich in fibre and vegetables, which are known to
enhance transit, is thought to protect against breast cancer 30 , there have been no studies to date demonstrating a
relationship between intestinal transit time and the risk of breast cancer. In addition, it has been shown that a diet
rich in fibre 31 reduces blood oestrogen levels in pre-menopausal women.
LIFESTYLES TO ENSURE REGULAR TRANSIT
1. Dietary measures
a - Enrichment of the diet with fibre
The dietary recommendation emphasises the need for adequate consumption of
fibre (at least 20 to 30 g per day) in the form of vegetables, fruit, wheat bran, etc.
Insoluble fibre increases hydration of stools within the colon and thus facilitates their
evacuation; soluble fibres are fermented by the bacterial flora, thereby increasing
their mass and consequently the volume and hydration level of stools.
b - Increased consumption of certain fermented dairy products
Consumption of dairy products rich in various strains of bifidobacteria helps improve
transit (see Chapter 6).
c - Adequate hydration
Consumption of at least 1 to 1.5 litres of water a day is necessary to ensure regular
transit.
2. Exercise and physical activity
Physical activity appears to increase colonic activity through the pressure exerted by
the abdominal muscles.
A number of simple steps are occasionally sufficient to deal with the problem of slow
transit. Defecation is easiest when accomplished close to the feeling of urgency,
which is stimulated by the arrival of matter in the rectum, most often in the morning
or after a meal.
Normal transit can be restored by means of bowel movements at regular times even
in the absence of any real desire. Similarly, sensation of urgent need to move the
bowels should never be ignored.
In conclusion, problems of intestinal transit constitute a daily preoccupation for a large proportion of the population
and affect women and elderly subjects in particular. The consequences of delayed transit and particularly of
constipation, may extend well beyond the daily discomfort that they generate and which considerably diminish
the quality of life of these subjects.
Intestinal transit is affected not only by the quality of diet but also by the intestinal flora. Maintaining a regular
intestinal transit is essential for health and general well being.
12 13

M O N O G R A P H F O R H E A L T H C A R E P R O F E S S I O N A L S
5
INTERACTION BETWEEN
FLORA AND TRANSIT
Researchers have only recently begun to examine the interaction between intestinal flora and transit. The majority
of studies demonstrating stimulation of transit by the intestinal flora have been conducted in animals.
The most recent studies have attempted to determine the mechanisms by which the intestinal flora stimulate transit
and have focused particularly on the effects on intestinal transit of the products of bacterial fermentation such as
SCFA and on physicochemical modifications induced by the flora (changes in pH, osmolarity).
Various hypotheses have been formulated concerning SCFA 32 :
• SCFA appear to have a direct effect upon intestinal motility via a calcium-dependent mechanism, by
stimulating contraction of the muscles in the intestinal wall.
• Animal studies 33 have suggested that the effects of SCFA on intestinal transit could be mediated by a
neuro-endocrine mechanism involving peptide YY. This peptide appears able to stimulate intestinal motility,
but this effect has not as yet been demonstrated in man.
• Other parameters also appear to implicate the action of SCFA in gastrointestinal transit as a result
of reduction of pH and increases osmolarity. This mechanism appears to depend upon the
concentration and type (acetate, propionate or butyrate) of SCFA in the intestinal tract.
Other hypotheses concerning various mechanisms have been formulated concerning the interactions between transit
and flora, but nothing has been demonstrated to date.
The following hypotheses 34,35,36,37 concern the effects of the intestinal flora on transit:
• Gas production, which accelerates transit,
• Increased intra-luminal content of certain musculo-active substances that could stimulate intestinal transit,
• Stimulation of CCK production,
• Reduction of the threshold of response of caecal smooth muscle to chemical stimulation,
• Microbial metabolism of bile acids released in the colon: this would appear to stimulate colonic transit,
• Increases stool weight through increase in bacterial mass, resulting in stimulation of transit.
MECHANISMS OF FLORA-TRANSIT
INTERACTION: MANY MECHANISMS
SUGGESTED BUT NONE AS YET
CLEARLY DEMONSTRATED
Hypothetical interaction
Demonstrated interaction
pH Osmolarity
Weight &
consistency of stools
Intestinal
Microflora
Muscular
activesubstances
Accelerated
intestinal transit
Gas
production
SCFA Production CCK Osmolarity
Direct neural
stimulation
Intestinal motility
Peptide
YY
[Ca 2+ ] of
Muscle cells
In faecal
bacteria
mass
Weight &
consistency of stools
Since certain strains of probiotics have been identified through their beneficial effect on the endogenous intestinal flora,
it was logical to assess their impact on transit. Lactobacilli and bifidobacteria have thus been particularly closely studied
in man 38 . Their effects on transit have been clearly demonstrated through studies performed recently with ACTIVIA by
Danone and its specific strain: Bifidobacterium animalis DN-173 010 42-45 .
pH
6
ACTIVIA AND
BIFIDOBACTERIUM ANIMALIS DN-173 010
Since 1987, Danone have marketed a range of dairy products containing Bifidobacterium animalis DN–173 010
under the name ACTIVIA. This strain of bifidobacteria was selected by Danone Vitapole Daniel Carasso Research
Centre. Many studies have been performed to determine the involvement of ACTIVIA and its specific starters in the
regulation of intestinal transit and its potential applications in nutritional advice suited to specific intestinal disorders.
ACTIVIA is a fermented milk that combines traditional yoghurt strains (Lactobacillus bulgaricus and Streptococcus
thermophilus) with a specific starter: Bifidobacterium animalis DN-173 010 (see photos page 8). This probiotic food
has been shown to have beneficial effects on health in man. It also possesses all the standard nutritional qualities
of a dairy product thanks to the proteins and calcium it contains.
The specific bifidobacterium present in this fermented milk is of food origin and is found live in large quantities in
this product (approximately 10 8 bacteria per gram of product) and this quantity persists until the shelf life date.
Various studies have been performed to evaluate survival of this strain in the gastrointestinal tract as well as the
beneficial effects on health of this product.
A STUDIES PERFORMED WITH ACTIVIA AND BIFIDOBACTERIUM ANIMALIS DN–173 010
1 Survival of Bifidobacterium animalis DN–173 010
Various studies have been performed to determine the survival of Bifidobacterium animalis DN-173 010
in the gastrointestinal tract.
a Bifidobacterium animalis DN-173 010 survives passage through the stomach 39
Study methodology: In this randomised, double-blind
study 10 healthy volunteers received two pots of 125 g
of ACTIVIA 14 days old, 2 pots of 125 g of ACTIVIA 24
days old, or two pots of 125 g of commercially available
product containing another strain of bifidobacteria, 14 days
old over 3 periods.
Evaluation criteria: Survival of the two different strains of
bifidobacteria in the stomach after 90 minutes, time to
evacuation of 80% of the stomach contents into the small
intestine.
Results: Bifidobacterium animalis DN-173 010 survived
very successfully for at least 90 minutes in the stomach
(2 to 3 log reduction in concentration, i.e. 10 5 -10 6 cfu/g).
The age of the product does not affect the survival capacity
of this starter. The strain of bifidobacteria contained in the
other commercially available product was much less
resistant (10 2 cfu/g; p

16
M O N O G R A P H F O R H E A L T H C A R E P R O F E S S I O N A L S
6
ACTIVIA AND BIFIDOBACTERIUM ANIMALIS DN-173 010
b Bifidobacterium animalis DN-173 010 survives passage through the small intestine 40
Study methodology: This was a cross over study in which each subjects
served as their own controls. Six healthy volunteers consumed 400 g of
milk fermented with Bifidobacterium animalis DN-173 010. They received
a total of 10 10 bacteria or a monitored diet containing no bifidobacteria.
Evaluation criterion: The mean concentration of bifidobacteria surviving in
the terminal ileum throughout the 8 hours following ingestion of the meal.
Results: Ileal flow of bifidobacteria increased significantly following ingestion
of milk fermented with Bifidobacterium animalis DN-173 010. After 8 hours
23.5% ±10% of Bifidobacterium animalis DN-173 010 were recovered
in the terminal ileum. In conclusion, large quantity of ingested bifidobacteria
reached the colon and could potentially modulate the functions of the
endogenous colonic microflora.
c Bifidobacterium animalis DN-173 010 survives passage through the
entire gastrointestinal tract
FIRST STUDY 41
Study methodology: This was a cross-over study in 12 healthy volunteers
(6 men and 6 women) ingesting either 3 125-g pots of ACTIVIA or 3
125-g pots of a standard yoghurt over a 10 day period. The study subjects
consumed no other fermented dairy product during the study. The period
of consumption of these products was also preceded by a 10 day period
during which no fermented milk products were consumed. Stool samples
were collected every 5 days.
Evaluation criterion: Investigation for Bifidobacterium animalis DN-173 010 in stools by counting colonies on a
selective medium.
Results: The strain Bifidobacterium animalis DN-173 010, incorporated in ACTIVIA, survived passage through the
gastrointestinal tract and was recovered in stools. Under physiological conditions, the strain was found live in large
quantities (>10 8 cfu/g) and did not appear to colonise the colon. Ten days after the end of consumption of ACTIVIA,
the level of bifidobacteria recovered in stool returned to its baseline value.
SECOND STUDY42 Study methodology: This study was
conducted in 5 healthy volunteers each
consuming three 125 g pots of ACTIVIA
per day for 7 days. Subjects served as
their own controls.
Evaluation criterion: Investigation for viable
bacteria in the stools by immunodetection
of colonies of Bifidobacterium animalis
DN-173 010 following culture in selected
medium.
Results: Bifidobacterium animalis
DN-173 010 was found live in stools in
large quantities (108 cfu/g).
These four studies showed that in man,
Bifidobacterium animalis DN-173 010
survives complete transit through the
digestive tract and is recovered live in
stools in large quantities in relation to the
quantity initially ingested.
Population (log CFU/g)
12
10
8
6
4
2
0
DURATION OF FLOW OF BIFIDOBACTERIA IN THE
ILEUM FOLLOWING INGESTION OF MILK FERMENTED
WITH BIFIDUS OR A CONTROLLED MEAL
10 Log (Bifidobacteria cfu/g)
10
9
8
7
6
5
4
3
2
0 2 4 6 8
Time (hours)
Bifidus milk
Controlled meal n= 6
BIFIDOBACTERIUM ANIMALIS DN-173 010 WAS FOUND LIVE IN LARGE
QUANTITIES IN STOOLS FOLLOWING CONSUMPTION OF ACTIVIA
Subject 1 Subject 2 Subject 3 Subject 4 Subject 5
BEFORE / AFTER CONSUMPTION OF ACTIVIA
Bifidobacteria without DN-173 010 Before / After ingestion of ACTIVIA
Strain DN-173 010 Before / After ingestion of ACTIVIA n=5
2 Effects of ACTIVIA and/or Bifidobacterium animalis DN-173 010 on transit
a Effects of a milk fermented with Bifidobacterium animalis DN-173 010 on chronic transit time in healthy adults 43
Study methodology: This was a double-blind parallel study in two groups comprising 72 healthy adult volunteers
(mean age 30 years) the effects comparing the effects of daily ingestion for 11 days of a fermented milk (3x125 g)
containing the strain Bifidobacterium animalis DN-173 010
and an identical fermented milk (3x125g) in which
bacteria were killed by heat treatment.
Evaluation criterion: Determination of colonic transit
time, both total and by individual segment, using a
radiopaque marker.
Results: Daily consumption of milk fermented with
Bifidobacterium animalis DN-173 010 significantly
reduces total colonic transit time by 21% and sigmoid
transit time by 39%. This effect on the sigmoid colon is
seen particularly in women. The improvement in total
colonic transit time was significant in both men
(p

M O N O G R A P H F O R H E A L T H C A R E P R O F E S S I O N A L S
6
ACTIVIA AND BIFIDOBACTERIUM ANIMALIS DN-173 010
Results: Total colonic and sigmoid transit times were significantly shortened (p< 0.05) with ACTIVIA in relation to
control (51.5 +/- 30.2 hours vs. 60.7 +/- 27.1; sigmoid: 21.6 +/- 14.9 hours vs. 26.8 +/- 14.2).
In women with a total transit time of more than 40 hours, the sigmoid transit time and total transit time are significantly
shorter following consumption of ACTIVIA in relation to the baseline values recorded prior to consumption.
The other analytical criteria (faecal mass, pH, bacterial mass, bile acids) were not significantly affected by consumption
of the study products, although a trend towards increased faecal mass and primary bile acids was noted during the
period of consumption of ACTIVIA.
Conclusion: consumption of 3 pots of ACTIVIA per day reduced total and sigmoid colonic transit time in women.
This effect was more pronounced in women with a long transit time. This effect was only obtained where
Bifidobacterium animalis DN–173 010 was present.
c Effects of ACTIVIA on total transit time in elderly subjects
FIRST STUDY 45
Study methodology: This was a randomised
study in four groups: 50 subjects with a stable
transit time below 40 hours and 50 subjects
with a stable transit time of 40 hours or more.
Subjects in each group were randomised to
receive 2 x 125 g or 3 x 125 g of ACTIVIA
per day for two weeks.
Evaluation Criterion: Determination of oral-faecal
transit time before and after consumption of
ACTIVIA using a coloured marker method.
Results: In the four groups, the reduction in
transit time was statistically significant
(p

M O N O G R A P H F O R H E A L T H C A R E P R O F E S S I O N A L S
6
ACTIVIA AND BIFIDOBACTERIUM ANIMALIS DN-173 010
d Other effects of Bifidobacterium animalis DN-173 010: in vitro and animal studies
1. Anti-mutagenic effect
Bifidobacterium animalis DN-173 010 reduces the mutagenic effect of direct and indirect mutagens in in vitro
models 47 . A positive correlation has been demonstrated between the anti-mutagenic effect exerted against
benzopyrene (an indirect mutagen) and the quantity of Bifidobacterium animalis in the culture medium.
In the rat 48 , administration of DMH carcinogens together with a preparation of milk or water enriched with
Bifidobacterium animalis DN-173 010 reduced the incidence of aberrant crypts within the intestine in comparison
with rats treated with a simple aqueous solution.
The effects of this strain were also studied at cellular level with a cancer cell line, model HT-29 49 . Bifidobacterium
animalis DN-173 010 significantly reduced the growth rate and number of colonic cancer cells on the one hand
and on the other induced a significant decrease in the total number of cellular proteins in relation to cells in the
control group.
2. Action on immunity
Bifidobacterium animalis DN–173 010 increases intestinal IgA anti-rotavirus 50 . The immuno-modulatory properties
of strain DN-173 010 against rotavirus were tested in axenic mice and in mice with Bifidobacterium animalis
DN-173 010. In mice with Bifidobacterium animalis DN-173 010, defence to rotavirus infection was earlier and
more extensive than in axenic animals.
B CONCLUSION ON ALL OF THE ABOVE STUDIES
All of the results obtained either with ACTIVIA by Danone or with the specific starter
Bifidobacterium animalis DN-173 010 demonstrate the following:
a) An effect in adults: consumption of ACTIVIA shortens intestinal transit
time particularly in women and elderly subjects,
b) “Dose-Effect”: a reduction in transit time occurred with consumption
of a single pot of ACTIVIA per day (125 g). The effect was more
pronounced with higher consumption (2 to 3 pots),
c) The effect of ACTIVIA is partly due to Bifidobacterium animalis
DN-173 010. It is essential that the starter be present live in large quantities in
the product consumed,
d) The product is particularly effective in subjects with a slow transit time. In subjects
with a normal transit time, no marked change or risk of diarrhoea was observed,
e) Finally, this effect is associated with regular consumption of ACTIVIA and ceases
several weeks after discontinuation of consumption.
GENERAL CONCLUSION
The scientifically demonstrated benefits allow us to recommend regular daily consumption
of ACTIVIA by Danone containing Bifidobacterium animalis DN-173 010 for
everyone.
ACTIVIA by Danone optimises the function of the gastrointestinal tract, resulting in
more regular transit and better elimination of waste from the body, leading in turn to
better daily well-being and long-term health.
20 21

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