Download Review Lactic acid bacteria and the human gastrointestinal

European Journal of Clinical Nutrition (1999) 53, 339±350
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Review
Lactic acid bacteria and the human gastrointestinal tract
H Hove1*, H Nùrgaard1 and P Brùbech Mortensen1
1
Medical Department CA, Division of Gastroenterology, Rigshospitalet and Paediatric Department L, Gentofte University Hospital,
Denmark.
Objective: This review summarises the effects of lactic acid bacteria on lactose malabsorption, bacterial=viral or
antibiotic associated diarrhoea, and describes the impact of lactic acid bacteria on cancer and the fermentative
products in the colon.
Results: Eight studies (including 78 patients) demonstrated that lactase de®cient subjects absorbed lactose in
yogurt better than lactose in milk, while two studies (25 patients) did not support this. Two studies (22 patients)
showed that unfermented acidophilus milk was absorbed better than milk, while six studies (68 patients) found
no signi®cant differences. Addition of lactose hydrolysing enzyme, lactase, to milk improved lactose
malabsorption in seven studies (131 lactose malabsorbers), while one study (10 malabsorbers) demonstrated
no improvement. Lactic acid bacteria alleviated travellers' diarrhoea in one study (94 individuals) while a study
including 756 individuals was borderline statistically signi®cant. One study (50 individuals) did not ®nd an effect
of lactic acid bacteria on travellers' diarrhoea. Six studies (404 infants) demonstrated a signi®cant effect of lactic
acid bacteria on infant diarrhoea, while one study (40 infants) did not. Lactic acid bacteria moderated antibiotic
associated diarrhoea in three studies (66 individuals), while two studies (117 individuals) were insigni®cant.
Conclusions: Lactase de®cient subjects bene®t from a better lactose absorption after ingestion of yoghurt
compared with milk and from milk added lactase, whereas ingestion of unfermented acidophilus milk does not
seem to improve lactose absorption. The majority of studies support that lactic acid bacteria alleviate
bacterial=viral induced diarrhoea, especially in infants, while the effect on antibiotic associated diarrhoea is
less clear.
Experimental studies indicate an effect of lactic bacteria on human cell cancer lines, but clinical evidence is
lacking. A `stabilising' effect of lactic acid bacteria on the colonic ¯ora has not been documented.
Descriptors: lactic acid bacteria; lactobacilli; bi®dobacteria; lactate; lactic acid; lactose malabsorption;
antibiotic associated diarrhoea; diarrhoea; rotavirus; colonic cancer
Introduction
Interest in the bene®cial effects of lactic acid bacteria dates to
the Russian scientist, E. Metchnikoff (1845 ± 1919), who
proposed that the extended longevity of the Balkan people
could be attributable to their practice of ingesting fermented
milk products (Metchnikoff, 1908). He believed that gastrointestinal disturbances occur by intestinal growth of putrefactive microbes, and that lactic acid bacteria could minimise
or prevent the harmful effects of these microbes. The role of
lactic acid bacteria within the gastrointestinal tract has been
one of the most controversial subjects of the area of intestinal
microbial ecology. No other group of bacteria has been
proposed to be responsible for so many different bene®cial
actions, but non-conclusive or insigni®cant results are often
reported when attempts are made to con®rm that lactic acid
bacteria improve the health of the host.
Lactic acid bacteria consists of heterogeneous group of
gram-positive bacteria, whose main fermentation product
from carbohydrate is lactate. The group comprises cocci
(streptococcus, pediococcus, leuconostoc) and rods (lactobacillus and bi®dobacterium), which are either exclusively
*Correspondence: Hanne Hove, Ph.D., Hovmarksvej 77, 2920
Charlottenlund.
Received 14 August 1998; revised 7 December 1998; accepted
20 December 1998
(homofermentative) or at least 50% (heterofer-mentative)
lactate producers (Kandler, 1983, Table 1).
Studies on the ¯ora of the gastrointestinal tract report
that numbers of bi®dobacteria may exceed 1011 per gram of
faeces (Finegold et al, 1983) accounting for 6 ± 25% of all
cultivable bacteria in faeces (Kitsuoka, 1984; Scardovi,
1986) whereas lactobacilli only constitute 0 ± 1% of the
bacteria in the faeces of healthy humans (Hill & Drasar,
1975; Gorbach, 1971; 1986, Brown, 1977). The exception
of this condition is the dominant presence of bi®dobacteria
in breast-fed infants (Stark & Lee, 1982). Lactic acid
bacteria are described to be of nutritional and therapeutic
bene®t to the host in several clinical conditions. The
proposed effects of lactic acid bacteria on the intestinal
tract are mentioned in Table 2. Discussion of these speci®c
health targets follow.
Lactic acid bacteria supposedly exert an impact on the
small as well as the large intestine. First, bacterial derived
lactase from ingested lactic acid bacteria might enhance the
hydrolysis of lactose to glucose and galactose in the small
intestine, which are rapidly absorbed or fermented. Secondly, lactic acid bacteria may have an impact on the
colonic ¯ora in situations in which some sort of imbalance
exists. The exact nature of this microbial imbalance and
how it is corrected by the ingestion of lactic acid bacteria is
not known.
Lactic acid bacteria
H Hove et al
340
Table 1 The genera of lactic acid bacteria, their fermentation type and main products (Kandler, 1983)
Genus
Fermentation type
Main product
Con®guration of lactate
Streptococcus
Pediococcus
Lactobacillus
Leuconostoc
Bi®dobacterium
homofermentative
homofermentative
homofermentative
heterofermentative
heterofermentative
lactate
lactate
lactate
lactate : acetate
lactate : acetate
L-lactate
DL-lactate
DL-lactate
D-lactate
L-lactate
Table 2 Studies evaluating the clinical effect of lactic acid bacteria
Yogurt improves lactose absorption compared with milk? (Table 3 a)
Unfermented acidophilus milk improves lactose absorption compared with milk? (Table 3 b)
Lactase relieves lactose malabsorption among lactose malabsorbers? (Table 5)
Lactic acid bacteria reduce incidence of travellers diarrhoea? (Table 6 a)
Lactic acid bacteria reduce incidence of diarrhoea among infants? (Table 6 b)
Lactic acid bacteria alleviate antibiotic associated diarrhoea? (Table 7 a)
Over the past decade there has been increased interest in
bacterial food supplements, called probiotics. The de®nition of a probiotic being: `A live microbial feed supplement
which bene®cially affects the host animal by improving its
intestinal microbial balance' (Fuller, 1989). There are
several characteristics that are of importance for organisms
used as probiotics (Kim, 1988). These include: the organism should maintain viability and activity in the carrier
food before consumption, should survive the upper gastrointestinal tract, be capable of surviving and growing in the
intestine, be a normal inhabitants of the intestinal tract, and
eventually produce bene®cial effects when in the intestinal
tract. Further, the organism must be non-pathogenic and
non-toxic.
Survival through the gastrointestinal tract
The effect of lactic acid bacteria in the intestine requires
that the bacteria or at least their enzymes survive the acid
gastric content and are active after the passage of the
stomach. Studies of orally administered lactic acid bacteria
have demonstrated that the lactic acid bacterial counts in
the small intestine increase signi®cantly after ingestion
(Robins-Browne et al, 1981). The ability of Bi®dobacterium bi®dum to survive the passage through the upper
gastrointestinal tract when ingested in fermented milk
was investigated by Pochart et al (1992) using in vivo
ileal perfusion, and he found that the average number of
bi®dobacteria recovered from the terminal ileum constituted approximately 25% of the number ingested (ingested
dose 1010 bacteria). This is in consistency with a study of
ileotomic patients ingesting lactic acid bacteria, where
bi®dobacteria were cultured from ileostomic contents in
eight of nine ileostomists within six hours oral administration of 1010 bacteria, while not present in the ileostomy
ef¯uents of patients during control sampling (Hove et al,
1994). Similarly, faecal levels of speci®c strains of lactic
acid bacteria increase after ingestion. Goldin et al (1992)
followed the excretion of Lactobacillus gg in faeces 3 and
7 d after subjects consumed 1011 of Lactobacillus gg as
either concentrate or as a whey drink. Strain gg increased
4 ± 6 log cycles in almost all subjects, and remained present
in faeces 7 d after feeding stopped. These results have also
been obtained with bi®dobacteria (Bouhnik et al, 1992),
Positive studies
Negative studies
8
2
7
1
6
3
2
6
1
2
1
2
where intake of marked bi®dobacteria resulted in a rise in
faecal levels to approximately 108 bi®dobacteria=g faeces
followed by a gradual decrease after ingestion ceased.
Thus, attempts to increase the number of lactic acid
bacteria in the gastrointestinal tract by ingestion generally
results in a temporary colonisation of the gut, which
persists as long as the lactic acid bacteria are ingested
(Goldin et al, 1992; Deneke et al, 1988; Saxelin et al,
1991). After consumption of a bacterium, recovery from
the faeces is not evidence of implantation, even if recovery
persists for a period after consumption has stopped. Continued faecal recovery of ingested lactic acid bacteria may
be because of residence time in the large intestine that
exceeds microbial generation time.
Impact on the small intestine
Relieving lactose intolerance in lactose malabsorbers
Lactose is the predominate carbohydrate in milk, and it
requires enzymatic hydrolysis to the monosaccharides glucose and galactose before intestinal absorption. Small
intestinal epithelial cells (enterocytes) produce b-galactosidase in childhood, and some people continue to produce
b-galactosidase throughout life, but globally most adults
are lactose malabsorbers and are as non-milk consumers
deprived of an important source of protein and calcium.
Although lactose malabsorption is common worldwide, the
symptomatic expression of lactose intolerance is less so.
Lactose intolerance has a substantial psychological component: among individuals who believed they were lactose
malabsorbers 64% were shown to be lactose digesters
(Rosado et al, 1987); most lactase-de®cient people can
consume one glass of milk per day asymptomatically
(Savaiano & Kotz, 1988), and 85% of individuals with
discomfort have only mild symptoms (Scrimshaw &
Murray, 1988).
Carbohydrate malabsorption increases the delivery of
unabsorbed carbohydrates to the colon bacteria and results
in increased intestinal production and respiratory excretion
of hydrogen. Breath hydrogen excretion is therefore used as
an indicator of malabsorption of simple carbohydrates as
disaccharides (Welsh et al, 1981). A dose-response relationship between breath hydrogen excretion and the amount
Lactic acid bacteria
H Hove et al
341
Figure 1 Prevalence of adult lactose malabsorption in Europe in percent (Gudmand-Hùyer & Skovbjerg, 1996). (Reprinted by permission of the author
and Scandinavian University Press).
of malabsorbed disaccharide (non-absorbable lactulose) has
been found by Rumessen et al (1990), while breath hydrogen excretion is of limited value in the evaluation of
malabsorption of complex dietary carbohydrates (Nordgaard et al, 1995).
The geographic incidence of lactose malabsorption is
shown in Figure 1 (Gudmand-Hùyer & Skovbjerg, 1996).
Yogurt is made from milk enriched with milk proteins
(to improve consistency), which is incubated with two or
three species of lactic acid bacteria (that is L. bulgaricus
and S. thermophilus) at 42 C until the pH drops to approximately 4.5 (Martini et al, 1987). The resulting yogurt is
cooled and stored until use.
In contrast to yogurt, sweet acidophilus milk is unfermented, made by adding high concentrations of viable L.
acidophilus cells to cold milk. In storage below 5 C L.
acidophilus do not multiply and thus, sweet acidophilus
milk has the bene®ts of lactase activity, without the acid
taste of the corresponding fermented product (Martini et al,
1991).
It seems evident that lactose intolerant individuals are
able to substitute fermented milk (yogurt) for fresh milk,
Table 3 (a).
The rational for using fermented milk relates to the fact
that lactose content is reduced between 25 and 50 percent
during the fermented process (McDonough et al, 1987;
Gorbach, 1990). Reduced malabsorption may, however, not
only be associated with the decreased lactose concentration, but also to high lactase activities in yogurt (Kolars et
al, 1984, Savaiano et al, 1984). In considering how much of
the improved digestion was due to reduction in lactose and
how much was due to ingested lactase supplied by the
cultures, the following investigations were performed
(Table 4).
When yogurt was heated in order to inactivate lactase,
malabsorption measured by breath hydrogen test was still
signi®cantly lower than after milk ingestion. Since both
products had little or no lactase activity, it was assumed
that the difference was due to reduced lactose in the heated
yogurt (McDonough et al, 1987). Similarly, when lactose
was added to yogurt so that lactose concentration was equal
to that in milk, the mean breath hydrogen value was
signi®cantly lower than the value for milk, thus indicating
a response to lactase activity (McDonough et al, 1987).
This was further substantiated by adding commercial lactase to heated yogurt, in an amount that produced an
activity level comparable to that found in yogurt, resulting
in signi®cantly lower breath hydrogen test than for heated
yogurt. With similar lactose content and lactase activity in
heated yogurt added lactase and in yogurt, the two products
Lactic acid bacteria
H Hove et al
342
Table 3 The ability of fermented and non-fermented milk products in relieving lactose malabsorption. Comparison of yoghurt with regular milk is
indicated by (a); while comparison of unfermented acidophilus milk with regular milk is indicated by (b). Comparison of lactose or lactulose with yogurt or
heated yogurt with yogurt is indicated by (c)
Reference
Number of lactose
malabsorbers
Test
Genera and dose
Results (absorption measured by
breath hydrogen test)
1981 Payne (b)
11
SAM vs milk
lactose conc.?
L. acidophilus
cfu=d?
NS between milk and SAM
1983 Kim (b)
12
SAM vs milk
lactose conc.?
L. acidophilus
1011 cfu=d
SAM signi®cantly better absorbed
than milk (P < 0.01)
1983 Newcomer (b)
18
SAM vs milk
lactose conc.?
L. acidophilus
109 cfu=d
NS between milk and SAM
1984 Gilliland (c)
6
Y vs HY
equal lactose conc.
L. bulgaricus
S. thermophilus
cfu=d?
Y signi®cantly better absorbed than
HY (P < 0.05)
1984 Kolars (a)
10
Y vs milk
18 g lactose
L. bulgaricus
S.thermophilus
Y signi®cantly better
absorbed than milk (P < 0.01)
1984 Savaiano (a,b)
9
Y, HY and SAM
vs milk
20 g lactose
genera?
109 ± 1011 cfu=d
1) Y sign®cantly better
absorbed than milk, HY, and SAM
(P < 0.05) 2) NS between milk and
SAM
1987 McDonough (a,b)
14
Y, HY,
Y ‡ lactose,
HY ‡ lactase, SAM,
SAM-S vs milk
L. bulgaricus
S. thermophilus
L. acidophilus
31011 cfu=d
1) Y signi®cantly better
absorbed than milk, HY, and Y ‡
lactose (P < 0.05)
2) Y ‡ lactose and SAM-S
signi®cantly better
absorbed than milk
(P < 0.05)
3) NS between SAM and milk and
between Y and
HY ‡ lactase.
Two kinds of Y sign®cantly better
absorbed than lactose (P < 0.05)
16 g lactose
1988 Wytock (c)
8
Lactose vs 3
kinds of Y
20 g lactose
L. bulgaricus
S. thermophilus
cfu=d?
1989 Onwulata (a,b)
10
Y, SAM vs milk
18 g lactose
L. bulgaricus
S. thermophilus
L. acidophilus
cfu=d?
1) Y signi®cantly better absorbed
than milk and SAM
2) NS between SAM and milk
1990 Marteau (a)
8
Y and HY vs
milk
18 g lactose
genera?
cfu=d?
1) Y and HY signi®cantly better
absorbed than milk
(P < 0.001)
2) NS between Y and HY
1991 Martini (a)
7
Y vs milk
18 g lactose
Y signi®cantly better absorved than
milk (P < 0.025)
1991 Lin (a,b)
10
Y and SAM vs
milk
20 g lactose
L. bulgaricus
S. thermophilus
1011 cfu=d
L. bulgaricus
S. thermophilus
L. acidophilus
41010cfu=d
1994 Arrigoni (a)
11*
Y vs milk
20 g lactose
genera?
cfu=d?
NS between milk and Y
1994 Kotz (a)
10
High galactosidase
Y vs milk
20 g lactose
L. bulgaricus
S. thermophilus
2108 cfu=d
High galactosidase Y signi®cantly
better absorbed than milk
(P < 0.05)
1995 Dehkordi (b)
6
SAM vs milk
18 g lactose
L. acidophilus
cfu=d?
NS between milk and SAM
1995 ShermaÈk (a)
14
Y and HY vs
milk
12 g lactose
L. bulgaricus
S. thermophilus
cfu=d?
NS between milk, Y and HY
1996 Vesa (c)
14
lactulose vs
3 kinds of fermented
milk products
L. bulgaricus
S. thermophilus
Bi®dobacteria
18 g lactose vs 10 g
lactulose
L. acidophilus
cfu=d?
1) Fermented milk signi®cantly
better absorved than lactulose
2) NS between the 3 kinds of
fermented
milk
1) Y signi®cantly better absorbed
than milk (P < 0.01)
2) SAM signi®cantly better absorbed
than milk (P < 0.05)
Abbreviations: Lactose malabsorption was determined by breath hydrogen test; Y: yogurt; HY: heated yogurt; SAM: sweet acidophilus milk; SAM-S:
sonicated sweet acidophilus milk (cell membranes disrupted); cfu=d: colony forming units lactic acid bacteria ingested per day; NS: not signi®cantly
different * : patients with jejunocolic anastomsis.
Lactic acid bacteria
H Hove et al
would be expected to have comparable utilisation and
indeed the breath hydrogen values were not signi®cantly
different (McDonough et al, 1987).
The majority of studies (Table 3a) support that yogurt
enhances absorption of lactose when compared with
equivalent amounts of lactose in milk. The improved
tolerance of lactose when consumed as yogurt containing
active live cultures is at least in part related to the inherent
galactosidase activity of the yogurt bacteria, which hydrolyse a part of the ingested lactose (Kotz et al, 1994;
SchermaÈk et al, 1995; Sanders, 1993).
In spite of similar average values for the area under the
breath hydrogen curve, yogurt and heated yogurt was
associated with a delay in the time to breath hydrogen
rise and the time to peak breath hydrogen when compared
with milk (ShermaÈk et al, 1995), and studies have
demonstrated a relationship between the rate of rise in
Table 4 Lactose and lactase activity of milk and yogurt test products
(McDonough et al, 1987)
Product
Control milk
Yogurt
Yogurt ‡ lactose
Heated yogurt
Heated yogurt ‡ lactase
Sweet acidophilus milk
Sweet acidophilus milk with
sonicated cells
Lactose
(g=250 ml)
Lactase
(mg glucose=dl)
15.7
12.0
15.7
12.0
12.0
15.7
15.7
26
3724
3724
43
4138
1427
4263
Lactase activity was determined by measuring the amount of glucose
released on hydrolysis during incubation at 37 C for 2 hours. Values are
means of triplicate analysis.
breath hydrogen excretion and the severity of gastrointestinal symptoms (Dehkordi et al, 1995; ShermaÈk et al, 1995).
In contrast to the above mentioned results, lactose
intolerant individuals who ingest an unfermented milk
product containing lactic acid bacteria (sweet acidophilus
milk) with low concentration of bacterial lactase have no
apparent bene®t from this as compared with milk, Table 3
(b), and Table 4. If, however, the bacterial cell-membranes
are damaged by sonication, and intracellular lactase is
released, breath hydrogen values were found in the same
low level as for heated yogurt (McDonough et al, 1987).
Thus, it seems that the bacterial lactase is not available or is
insuf®cient to exert a measurable effect in sweet acidophilus milk during digestion, but can be made accessible after
disruption of the cell membrane (Kolars et al, 1984;
McDonough et al, 1987). In accordance, an increase in
microbial galactosidase of yogurt, enhance lactose absorption compared with conventional yogurt (Kotz et al, 1994).
These results are not supported by Kim & Gilliland 1983)
and Lin et al (1991), but are in accordance with Hove et al
(1994), who did not ®nd an improved lactose utilisation in
lactase de®cient subjects after intake of large amounts of B.
bi®dum (4.21010 cells).
The ingestion of commerical lactase (often of yeast
origin) either together with, immediately before or within
5 minutes after milk consumption (meal-time treated milk)
is reported to improve lactose utilisation in most studies,
while refuted in a single study (Onwulata et al, 1989),
(Table 5). Milk treated with a commercial lactase preparation 20 ± 24 h prior to ingestion is approximately 90%
hydrolysed (Payne et al, 1981). This milk has therefore a
sweeter taste than regular milk. Aspects of lactic acid
cultures effect on lactose digestion in lactose malabsorbers
are discussed in detail in review articles (Gorbach, 1990;
Table 5 Ability of commercial lactase in relieving lactose malabsorption in lactose malabsorbers. The b-galactosidase preparations were ingested
immediately before or after milk consumption ( 5 min)
References
Lactose malabsorbers
Treatment
Doses
Results
1984, Rosado
13
LactAid, Lactase N
vs milk
18 g lactose
1.5 g LactAid
0.4 g Lactase N
LactAcid and Lactase N
signi®cantly improved
lactose absorption
1985 Solomons
10
LactAid, Lactase N
vs milk
18 g lactose
2 g LactAid
0.3 g Lactase N
1986 Rosado
21
1987 Barillas
9 infants
Lactase N vs
milk
LactAid, Takamine
vs milk
18 g lactose
0.4 g Lactase N
12 g lactose
1.0 g LactAid
0.3 g Takamine
LactAid signi®cantly improved
lactose absorption
(P < 0.01). Lactrase N did
not improve absorption.
Lactase N signi®cantly
improved lactose absorption
LactAid and Takamine
signi®cantly improved
lactose absorption
1988 Lami
52
LactAid vs milk
25 g lactose
LactAid?
LactAid signi®cantly improved
lactose absorption
(P < 0.0005)
1989 DiPalma
10
Lactrase vs
milk
50 g lactose
0.5 g Lactrase
Lactrase signi®cantly improved
lactose absorption (P < 0.05)
1989 Onwulata
10
LactAid vs milk
18 g lactose
LactAid?
LactAid did not improve
lactose absorption
1992 Corazza
16
A. niger
b-galactosidase
Lactose?
Galactosidase?
A. niger b-galactosidase
signi®cantly improved
lactose absorption (P < 0.01)
Abbreviations: Lactose malabsorption was determined by the use of breath hydrogen test after ingestion of lactose; A niger: Aspergillus niger derived bgalactosidase. LactAid is a b-galactosidase derived from the yeast Kluyveromyces lactis (pH and temperature optimum 6.8 and 37 C). Lactase N,
Takamine and Lactrase are b-galactosidase preparations derived from the fungus Asperigillus (Lactase: Aspergillus niger: pH and temperature optimum 4.4
and 60 C; Takamine and Lactrase: Aspergillus oryzae).
343
Lactic acid bacteria
H Hove et al
344
Sanders, 1993; Gurr, 1987, Fuller, 1989, Shahani & Ayebo,
1980; Bengmark, 1998).
Prophylaxis against E. coli and antibiotic associated
diarrhoea
Although the intestinal ¯ora is a very steady ecosystem, the
balance can be disturbed by a number of factors such as
bacteria, viruses and antibiotics.
Travellers from United States and Northern Europe
often suffer diarrhoea when visiting less developed regions
of the world. The clinical picture varies from a short and
mild attack with watery diarrhoea to a severe incapacitating
disease with a duration of more than a week. In 40 ± 70% of
the cases the etiological agent is enterotoxigenic Escherichia coli (E. coli) (Merson et al, 1976; Gorbach et al,
1975). It is well established that travellers' diarrhoea to a
great extent can be prevented by prophylactic intake of
antibiotics, which have been reported to provide protection
rates in the range of 60 ± 95% (DuPont et al, 1986; Sack,
1986). The use of these agents may cause adverse reactions
and lead to emergence of resistant bacterial strains. Therefore, the effect of lactic acid bacteria and other probiotics in
promoting gastrointestinal health by inhibiting or eliminating enteric pathogens have been investigated.
Numerous publications based on uncontrolled clinical
observations have suggested a role for lactic acid bacteria
in the prevention of diarrhoea (Beck & Necheles, 1961;
Winkelstein, 1955), and several preparations of lactic acid
bacteria (Paraghurt1, Trevis1, Biotura1) are available
without prescription as prophylaxis against diarrhoea.
Table 6 The effect of lactic acid bacteria on travellers' diarroea (a), diarrhoea in infants (b) and E. coli induced diarrhoea (c)
References
No. individuals
Treatment
Doses
9
Results
1978 P.-Olano (a)
50* DB, R
Travel to Mexico
Lactinex
610 =d
Results (no. indiv. with
diarrhoea=no. indiv.)
7=17 lactic acid bact.
2=14 placebo (NS)
1981 Clements (c)
48 DB, R
Challenge with 1081010E. coli
Lactinex
2109=d
Results (no. indiv. with
diarrhoea=no. indiv.)
16=23 lactic acid bact.
17=25 placebo (NS)
1985 Black (a)
94* DB, R
Travel to Egypt
L. acidophilus, B.
bi®dum, L. bulgaricus, S. thermophilus
9109=d
Results (no. indiv. with
diarrhoea=no. indiv.)
17=40 lactic acid bact.
29=41 placebo (P ˆ 0.019)
1990 Boudraa (b)
45 infants (3 ± 36 m)
R. Persistent diarrhoea
Yogurt vs milk
?
Diarrhea > 5 days:
3=21 yogurt
8=24 milk (P < 0.05)
Weight loss > 5%:
0=21 yoghurt
2=24 milk ((P < 0.05)
1990 Oksanen (a)
756 DB, R.
Travel to Turkey
Lactobacillus GG
2109=d
Frequency of diarr. (%):
41.0% lactic acid bact.
46.5% placebo (P ˆ 0.065)
1991 Isolauri (b)
71 infants (4 ± 45 m), R
Lactobacillus gg
1) yogurt
2) freeze-dried
powder
1010 ± 11)=d
Duration of diarr. (days):
1.4 0.8 yogurt
1.4 0.8 lactbact. powder
2.4 1.1 placebo (P < 0.001)
1010 ± 11=d
Results (no. indiv. with
diarrhoea=no.indiv.)
2=29 lactic acid bact.
8=26 placebo (P ˆ 0.035)
Rotavirus shedding:
3=29 lactic acid bact.
10=26 placebo (P ˆ 0.025)
Rotavirus diarrhoea
1994 Saavedra (b)
55 infants (5 ± 24 m)
DB, R
Rotavirus diarrhoea
B. bi®dum, S. termophilus
philus
1995 Majama (b)
49 infants
DB, R.
Rotavirus diarrhoea
Three groups
1) Lactobacillus gg
2) Lactophilus
3) Yalacta
1997 Guarino (b)
61 infants (3 ± 36 m)
R.
Rotavirus diarrhoea
oral rehydration liophylised Lactobacillus gg
6109=d
Duration of diarr. (days):
2.9 1.2 lactic acid bact.
6.1 1.7 no lactic acid bact.
(P < 0.01)
1997 Shornikova (b)
40 infants (6 ± 36 m)
R.
Acute diarrhoea
freeze-dried Lacto
bacillus reuteri
1010 ± 11=d
Duration of diarr. (days):
1.7 1.6 lactic acid bact.
2.9 2.3 placebo (P ˆ 0.07)
1997 Shornikova (b)
123 infants (1 ± 36 m)
DB, R.
Acute diarrhoea
oral rehydration freeze-dried Lactobacillus gg
5109=d
Duration of diarr. (days):
2.7 2.2 lactic acid bact.
3.7 2.8 placebo (P ˆ 0.03)
Duration of diarr. (days):
1.8 0.8 Lactobacillus gg
2.8 1.2 Lactophilus
2.6 1.4 Yalacta (P ˆ 0.04)
* Number of patients in the study; results only given for a part of the group.
Lactinex: a commercial preparation of lactobacilli, containing dried viable L. acidophilus and L. bulgaricus in equal proportions (5108 bacteria per g).
Lactobacillus gg: aq lactobacillus strain isolated from healthy humans on the basis of its ability to resist acid and bile, and to adhere to the intestinal
mucosa. Lactophilus: lactobacillus casei subsp. Rhamnosus. Yalacta: combination of S. thermophilus, L. delbruÈckii and L. casei.
Abbreviations: No. indiv. with diarr.=no. indiv.: Number of individuals with diarrhoea=total number of individuals; DB.: double blind; R.: randomised;
bact.: bacteria, m: months; y: years.
Lactic acid bacteria
H Hove et al
Table 7
The effect of lactic acid bacteria on antibiotic associated diarrhoea (a) and Clostridium dif®cile induced diarrhoea (b).
References
No. individuals
Treatment
Doses
9
Results
1979 Gotz (a)
79 patients (19 ± 88y)
DB, R.
*) Ampicillin therapy
Lactinex
210 =d
No. indiv. with
diarrhoea=no. indiv.
3=36 lactic acid bact.
9=43 placebo (NS)
1987 Colombel (a)
10 volunteers (22 ± 50y)
DB, R.
Erythromycin
(2 g=d for 3 days)
Bi®dobact. longum
?
Stools per day:
1.2 0.1 lactic acid bact.
1.9 0.4 placebo
(P < 0.025)
Stool weight (g):
145 16 lactic acid bact.
208 29 placebo (P < 0.025)
1987 Gorbach (b)
5 patients (24 ± 93 y)
C. dif®cile induced
diarrhoea **)
Lactobacillus gg
1010=d
4 patients responded
with decrease in
stool frequency and became
cytotoxin negative.
1990 Siitonen (a)
16 volunteers R.
Erythromycin
(1.2 g=d for 7 days)
38 infants (5 ± 72 m)
DB, R.
*) Amoxicillin
Lactobacillus gg
?
Lactinex
2109=d
Stools per day are reduced
when receiving lactic acid
bacteria (P < 0.05)
No. indiv. with
diarrhoea=no. indiv.
10=15 lactic acid bact.
16=23 placebo (NS)
1991 Contardi (a)
40 Infants (8 ± 36 m); R.
Oral amoxicillin (50
mg=kg=d)
B. bi®dum
L. acidophilus
?
Stools per day:
2.0 0.3 lactic acid bact.
2.7 0.5-lactic acid bact.
P < 0.001
1995 Biller (b)
4 Infants (5 ± 70 m)
C. dif®cile induced
diarrhoea**)
Lactobacillus gg
1109=d
All patients responded within
5 ± 7 d: decrease in stool
frequency and became
cytotoxin negative
1990 Tankanow (a)
Lactinex is a commercial preparation of dried viable L. acidophilus and L. bulgaricus in equal proportions (5108 bacteria=1 g (Tankanow et al, 1990)).
Abbreviations: No. indiv. with diarr.=no. indiv.: Number of individuals with diarrhoea=total number of individuals; DB.: double blind; R.: randomised;
bact.:bacteria; *): both oral and=or injectable ampicillin against infectious disease other than diarrhoea; **) positive test for C dif®cile cytotoxin in the
stool; m: months.
In controlled clinical trials lactic acid bacteria have
had varying degrees of success in preventing diarrhoea:
in a double-blinded randomised study, 48 volunteers
received either Lactinex (L. acidophilus and L. bulgaricus)
in total of 2108 bacteria=d or placebo and were challenged
with enterotoxin producing E. coli (108 Ð 1010). No signi®cant differences were noted with respect to attack rate,
incubation period, duration of diarrhoea, volume or number
of liquid stools (Clements et al, 1981), (Table 6 (c)). On the
contrary, a prospective double blind investigation of travellers' diarrhoea in 94 tourists travelling to Egypt found
that daily intake of 1010 lactic acid bacteria (L. acidophilus,
B. bi®dum, L. bulgaricus, S. thermophilus) signi®cantly
reduced the incidence of diarrhoea compared to the placebo
treated group (17 cases of diarrhoea in the lactic acid
bacteria treated group in comparison with 29 in the placebo
treated group, P ˆ 0.02) (Black et al, 1989), Table 6 (a).
Rotavirus is a common cause of non-bloody diarrhoea in
children accounting for 50 ± 75 percent of episodes of acute
diarrhoea in children below 3 y referred to the hospital
(Guarino et al, 1997; Shornikova et al, 1997). No speci®c
therapy is available for rotavirus, and treatment is limited to
rehydration. Probiotics has been suggested as a mode of
preventing or moderating the infection. The group of
Isolauri et al (1991) has reported a positive effect of a
human lactic acid bacterial species, Lactobacilli casei
strain gg, on the recovery from acute rotavirus induced
diarrhoea in children. The children were randomised to
either a lactic acid bacteria fermented milk product
containing 1010 ± 11 Lactobacillus casei, a Lactobacillus
casei freeze-dried powder (1010 ± 11), or placebo (pasteurised yogurt with only trace amounts of live lactic
acid bacteria). The mean duration of diarrhoea after
commencing the therapy was signi®cantly shorter in the
two groups receiving live lactic acid bacteria in comparison with the placebo group, P < 0.001. Analysis of
speci®c antibody-secreting cells among circulating lymphocytes revealed that lactic acid bacterial therapy
resulted in an augmentation of the local immune defence
re¯ected in an IgA speci®c antibody-secreting cell
response to rotavirus (Kaila et al, 1992).
The use of lactic acid bacteria as prophylaxis against E.
coli diarrhoea is supported by both in vitro and in vivo
animal studies. Investigations using rabbit ileal loops have
shown that lactic acid bacteria signi®cantly reduce the ¯uid
retention caused by enterotoxigenic E. coli (Foster et al,
1980; Johnson & Calia, 1979). The reduced ¯uid accumulation depended on the administration of a large dose of
lactic acid bacteria (108=bacteria), whereas the individual
ingredients in the lactic acid bacterial preparation did not
demonstrate any anti¯uid response.
In vivo studies of 28 piglets placed in pens, contaminated with enterotoxigenic E. coli demonstrated that prophylactic feeding with lactic acid bacteria (109=d)
signi®cantly reduced the mortaility of E. coli enteropathy
(1=14 in treatment group in comparison to 7=14 in the
control group) (Nielsen et al, 1988). Further, the average
daily weight gain (0 ± 14 d post weaning) was signi®cantly
345
Lactic acid bacteria
H Hove et al
346
higher in the treatment group (231 g) compared to the
surviving control group (101 g).
Similar convincing results has been reported by Underdahl et al (1982). When Streptococcus faecium were fed to
gnotobiotics (animals which are obtained by hysterotomy
and kept under sterile conditions and therefore have no
intestinal ¯ora) to prevent E. coli induced diarrhoea. Pigs
fed S. faecium and challenge exposed with E. coli developed mild diarrhoea, but none of the pigs died, and they
continued to eat well and gained weight. Pigs given E. coli
only, developed severe diarrhoea and lost weight, and 5 of
8 infected pigs died.
How lactic acid bacteria diminish diarrhoeal disease is
not known. One proposed mechanism is competitive colonisation. Competitive colonisation occurs when one intestinal microbe interferes with the colonisation of another. But
documentation of this phenomenon by observing lactic
cultures displacing pathogens or preventing pathogen
adherence has been dif®cult experimentally.
Other studies have demonstrated that lactic acid bacteria
stimulate macrophage phagocytosis of viable Salmonella
(Hatcher & Lambrecht, 1993), enhance IgA production in
intestinal secretions (Perdigon et al, 1990), produce an
antimicrobial substance (Shahani & Ayebo, 1980; Silvia
et al, 1987), inhibit cell attachment and cell invasion by
enterovirulent bacteria (Bernet et al, 1994), and decrease
intestinal permeability for macromolecules during rotavirus
induced diarrhoea (Isolauri et al, 1993).
In conclusion, Table 6 shows that seven of nine
studies since 1985, show an effect of lactic acid bacteria
on a 5% signi®cance level while two studies show an
effect on a 7% sign®cance level. Two early studies are
insigni®cant. The overall impression left by the mentioned human studies is that lactic acid bacterial therapy
can limit the course of diarrhoeal diseases, especially
rotavirus diarrhoea (Table 6). A possible explanation for
the often found inconsistency of results may be the use of
different species and subspecies of lactic acid bacteria
with different af®nity towards the human intestine. Host
speci®city in colonisation by individual species has been
demonstrated: L. acidophilus, L. fermentum, and L. plantarum are commonly found in the faeces of humans,
whereas L. bulgaricus, the organism used in combination
with S. thermophilus to make yogurt, is unable to
colonise the bowel. The speci®city is possibly related
to the individual lactic acid bacteria ability to colonise
mucosal surface by binding to epithelial cells. Variations
in lactic acid bacterial preparations and storage of fermented products may also in¯uence results (Gorbach,
1990).
The best results seem to have been obtained by using
Lactobacillus gg (Isolauri et al, 1991, Siitonen et al, 1990),
which is a lactobacillus strain initially isolated from healthy
humans. The strain was originally selected for its tolerance
to acid and bile and the ability to adhere to human small
intestinal cells.
The results of lactic acid bacteria treatment against
antibiotic associated diarrhoea are shown in Table 7 (a).
Siitonen et al (1990) studied 16 subjects, who ingested
400 mg erythromycin three times daily for seven days
together with either 125 ml Lactobacillus gg fermented
yogurt or 125 ml pasteurised regular yoghurt. The subjects
receiving Lactobacillus gg yogurt were colonised with
these bacteria even during antibiotic treatment and had
fewer daily defecations than the group ingesting pas-
teurised yoghurt, Table 7. Further, usual side effects as
abdominal distress, pain and ¯atulence tended to be
reduced in the lactic acid bacterial treated group, while
the difference in faecal volumes was not signi®cantly
different. In ®ve studies of antibiotic associated diarrhoea
including 183 subjects, an alleviating effect of lactic acid
bacteria ingestion was found in 3 studies including 66
individuals. Therefore, no convincing effect of lactic acid
bacteria on antibiotic associated diarrhoea was demonstrated. The studies of C. dif®cile induced diarrhoea
included only ®ve and four patients, allowing no conclusions to be drawn. Recent controlled studies have demonstrated that another probiotic, the yeast Saccharomyces
bouradii, reduce the risk of recurrent Clostridium dif®cile
associated disease (including patients with Clostridium
dif®cile diarrhoea, colitis and pseudomembranous colitis
(McFarland et al, 1994)) and antibiotic associated diarrhoea
(McFarland et al, 1995; Surawicz et al, 1989).
Impact on colon
Prevention of colonic cancer
There is considerable interest in the metabolic activities of
the intestinal micro¯ora, especially in relation to the
aetiology of colon cancer. Epidemiological studies have
suggested a correlation between intake of a `Western diet'
abundant in beef, fat, and protein but low in ®bre, fruit, and
vegetables, and the occurrence of colon cancer. Indeed, a
positive correlation has been found in several countries
between dietary factors such as meat and animal fat
consumption and the incidence of large bowel cancer
(Howel, 1975). Finland is an exception, being a nation
with a high per capita fat consumption and a relatively low
incidence of colon cancer (Armstrong & Doll, 1975). Dairy
products, especially yogurt, are a common compound of the
Finnish diet, and possibly as a result, the intestinal micro¯ora of the Finns harbours high numbers of lactic acid
bacteria (International Agency for Research on Cancer,
1997). In an attempt to explain these epidemiological
®ndings, alterations in the metabolic activity of the intestinal ¯ora have been studied. The studies have involved
measurements of key enzymes: b-glucuronidase, azoreductase, and nitroreductase, which catalyse the conversion of
indirect acting carcinogens to proximal carcinogens in the
large bowel (Goldin & Gorbach, 1984). Oral supplementation of the diet with viable bile-resistant L. acidophilus of
human origin caused a signi®cant decline in these three
key-enzymes (Goldin & Gorbach, 1984; Gordin et al,
1980). These results were only partly con®rmed by Marteau
et al (1990) in a study where 9 subjects ingested lactic acid
bacteria (L. acidophilus, B. bi®dum) for 3 weeks. He
reported of unchanged levels of faecal azo-reductase and
b-glucuronidase, while only nitroreductase decreased
during the observation period.
The studies were extended in an animal model of colon
cancer induced by the chemical carcinogen, 1,2-dimethylhydrazine dihydrochloride (DMH). The activation of DMH
to a potent carcinogen occurs in the large intestine, and the
bacterial enzyme-b-glucuronidase is involved in this process. Suppression of this enzyme might reduce DMH
activation and subsequent tumour formation. In experiments DMH-treated animals with given L. acidophilus in
powdered form and compared with controls (Goldin &
Gorbach, 1980). At 20 weeks, 40% of the L. acidophilus
Lactic acid bacteria
H Hove et al
treated animals had colon tumours versus 77% of the controls,
P ˆ 0.02. At 36 weeks, however, 73% of the L. acidophilus
treated animals and 83% of the controls had colon tumours.
These studies show that the addition of lactic acid bacteria to
the diet may delay colon tumour formation by prolonging the
induction, indicating that lactobacilli may slow tumor development in experimental animals.
Lactic acid bacteria have shown antineoplastic properties
in a variety of cancer cell lines of both human and animal
origin. The literature substantiating this in vitro effect has
increased tremendously over the last decade. In brief, lactic
acid bacteria reduce tumour cell viability (McGroatry et al,
1988; Sekine et al, 1985; Reddy et al, 1973; Reddy et al, 1983;
Kato et al, 1981), suppress induced carcinogenesis in the liver
and colon (Reddy & Riverson, 1993), inhibit mutagenic
activity (Hosono et al., 1986; Renner & MuÈntzner, 1991),
and bind potent mutagenic metabolic compounds (Morotomi
& Mutai, 1986) and food mutagen (Zhang et al, 1990).
However, in spite of a wealth of indirect evidence, no direct
data have yet proven cancer suppression in humans, as a result
of consumption of lactic cultures in fermented or unfermented
dairy products.
High concentrations of faecal bile acids have also been
associated with the development of colon cancer, and the
lithocholic acid=deoxycholic acid ratio has been reported to
be increased in patients with colon cancer compared to
controls (Owen et al, 1987). Ingestion of L. acidophilus for
6 weeks have been demonstrated to lower concentrations of
total bile acid and deoxycholic acid (Lidbeck et al, 1991),
although the changes were not signi®cant.
Correcting of a colonic `imbalance'
Lactic acid bacteria may have an impact on the colonic
¯ora in situations where some sort of imbalance exists. The
exact nature of this microbial imbalance and how it is
corrected by the ingestion of lactic acid bacteria has not
been substantiated. A prerequisite for an effect on the
colonic ¯ora is that a substantial number of ingested
lactic acid bacteria reach the large bowel. The work of
others (Robins-Browne et al, 1981; Hove et al, 1984;
Goldin et al, 1992; Saxelin et al, 1991; Lidbeck et al,
1991) indicate that ingested lactic acid bacteria do reach the
caecum. It is, however, questionable whether an ingested
dose of lactic acid bacteria in the range of 1010 ± 11 bacteria
is able to in¯uence the colonic ¯ora, which number
approximately 1013 bacteria (1011 g), a number of 100 ±
1000 times higher than the ingested amount of lactic acid
bacteria. This question is even more pertinent in light of the
widely held belief that a dietary culture, even one possessing in vitro adhering capabilities, is highly unlikely to
displace any bacterial strain that colonises a healthy human
intestinal tract (Savage, 1977). Human gastrointestinal
microbiology is notably a dif®cult ®eld to study because
of limits on direct experimentation and the dif®cult physiological requirements of the intestinal microbes. As
indicated by Tannock (1984): `All investigators approaching the study of the normal ¯ora of the gastrointestinal tract
must sooner or later be horri®ed by the complexity of an
ecosystem that contains about 500 species of bacteria most
of which are technically dif®cult to work with under
laboratory conditions'.
The ability of lactic acid bacteria to in¯uence the
fermentation processes, that is changes in organic acid
production was examined by investigation of the fermentative products of human ileostomic ef¯uent after ingestion
of large quantities of B. bi®dum (Hove et al, 1994). When
in isolated culture, B. bi®dum had a speci®c fermentative
pattern, but this pattern could not be reencountered in the
ileostomic outputs of nine ileostomists after oral ingestion
of large quantities of B. bi®dum.
As B. bi®dum, L. acidophilus had a speci®c fermentation
pattern when in isolated culture, but after incubation in
mixed lactic acid bacteria=faecal incubations the speci®c
pattern disappeared although L. acidophilus was added in
unphysiological large amounts constituting 50 ± 90% of the
total ¯ora. The fermentation products in mixed L. acidophilus=faecal incubations were related to the type of
added substrate rather than to the addition or not of acid
bacteria (Hove et al, 1994). This does not imply that lactic
acid bacteria do not contribute to the organic acid formation in the mixed homogenates, but rather that the capability for saccharide fermentation represented by the
added bacteria already exists in the faecal ¯ora. New
perspectives of modulating the colonic ¯ora has recently
been introduced by Gibson et al. (1995), who showed that
oral ingestion of a diet rich in the indigestible carbohydrates oligofrutose and inulin signi®cantly increases the
number of bi®dobacteria. Therefore, the prospect of lactic
acid bacteria therapy may be a change in diet which
subsequently alters colonic ¯ora rather than ingestion of
cultures of lactic acid bacteria themselves.
Lactic acid bacteria as pathogenic organisms
Although infections with these organisms are rare, it has
been reported that lactic acid bacteria may play a role in a
variety of serious infections. These include endocarditis
(Axelrod et al, 1973), bacteraemia (Bayer et al, 1978),
gastrointestinal infections (Bourne et al, 1978), and splenic
abscess (Sherman et al, 1987). A risk factor is immunosuppressive therapy (Sherman et al, 1987) and poor oral
hygiene where dental procedures can cause endocarditis.
Treatment of lactic acid bacterial infections can be dif®cult
since eradication is complicated by the often deep-seated
location, the antimicrobial resistance to antibiotics, and the
problem in identifying the organisms and thereby to initiate
apppropriate treatment (Sherman et al, 1987). In a single
case L. acidophilus ingestion has been associated with the
development of D-lactic acidosis (Mason, 1986).
Conclusion
Lactic acid bacteria appear to alleviate lactose malabsorption in lactose malabsorbers when administered in fermented dietary milk products (yogurt, Table 3 (a)), but not in
infermented milk products (set acidophilus milk, Table
3(b)). Lactic acid bacteria seem to shorten the course of
infectious diarrhoea especially in infants with rotavirus
diarrhoea (Table 6 (b)) and reduce the risk of travellers'
diarrhoea (Table 6 (a)). The ability of lactic acid bacteria to
prevent antibiotic associated diarrhoea is less convincing,
and results from studies of Clostridium dif®cile are preliminary and yet inconclusive. Experimental studies indicate an effect of lactic acid bacteria on human cell cancer
lines, but clinical evidence is lacking.
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