International Journal of Food Microbiology 70 2001.

213220
www.elsevier.comrlocaterijfoodmicro

Effects of different probiotic strains of Lactobacillus and

Bifidobacterium on bacterial translocation and liver injury in an
acute liver injury model
Diya Adawi a,) , Siv Ahrne b, Goran
Molin b
a

Department of Surgery, Experimental Research, Malmo Uniersity Hospital, S-205 02, Malmo,
Sweden
b
Department of Food Technology, Lund Uniersity, Lund, Sweden
Received 29 October 2000; received in revised form 11 March 2001; accepted 18 May 2001

Abstract
Septic complications represent frequent causes of morbidity in liver diseases and following hepatic operations. Most
infections are caused by the individual own intestinal microflora. The intestinal microflora composition is important in
physiological and pathophysiological processes in the human gastrointestinal tract, but their influence on liver in different
situations is unclear. We therefore studied the effect of different Lactobacillus strains and a Bifidobacterium strain on the
extent of liver injury, bacterial translocation and intestinal microflora in an acute liver injury model.
SpragueDawley rats were divided into five groups: acute liver injury control, acute liver injuryq B. animalis NM2,
acute liver injuryq L. acidophilus NM1, acute liver injuryq L. rhamnosus ATCC 53103, and acute liver injuryq L.
rhamnosus DSM 6594 and L. plantarum DSM 9843. The bacteria were administered rectally daily for 8 days. Liver injury
was induced on the 8th day by intraperitoneal injection of D-galactosamine 1.1 grkg BW.. Samples were collected 24 h
after the liver injury. Liver enzymes and bilirubin serum levels, bacterial translocation to arterial and portal blood, liver and
mesenteric lymph nodes MLNs.., and intestinal microflora were evaluated.
L. acidophilus NM1; L. rhamnosus ATCC 53103, and L. rhamnosus DSM 6594 q L. plantarum DSM 9843 decreased
bacterial translocation compared to the liver injury control group. B. animalis NM2 increased bacterial translocation to the
mesenteric lymph nodes. The levels of alanine aminotransferase ALAT. were significantly lower in the L. acidophilus, L.
rhamnosus ATCC 53103, L. rhamnosus DSM 6594 q L. plantarum DSM 9843 groups compared to the liver injury group.
The L. rhamnosus and L. rhamnosusq L. plantarum groups significantly reduced ALAT levels compared to the B.
animalis group. All administered bacteria decreased the Enterobacteriaceae count in the cecum and colon.
Administration of different lactobacilli and a Bifidobacterium strain in an acute liver injury rat model, has shown
different effects on bacterial translocation and hepatocellular damage. L. acidophilus, L. rhamnosus, and L. rhamnosusq L.
plantarum reduced bacterial translocation and hepatocellular damage. B. animalis NM2 increased bacterial translocation to
the mesenteric lymph nodes and did not affect hepatocellular damage. q 2001 Elsevier Science B.V. All rights reserved.
Keywords: Enterobacteriaceae; hepatocellular damage; intestinal microflora; lactic acid bacteria; Lactobacillus plantarum

Corresponding author. Tel.: q46-40-332074; fax: q46-40-336207.

E-mail address: Diya.Adawi@kir.mas.lu.se D. Adawi..

0168-1605r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 8 - 1 6 0 5 0 1 . 0 0 5 5 0 - 5

214

D. Adawi et al.r International Journal of Food Microbiology 70 (2001) 213220

1. Introduction
The intestinal epithelium serves a vital protective
function, preventing passage of a variety of harmful
substances and the gut plays an important role in
many clinical infections Wilmore et al., 1988.. Most
bacterial infections in critically ill or immunocompromised patients are caused by the patients own
microflora, and many patients dying of sepsis or
multiple system organ failure have enteric bacteremia for which no septic focus can be identified
Deitch, 1992; Marshall et al., 1993.. Septic complications represent frequent causes of morbidity in
liver diseases and following hepatic operations
Iwatsuki and Strazl, 1988; Pace et al., 1989..
The importance of the intestinal microflora composition in physiological and pathophysiological processes in the human gastrointestinal tract is becoming more evident. Examples of such processes are
translocation, the production and resorption of endotoxins, immune-modulation, and colonic motility
Kasper, 1998.. Certain fractions of the intestinal
microflora can have beneficial effects on gastro-enteritis resistance, blood lipids, anti-tumour properties, lactose tolerance and gastrointestinal immunity
Collins and Gibson, 1999.. Lactobacilli constitute
integral parts of the normal gastrointestinal microecology, and they are involved in host metabolism
Fernandes et al., 1987.. Lactobacillus and Bifidobacterium are thought to play an important role in
the maintenance of the colonisation resistance and
prevention of overgrowth of enteric pathogens Wells
et al., 1987..
We have previously shown in an experimental
liver injury model that modulation of the intestinal
microflora by the administration of L. plantarum
DSM 9843 s strain 299v. reduces bacterial translocation to extraintestinal sites and the extent of liver
injury Adawi et al., 1997.. On the other hand,
modulations of the intestinal microflora by different
bacterial types, representing different predominant
taxa of the intestinal microflora, have different effects on the extent of the liver injury and bacterial
translocation Adawi et al., 1999.. In the present
study, we evaluated the effects of the administration
of different Lactobacillus strains and a Bifidobacterium strain on the extent of liver injury and bacterial translocation in an acute liver injury model. All

the strains are included as probiotics in commercially

available products.

2. Materials and methods

2.1. Bacterial strain
Five different bacterial strains: L. acidophilus
NM1 isolated from the probiotic preparation culture.; L. rhamnosus ATCC 53103 American Type
Culture Collection; s strain GG. Alander et al.,
1999.; L. plantarum DSM 9843 Deutsche Sammlung von Microorganismen; s strain 299v. Molin et
al., 1993. q L. rhamnosus DSM 6594 s strain 271.
Molin et al., 1993., and B. animalis NM2 isolated
from the probiotic preparation culture. were administered rectally daily, for 8 days. The amount of daily
supplementation was about 3 = 10 9 colony forming
unit CFU. per animal.
2.2. Experimental design
Male SpragueDawley rats BK Universal, Sollentuna, Sweden., with a weight ranging from 200 to
300 g, were used, and divided into 5 groups 6 rats
each.: controls with acute liver injury ALI. alone,
and simultaneous administration of each of the different bacterial strains. The samples were collected
24 h after the liver injury. All animals received
normal rat chow R3, Lactamin, Stockholm, Sweden. and water ad libitum throughout the experiment
and were kept in a 12-h lightrdark cycle at room
temperature 22 8C.. The experimental protocol was
approved by the Animal Ethics Committee of Lund
University and adhered to Guiding Principles in the
Care and Use of Animals.
Acute liver injury was induced on the 8th day by
intraperitoneal injection of D-galactosamine G0264,
Sigma, St. Louis, USA. 1.1 grkg body wt. Sommer
et al., 1979.. The bacterial strains were administered
rectally once daily for 8 days through a rectal tube.
In the acute liver injury control group, normal saline
in the same volume as the bacterial preparation was
administered daily through a rectal tube for 8 days
and liver injury was induced on the 8th day. Samples
were collected 24 h after induction of liver injury.
Under ether anaesthesia, a laparotomy was per-

D. Adawi et al.r International Journal of Food Microbiology 70 (2001) 213220

Table 1
Incidence of bacterial translocation to the extraintestinal sites in
the experimental groups

LI
BA
Lb. A
Lb. R1
Lb. R2qLb. P

Portal
blood

Arterial
blood

Liver

MLN

4r6
2r6
0r6 )
1r6
0r6 )

5r6
2r6
0r6 ) )
2r6
5r6

6r6
6r6
5r6
5r6
3r6

6r6
5r6
3r6
3r6
1r6 ) )

LI: Liver injury; BA: B. animalis NM2; Lb. A: L. acidophilus

NM1; Lb. R1: L. rhamnosus ATCC 53103; Lb. R2HLb. P: L.
rhamnosus DSM 6594q L. plantarum DSM 9843. MLN: mesenteric) lymph nodes.
Denotes p- 0.05 compared to liver injury group.
))
Denotes p- 0.01 compared to liver injury group.

formed through a midline incision using aseptic technique. Aortic blood was collected for bacteriological
and liver enzyme tests. Samples for bacteriological
analysis were also taken from the portal blood, the
caudate lobe of the liver, the mesenteric lymph nodes
MLNs. and the cecal and colonic contents.
2.3. Bacteriological analysis of blood and organs
Blood samples were immediately placed in sterile
tubes containing EDTA. Tissue samples were placed
in 5 ml of sterile transport medium Johansson et al.,
1993.. Samples were placed in ultrasonic bath Millipore, Sweden. for 5 min and then rotated on Chiltern
Terma-Glas, Gothenberg, Sweden. for 2 min. A
mesophilic aerobic plate count was made by placing
1.0 ml of the sample on Brain Heart Infusion BHI.
agar Difco, Detroit, MI, USA. and incubating at 37

215

8C for 3 days. A mesophilic anaerobic plate count

was made by placing the samples on BHI and incubating under anaerobic conditions Gas Pack System,
Gas Pack, Becton Dickinson Microbiology Systems,
Cockeynsville, MD, USA. at 37 8C for 3 days. After
3 days, the number of colonies formed on each plate
was counted and adjustment was made for the weight
of the original tissue, i.e. tissue samples were given
as CFUrg of tissue while blood samples were given
as CFUrml blood.
2.4. Intestinal microflora
Samples taken from cecal and colonic content
were immediately placed in 5 ml of sterile transport
medium, transferred to an ultrasonic bath and rotated
on chiltern, as above. After a conventional dilution
procedure, viable counts were obtained from BHI
that was incubated aerobically and anaerobically at
37 8C for 72 h aerobic and anaerobic bacterial
count, respectively., and from Rogosa agar Oxoid,
Hampshire, England. that was incubated anaerobically at 37 8C for 72 h lactobacilli counts.. Viable
counts were also obtained from violet red-bile-glucose agar VRBG. Oxoid. that was incubated aerobically at 37 8C for 24 h Enterobacteriaceae counts.
and from BHI agar containing Gram-negative anaerobic supplement Oxoid. that was incubated anaerobically at 37 8C for 72 h Gram-negative anaerobic
bacterial counts..
2.5. Lier enzymes and bilirubin
After centrifugation of the blood, 1000 g, 10
min. serum bilirubin Bil., alkaline phosphatase

Table 2
Bacterial translocation to the extraintestinal sites in the experimental groups CFUrml blood or g tissue.
Groups

Portal blood

Arterial blood

Liver

MLN

LI
BA
Lb. A
Lb. R1
Lb. R2 q Lb. P

40 " 20
20 " 15 )
0"0)
5 " 5)
0"0)

190 " 160

20 " 15 )
0"0)
50 " 45 )
20 " 10 )

4300 " 800

3600 " 1800
1600 " 620
1800 " 1500
1600 " 860

4500 " 1000

19,900 " 13,300 )
1800 " 1200 )
240 " 110 )
110 " 110 )

LI: Liver injury; BA: B. animalis NM2; Lb. A: L. acidophilus NM1; Lb. R1: L. rhamnosus ATCC 53103; Lb. R2 H Lb. P: Lb.
rhamnosus DSM 6594 q Lb. plantarum DSM 9843. MLN: mesenteric lymph nodes.
)
Denotes p - 0.05 compared to liver injury LI. group. KruskalWallis followed by comparisons of all groups vs. control group:
Dunnetts method..

D. Adawi et al.r International Journal of Food Microbiology 70 (2001) 213220

216

Table 3
Liver enzymes and bilirubin levels in the experimental groups

LI
BA
Lb. A
Lb. R1
Lb. R2qLb. P

ALP
mKatrl.

Bilirubin
mmolrl.

ALAT
mKatrl.

13.7"0.7
14.0"4.2
10.0"1.2
10.9"3.0
6.2"1.5

15.3"1.5
11.6"0.8
12.6"0.7
13.1"1.3
14.3"1.3

27.5"0.7
18.9"6.9
11.3"2.2 )
5.4"2.4 ) ,
6.8"1.0 ) ,

LI: Liver injury; BA: B. animalis NM2; Lb. A: L. acidophilus

NM1; Lb. R1: L. rhamnosus ATCC 53103; Lb. R2HLb. P: Lb.
rhamnosus DSM 6594q Lb. plantarum DSM 9843.
)
Denotes p- 0.05 compared to LI group.

Denotes p- 0.05 compared to BA group. All pairwise

multiple comparisons: StudentNewmanKeuls method..

ALP., and alanine aminotransferase ALAT. levels

in aortic blood were measured according to the
recommendations of the Committee on Enzymes of
the Scandinavian Society for Clinical Chemistry and
Clinical Physiology The Committee on Enzymes of
the Scandinavian Society for Clinical Chemistry and
Clinical Physiology, 1974..
2.6. Statistics
Values are presented as means" SEM. Differences between groups were evaluated by using the

one-way ANOVA test followed by all pairwise multiple comparison StudentNewmanKeuls method
or KruskalWallis followed by comparison of all
groups vs. control group: Dunnetts method when
appropriate Godfrey, 1986.. The incidence of bacterial translocation was evaluated using Fishers exact
test. Probability levels of less than 0.05 were considered significant p - 0.05..

3. Results
There was no mortality in the different experimental groups.

3.1. Bacterial translocation

The incidence of bacterial translocation to portal
blood decreased significantly in L. acidophilus and
L. rhamnosusq L. plantarum groups compared to
the liver injury control group. In arterial blood bacterial count decreased significantly in the L. acidophilus group compared to the liver injury group.
The incidence of bacterial translocation to the
mesenteric lymph nodes decreased significantly in L.

Table 4
Cecal and colonic bacterial microflora in the different experimental groups log CFUr g content.
Total aerobes

Total Anaerobes

G-ve anaerobes

Enterobacteriaceae

Lactobacillus

Cecum
LI
BA
Lb. A
Lb. R1
Lb. P q Lb. R2

7.09 " 0.34

7.11 " 0.34
7.17 " 0.15
7.47 " 0.12
7.49 " 0.1

7.37 " 0.33

7.52 " 0.43
7.19 " 0.19
7.59 " 0.10
7.82 " 0.11

6.80 " 0.48

7.38 " 0.51
7.20 " 0.12
7.44 " 0.13
7.69 " 0.10

5.95 " 0.34

0)
4.71 " 0.95a,
4.42 " 0.89 a,
1.83 " 1.16 )

7.18 " 0.30

7.33 " 0.38
7.29 " 0.12
7.67 " 0.13
7.71 " 0.06

Colon
LI
BA
Lb. A
Lb. R1
Lb. P q Lb. R2

7.23 " 0.46

7.65 " 0.16
7.27 " 0.20
7.61 " 0.16
7.83 " 0.15

7.38 " 0.41

7.59 " 0.11
7.68 " 0.14
7.89 " 0.17
8.20 " 0.14

7.23 " 0.57

7.42 " 0.12
7.75 " 0.19
7.52 " 0.29
8.01 " 0.12

6.82 " 0.32

3.38 " 1.07 )
3.11 " 1.40 )
3.85 " 1.22 )
3.73 " 1.18 )

6.88 " 0.35

7.61 " 0.15
7.79 " 0.10
7.94 " 0.10 )
7.99 " 0.15 )

LI: Liver injury; BA: B. animalis NM2; Lb. A: L. acidophilus NM1; Lb. R1: L. rhamnosus ATCC 53103; Lb. R2 H Lb. P: L. rhamnosus
DSM 6594 q L. plantarum DSM 9843.
)
Denotes p - 0.05 compared to LI.
a
Denotes p - 0.05 compared to BA.

Denotes p - 0.05 compared to Lb. P q Lb. R2 NewmanKeuls all pairwise multiple comparison..

D. Adawi et al.r International Journal of Food Microbiology 70 (2001) 213220

rhamnosusq L. plantarum group compared to the

liver injury group Table 1.. The number of translocated bacteria to portal blood, arterial blood and
mesenteric lymph nodes decreased in the L. acidophilus, L. rhamnosus, and L. rhamnosusq L.
plantarum groups compared to the liver injury group.
It increased in the B. animalis group compared to
the liver injury control group Table 2..
3.2. Lier enzymes and bilirubin
The release of ALAT was significantly lower in
the L. acidophilus, L. rhamnosus, and L. rhamnosus
q L. plantarum groups compared to the liver injury
group. The L. rhamnosus and L. plantarumq L.
rhamnosus groups significantly reduced ALAT levels compared to the B. animalis group Table 3..
3.3. Cecal and colonic bacterial microflora
The number of Enterobacteriaceae in the cecum
was decreased in B. animalis no growth. and L.
rhamnosusq L. plantarum groups compared to the
liver injury group. On the other hand, the Enterobacteriaceae count increased significantly in L. acidophilus and L. rhamnosus groups compared to B.
animalis and L. rhamnosusq L. plantarum groups
Table 4..
In the colon, the Enterobacteriaceae decreased
significantly in all the treatment the B. animalis, L.
acidophilus, L. rhamnosus, and L. rhamnosusq L.
plantarum. groups compared to the liver injury group
Table 4.. The lactobacilli count increased significantly in the L. rhamnosus, and L. rhamnosusq L.
plantarum groups compared to the liver injury control group Table 4..

4. Discussion
Lactobacillus and Bifidobacterium exert many
beneficial effects Fernandes et al., 1987. and they
play an important role in colonisation resistance and
prevention of overgrowth of enteric pathogens Wells
et al., 1987.. They are suggested to modulate the
different immune systems each in its own way and
prevent against various diseases Yasui et al., 1999..

217

Some of the lactic acid bacteria showed beneficial

effects and there could be differences in the effects
between the different Lactobacillus and Bifidobacterium strains. We studied the effects of different
Lactobacillus strains and a Bifidobacterium strain on
bacterial translocation and the extent of liver injury
in an acute liver injury model.
Administration of different bacterial strains in an
acute liver injury rat model has shown different
effects on bacterial translocation and liver injury
indicated by the release of the liver enzymes. Intestinal microflora play an important part in enhancement
or prevention of bacterial translocation Berg, 1992.,
and overgrowth of some intestinal bacteria enhances
bacterial translocation Maddaus et al., 1989..
The administration of Lactobacillus strains decreased bacterial translocation. Administration of B.
animalis increased bacterial translocation to the
mesenteric lymph nodes while it caused low numbers of bacteria in the portal and arterial blood. We
have shown previously that L. plantarum DSM 9843
administration decreased bacterial translocation in
the same model Adawi et al., 1997.. Thus, there are
no additive effects between L. plantarum and L.
rhamnosus DSM 6594. However, in the same model
Bacteroides fragilis increased the translocation
Adawi et al., 1999.. From the present study it seems
that the different Lactobacillus strains have different
effects on bacterial translocation. L. acidophilus; L.
rhamnosus ATCC 53103, and L. rhamnosus DSM
6594 q L. plantarum DSM 9843, decreased bacterial
translocation to a different degree. Moreover, B.
animalis increased the translocation to the mesenteric lymph nodes, but the type strain of B. longum
has previously been shown to decreased bacterial
translocation to all examined extraintestinal sites
Adawi et al., 1999..
It has been shown that mucosa-associated lactobacilli can be potent stimulators of IL-12, and thus
potentially of cell-mediated immunity, if they pass
over the gut epithelial barrier and interact with cells
of the gut immune system Hessle et al., 1999..
Administration of L. plantarum DSM 9843 enhances
gut immune function Mao et al., 1996a,b. and stimulates gastrointestinal epithelial proliferation and
barrier function Mao et al., 1996a,b.. It has been
indicated that Lb. plantarum colonisation competes
with Escherichia coli for intestinal colonisation and

218

D. Adawi et al.r International Journal of Food Microbiology 70 (2001) 213220

can influence intestinal and systemic immunity

Herias et al., 1999.. Continuous feeding with L.
plantarum could attenuate established colitis in IL10-deficient mice Schultz et al., 1998.. In the
neonatal period, IL-10 gene-deficient mice have decreased levels of colonic Lactobacillus and an increase in colonic mucosal adherent and translocated
bacteria. Oral administration of a mixture of 4 different probiotic strains of L. acidophilus, L. rhamnosus
GG, L. reuteri and B. animalis to immunodeficient
euthymic or athymic mice decreases systemic Candida albicans dissemination with concomitant reduction of mortality Wagner et al. 1997.. Oral administration of L. rhamnosus GG is effective in
rotavirus-positive and rotavirus-negative ambulatory
children with diarrhoea. Furthermore, it reduces the
duration of rotavirus excretion Guarino et al., 1997..
Administration of yoghurt supplemented with L. acidophilus and Bifidobacterium spp. enhanced mucosal and systemic IgA responses to the cholera
toxin immunogen Tejada-Simon et al., 1999.. The
effects of lactobacilli on bacterial translocation could
be mediated via maintenance of gastrointestinal epithelial proliferation and function, growth inhibition
of potentially pathogenic bacteria, stimulation of
mucin production, activation and augmentation of
systemic immune responses and intestinal mucosal
immune system. The reduced bacterial translocation
in our study could be one of the mechanisms for
reducing hepatocellular damage.
The administered lactic acid bacteria showed different effects on hepatocellular damage indicated by
the release of liver enzymes. All the tested Lactobacillus strains decreased hepatocellular damage indicated by decreasing the release of the enzyme
ALAT compared to the liver injury control group.
On the other hand, the B. animalis group showed no
difference in the release of ALAT compared to the
liver injury control group, while it showed higher
values compared to the lactobacillus groups with a
significant difference compared to L. rhamnosus,
and L. rhamnosusq L. plantarum groups. We used
the enzyme ALAT for the evaluation of the hepatocellular damage because it is more specific to the
liver injury than aspartate aminotransferase ASAT..
The effect on hepatocellular damage could be partly
through decreasing bacterial translocation and there
could be an augmentation of the systemic immune

responses and intestinal mucosal immune system.

The effects could also be mediated via stimulatory
effects of intestinal mucosa, alteration of intestinal
microflora and thus affecting the intestinal barrier.
The gut bacteria are important in maintaining Kupffer cell responses, and over-growth of Gram-negative
bacteria potentiates Kupffer cell responses to lipopolysacharides Billiar et al., 1988a,b.. Our results
showed that the administered bacteria decreased the
Enterobacteriaceae count in the cecum and colon.
Feeding strains of lactobacilli that survive in the
gastrointestinal tract reduces endotoxemia and alcohol-induced liver injury in the rat Nanji et al.,
1994.. L. rhamnosus GG provides a potential nontoxic form of therapy for both endotoxemia and
alcoholic liver disease Nanji et al., 1994.. Liver
cirrhosis patients are prone to bacterial infection
Gulberg et al., 1999., and septic complications represent frequent causes of morbidity in liver diseases
and following hepatic operations Iwatsuki and Strazl,
1988; Pace et al., 1989.. It seems that maintaining
the intestinal barrier functions and decreasing the
number of the translocated bacteria could be one of
the factors counteracting the liver injury. There are
important interactions between intestinal luminal
bacteria, endotoxin, and liver function. It has been
described how changes in gut bacteriology and physiology modulate hepatocellular function and systemic immunity through what has been called the
Agut liver axisB Marshall et al., 1988, 1993..
It seems that lactic acid bacteria have different
effects on bacterial translocation and hepatocellular
damage. Lactobacillus speciesrstrains could differ
also in their effects. Knowing, characterisation, definition and understanding of the most beneficial strains
and their mechanisms are of utmost importance.

Acknowledgements
This study was supported by grant No K200072X-11616-04C from the Swedish Medical Research
Council, by the Cancer Foundation, Pahlssons

Foundation, Malmo University Hospital, Nilsson

Cancer Foundation, Lundgrens Foundation, Bergqvist Cancer Foundation, the Swedish Council for

D. Adawi et al.r International Journal of Food Microbiology 70 (2001) 213220

Forestry and Agricultural Research and Norwegian

Dairies.

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