Medical Hypotheses (2003) 61(2), 307313

2003 Elsevier Science Ltd. All rights reserved.

doi:10.1016/S0306-9877(03)00192-0

Probiotics can treat hepatic

encephalopathy
S. F. Solga
Johns Hopkins Hospital, Baltimore, USA

Summary Hepatic encephalopathy (HE) is a common and dreaded complication of liver disease. The
effects of HE can range from minimal to life threatening. Even minimal HE causes major dysfunction in many
aspects of daily living.
The exact pathogenesis of HE remains unknown. However, the products of gut flora metabolism are universally
recognized as critical. Present treatments for HE include the cathartic agent lactulose and poorly absorbable
antibiotics. While effective, these treatments incur numerous side-effects and cost.
Probiotics are viable bacteria given orally to improve health. Probiotics have multiple mechanisms of action that
could disrupt the pathogenesis of HE and may make them superior to conventional treatment.
2003 Elsevier Science Ltd. All rights reserved.

BACKGROUND/SIGNIFICANCE
Disease and pathogenesis
Hepatic encephalopathy (HE) is a common and serious
complication of chronic liver disease. This complex
neuropychiatric syndrome has been defined as a disturbance in central nervous system function because of
hepatic insufficiency (1). At least 5070% of patients
with cirrhosis will demonstrate abnormalities on pyschometric testing (2,3), and many will have significant
functional impairment. Encephalopathy can occur in
patients with both acute and chronic liver disease, and
can be clinically overt or less apparent.
Minimal encephalopathy is a term that describes
patients with chronic liver disease who have no clinical
symptoms of brain dysfunction, but perform substantially worse on pyschometric tests compared to healthy
controls (4). An extensive body of research has consistently documented cognitive deficits in these patients,
including impaired psychomotor speed, attention, and

Received 3 September 2002

Accepted 11 November 2002
Correspondence to: Steven F. Solga MD, 600 North Wolfe Street, Blalock 4,
Division of Gastroenterology, Johns Hopkins Hospital, Baltimore, MD 21205,
USA. Phone: 410-502-7729; Fax: 410-955-2108;
E-mail: solga@jhmi.edu

visual perception. Predictably, such impairments lead to

major difficulties in safely performing routine activities
of life. Landmark work by Schomerus et al. (5) demonstrated that 60% of cirrhotics with minimal HE were
unfit to drive, and an additional 25% were possibly
unfit to drive. In agreement with this finding, other
investigators have found impaired earning capacity,
particularly amongst blue-collar workers requiring psychomotor skills in order to perform their jobs (6). Further, extensive work using a 136 part sickness impact
profile (a generic, non-disease-specific quality of life
questionnaire) found that minimal HE has major impact
on all aspects of a patients life (7).
Clinically apparent encephalopathy has been subdivided into a semi-quantative grading scheme ranging
from mild (grade I) to severe (grade IIIV). According to
the West Haven Criteria (8), grade I encephalopathy indicates a patient with trivial lack of awareness, euphoria
or anxiety, shortened attention span, and impaired performance of addition. At times, clinicians may have
difficulty distinguishing these patients from patients
with minimal encephalopathy.
The pathogenesis of HE is unknown, but is almost
certainly multi-factorial. Gut-derived nitrogenous substances are universally acknowledged to play a major
role. Specifically, ammonia is thought to be a critical
factor in the pathogenesis. While ammonia is produced
by many tissues, most results from the activity of urease

307

308 Solga

producing gut flora and is released into the portal vein

after absorption by the intestinal epithelium. Ammonia
is converted into urea in the liver, carried to the kidneys,
and then excreted into the urine. Normally a very efficient process, humans excrete over 20 pounds of urea a
year (9) and first pass hepatic clearance of ammonia is
around 80% (10). See Fig. 1.
Further understanding of urease and ammonia is important to the pathophysiology of HE and potential
treatments. Urease-producing bacteria exist in abundance in the gut of ureolytic animals (11). Ureolytic
animals, including humans, excrete nitrogenous waste
primarily via urea in the urine. Urease is a bacterial
enzyme that catalyzes the hydrolysis of urea to carbamate and ammonia (12). Bacteria from many different
genera produce urease, and its expression can be nitrogen regulated, urea inducible, or constitutive (13). Urease-producing bacteria are frequently gram negative
Enterobacterceae. The potential therapeutic consequences of blocking urease activity were established
decades ago by demonstrations that injection of antiurease antibodies reduced ammonia production and
improved encephalopathy (14). Such immunization
against urease, however, caused many side effects and
was ultimately abandoned (15).
Ammonia is a weak base with a pKa of 9.25 (16).
Therefore, decreases in lumenal pH increases the ratio of
ionized to unionized ammonia, and decreases passive
non-inonic diffusion. As a result, less ammonia is absorbed into the portal blood and more is excreted in
feces (17). Further, lower lumenal pH itself reduces the
degradation of nitrogenous compounds (proteins and
amino acids) and production of ammonia (18).
The physiologic balance of ammonia production and
clearance is disrupted on multiple levels in patients with
cirrhosis, resulting in HE. An extensive body of evidence
reports that cirrhotics harbor more gut urease-active
bacteria than controls (19), and that this leads directly to
increased intestinal hydrolysis of urea and absorption of
nitrogenous products (20). Altered small intestinal

dysmotility frequently accompanies cirrhosis (21) and

likely exacerbates this problem. Further, increased portal
ammonia results in markedly increased systemic ammonia because of: (1) impaired hepatic processing of ammonia and (2) the shunting of portal blood away the
liver. Finally, ammonia crosses the bloodbrain barrier
more readily patients with HE (22), where it acts on
impaired astroctyes and results in a cascade of pathopysiologic neurochemical events (23). See Fig. 2.
Other gut-derived toxins may also play a role in the
pathogenesis of HE (24). For example, intestinal flora
may produce benzodiazepine-like substances (25) or
mercaptans (26) which can be additive or synergistic to
the effects of ammonia. The importance of gut-derived
products for HE is further supported by the efficacy of
complete surgical exclusion (e.g., total colectomy) in the
treatment of refractory HE (27).
Standard treatment options
Presently, lactulose and poorly absorbable antibiotics
are the mainstay of treatment for HE. Lactulose is a nonabsorbable, synthetic disaccharide that has multiple effects on gut flora and, therefore, several potential
mechanisms of action. Its most obvious effect is as a
laxative; however, laxatives alone (e.g., water enemas)
(28) are ineffective for HE. Additional putative mechanisms for the efficacy of lactulose may include:
1. Decreasing ammonia production by decreasing urease activity and increasing assimilation of nitrogenous products by bacteria;
2. Acidifying the colon contents resulting in a decrease
in ammonia absorption into the gut; and
3. Decreasing toxic C4C6 short chain fatty acid production by enhancing the production of non-toxic
acetate (29).
Finally, lactulose may function as a prebiotic in the
treatment of hepatic encephalopathy (30). A prebiotic is
defined as a non-digestible food ingredient that

Fig. 1 Normal physiology. (A) Urease producing gut flora cleave urea in an enzymatic process resulting in net ammonia production. (B) Portal
blood is then processed in the liver where most of it is cleared, allowing for normal brain function, (C).

Medical Hypotheses (2003) 61(2), 307313

2003 Elsevier Science Ltd. All rights reserved.

Probiotics can treat hepatic encephalopathy

309

Fig. 2 Pathophysiology in cirrhosis. Intestinal dysmotility (A) exacerbates overgrowth of urease bacterial (B) and increased absorption
of nitrogenous products (C) into the portal blood. Shunting (D) and impaired hepatic processing (E) result in increased systemic exposure
to an impaired bloodbrain barrier (F) and astrocyte dysfunction (G) results.

beneficially affects the host by selectively stimulating

the growth and/or activity of one or a limited number of
bacteria in the colon, and thus improves host health
(31). Specifically, lactulose significantly increases concentrations of bifidobacteria and lactobacilli, and may
have therapeutic effect through the mechanisms of
these flora (32,33).
Non-absorbable antibiotics, principally neomycin and
metronidazole, are also effective, presumably by killing
gram negative and anaerobic urease producing bacteria.
Further treatments can include dietary protein restriction (34), ornithine salts (35), and benzoate (36), although the latter are rarely used in practice.
While these treatments are effective, they impose side
effects, toxicities, and cost. Lactulose has an unpleasant
taste and causes flatulence and diarrhea. Due to unpredictable doseresponses, the diarrhea can be severe and
result in hypertonic dehydration with hypernatremia
with subsequent hyperosmolarity and altered mental
status (37). Neomycin causes auditory loss, renal failure,
diarrhea, and staphylococcal superinfection. Metronidazole neurotoxicity can be severe in cirrhotics (38).
Antibiotics alter flora and result in bacterial resistance.
Even dietary recommendations come with disadvantages; compliance is low, and an overly negative protein
balance lead to loss of muscle mass and susceptibility to
infections (39).
As a result of these concerns, clinicians and patients
at times under-appreciate and under-treat HE, and often
overlook minimal HE. Clearly, safe, well-tolerated, inexpensive alternatives are needed.
Rationale for probiotics
Probiotics may have multiple beneficial effects in the
treatment of minimal HE. In principle, probiotics may
2003 Elsevier Science Ltd. All rights reserved.

exhibit efficacy in the treatment of hepatic encephalopathy by:

1. Decreasing total ammonia in the portal blood by:
(a) decreasing bacterial urease activity,
(b) decreasing ammonia absorption by decreasing pH,
(c) decreasing intestinal permeability,
(d) improving nutritional status of gut epithelium.
2. Decreasing inflammation and oxidative stress in the
hepatocyte leading to increased hepatic clearance of
ammonia and other toxins.
3. Decreasing uptake of other toxins.
These processes may be additive or synergistic in treating minimal HE.
First, by altering gut flora composition, selected viable, non-pathogenic bacteria can directly decrease ammonia production and absorption. This can be
accomplished by changes in gut metabolism and pH, gut
permeability, and the nutritional status of gut epithelium. As noted above, urease is a critical enzyme of
bacterial lumenal metabolism that results in ammonia
production and increased pH. Increased ammonia generation and higher pH accelerate ammonia absorption
into the portal blood; decreased pH result in decreased
ammonia absorption. Probiotics may alter this process
by competitive inhibition with urease-producing bacteria and increasing lumenal bacteria concentration. Experimental evidence (presented below) have proven
these mechanisms in humans. The exact mechanism by
which probiotics have been shown to decrease fecal
urease activity and pH are uncertain, but probiotics have
been demonstrated to result in reduced concentrations
of many bacteria (40), particulary gram negatives that
produce urease. Further, probiotics improve human intestinal permeability in experimental models (41).
In addition, some have proposed that probiotics may
Medical Hypotheses (2003) 61(2), 307313

310 Solga

enhance intestinal epithelial viability by providing essential nutritional support (e.g., medium chain fatty acids) that inhibits apoptosis of lumenal epithelial cells
(42). Thus, there are numerous possible mechanisms by
which probiotics could decrease the absorption of ammonia into the portal blood.
Second, an extensive body of research has demonstrated that gut-derived inflammatory signaling adversely effects the hepatocyte itself, and that therapy
directed against gut flora (e.g., probiotics) can limit or
reverse this damage. These observations were first made

inflammation (i.e., NfK-B and TNFa) in the livers of mice

that were fed oral probiotics (48).
Third, probiotics might inhibit the uptake of toxins
other than ammonia that have not yet been identified.
This notion is supported by research in patients with end
stage renal disease on hemodialysis. These patients often have altered mental status due in part to gut-derived
toxins, such as phenol and indican, that not cleared by
dialysis. Trials of lactic acid probiotics in humans with
end stage renal disease to alter the gut flora and consequently reduce such toxins have demonstrated efficacy

Summary of putative mechanisms

Lactulose
Antibiotics
Probiotics

+ Intra-luminal pH,
Alter flora,
+ N4 production + N4 absorption

Alter short chain

+ Intestinal
fatty acid production permeability

p
p
p

in rodent studies that identified a pathogenic role for

intestinal bacteria in alcohol-induced liver disease.
When ethanol-fed rats are given neomycin (to partially
decontaminate the gut) polymyxin (43) (to bind lipopolysacchride (LPS) and reduce its translocation from the
intestinal lumen into the mesenteric blood) or lactobacillus (44) (to modify intestinal flora), they are protected
from alcohol-induced liver damage. This protective effect is the result of reduced hepatic exposure to intestinal products, such as LPS, that promote the release of the
pro-inflammatory cytokine, tumor necrosis factor alpha
(TNFa), from hepatic macrophages.
Similar mechanisms are now acknowledged to be
important for the pathogenesis of both alcohol-related
and non-alcohol related fatty liver disease (45,46), and a
growing body of evidence suggests that the same
mechanism may also contribute to liver damage caused
by other hepatotoxins. Accordingly, there may be a
common mechanism (namely, LPS-induced hepatotoxicity) that explains how diverse insults lead to liver
damage (47). Such damage, in turn, disrupts normal
hepatocyte function and leads to mitochrondial oxidative stress. Ultimately, the hepatocyte is impaired, and
the clearance of toxins (including ammonia) is reduced.
Treatment with probiotics may be ideal because they
may protect against inflammation and hepatocyte damage from intestinal flora due to numerous mechanisms.
As noted above, this has already been demonstrated in
rodent models of alcohol liver disease. Recent work on a
murine model of non-alcoholic fatty liver disease also
supports this concept. These investigators found
improvement in numerous molecular markers of
Medical Hypotheses (2003) 61(2), 307313

+ Inflammatory
signaling, mitochondrialoxidative stress in
hepatocyte

+ Absorption of
other toxins

(49,50). As noted above, some of the efficacy lactulose

may indeed derive from its action as a prebiotic encouraging the growth of the same lactic acid bacteria
used in probiotics. Probiotics are inexpensive, safe, and
have no known negative long-term effects. This hypothesis is especially timely given that the expanding list
of positive effects of probiotics are delineated by various
laboratories (51,52). Further, probiotics are a natural
therapy and, as such, are widely accepted by the public.
Indeed, they are sometimes considered part of complementary or alternative medicine (CAM). Studies consistently demonstrate extensive use of CAM by patients,
including those with liver disease (53).
PRELIMINARY DATA
The study of hepatic encephalopathy has been greatly
hindered by the lack of properly designed therapeutic
trials (54). According to a recent consensus statement,
criticisms that apply, to some degree, to all trials include
the large spectrum of clinical conditions summarized
under the [term hepatic encephalopathy], the definition
of study endpoints, the treatment of control groups, and
the methods used to quantify therapeutic effects (55).
Unfortunately, no useful animal models exist to study
minimal hepatic encephalopathy. Accordingly, preliminary data must nevertheless come from relevant
human trials and consideration of the relevant mechanisms of action.
All four published studies on the effect of probiotics
on hepatic encephalopathy have demonstrated efficacy
(5659). These trials employed high doses of non 2003 Elsevier Science Ltd. All rights reserved.

Probiotics can treat hepatic encephalopathy

urease-producing bacteria, either Lactobacillus acidophilus or Enterococcus faecium SF68. Because these studies
did not employ highly concentrated, viable bacteria, they
required frequent dosing and/or ingestion of a large
quantity of fluid (up to a liter). Further, the mechanisms
of action of these probiotic strains in liver disease or
hepatic encephalopathy are uncertain, and have not
been thoroughly studied with this interest in mind. Finally, these studies were small, lacked a placebo controlled design and firm, well-established endpoints.
Nevertheless, their success demonstrates a certain proof
of principle that warrants further attention.
One possible probiotic compound that might be ideally suited to HE is the highly concentrated combination
probiotic, VSL#3.This product contains 5  1011 cfu/g of
viable, lyophilized bifidobacteria (Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium
breve), lactobacilli (L. acidophilus, Lactobacillus casei,
Lactobacillus delbrueckii subsp. Lactobacillus bulgaricus,
and Lactobacillus plantarium) and a mixture of Streptococcus thermophilus strains. Viability has been proven by
stool collection (60). Potential advantage for its application to HE include:
1. VSL#3 has been shown to reduce stool urease activity
in humans.
2. VSL#3 has been shown to reduce stool pH in humans.
3. VSL#3 alters production of short chain fatty acids in
humans.
4. VSL#3 improves intestinal permeability and decrease
inflammatory signals in murine and human colonic
cell culture models.
First, VSL#3 has been proven to reduce stool urease activity. In a clinical trial (61), 10 patients with irritable
bowel syndrome or functional diarrhea were given
VSL#3, and urease activity was measured at study entry,
20 days after VSL#3 administration, and 10 days after
discontinuation. The investigators found a greater than
50% reduction during VSL#3 administration, and a
subsequent return toward baseline levels upon discontinuation.
Second, VSL#3 is proven to reduce stool pH (60). Stool
specimens were studied in 20 patients with ulcerative
colitis who were intolerant of or allergic to 5-aminosalicylic acid in order to determine the impact on fecal composition by VSl#3. Stool composition of component
bacteria all increased significantly. Of particular interest is
that the stool pH dropped significantly (p < 0:005) and
remained stable throughout the treatment. Since uptake
of nitrogenous compounds is favored by a higher pH and
diminished by a lower pH, this effect could have a major
impact on ammonia generation in patients with cirrhosis.
Further, VSL#3 may reduce short chain fatty acids,
including butyrate in particular. In vitro culture of
2003 Elsevier Science Ltd. All rights reserved.

311

human ileostomy effluent inoculated with VSL#3 demonstrated a decrease in short chain fatty acids and butyrate compared to control (62). VSL#3 also improves
intestinal permeability and decreases inflammatory signaling in murine colitis models (the interleukin-10
knockout mouse) and human colonic cell cultures (T84
monolayers) (63). Oral VSL#3 for four weeks lead to decreases in mucosal secretion of the pro-inflammatory
cytokines TNFa and interferon c and increased resistance to samonella invasion.
Finally, as noted previously, an attribute shared by all
probiotics is their intrinsic safety and tolerability.
CONCLUSIONS
Hepatic encephalopathy is a serious and common complication of liver disease. While the exact pathogenesis
remains uncertain, nitrogenous products of gut flora
metabolism certainly play a critical role. Present treatment strategies, including lactulose and poorly absorbable antibiotics, may not be optimal therapy for all
patients with liver disease due to side-effects and cost.
Compliance with therapy, particularly for minimal HE, is
often low.
Probiotics have multiple mechanisms of action that
may make them superior to conventional therapy. Since
probiotics are a safe, natural, well-tolerated therapy appropriate for long-term use, probiotic therapy for HE
may be ideal. Amongst presently available probiotic
products, VSL#3 may be best suited for this purpose.
This hypothesis should be tested in rigorously designed
clinical trials.
ACKNOWLEDGEMENT
The author would like to acknowledge Anna Mae Diehl, MD, for
advice and support.

REFERENCES
1. Blei A., Cordoba J. Hepatic encephalopathy. Am J
Gastroenterol 2001; 96(7): 19681976.
2. Gilberstadt S. J., Gilberstadt H., Zieve L., Buegel B., Collier
R. O., Jr, McClain C. J. Psychomotor performance defects in
cirrhotic patients without overt encephalopathy. Arch Intern
Med 1980; 140: 519521.
3. Gitlin N., Lewis D. C., Hinkley L. The diagnosis and
prevelance of subclinical hepatic encephalopthy in
apparently healthy, ambulant, non-shunted patients with
cirrhosis. J Hepatol 1986; 3: 7582.
4. Weissenborn K., Ennen J. C., Schomerus H., Ruckery N.,
Hecker H. Neuropsychological characterization of hepatic
encephalopathy. J Hepatol 2001; 34: 768773.
5. Schomerus H., Hamster W., Blunck H., Reinhard U., Mayer
K., Dolle W. Latent portosystemic encephalopathy. I. Nature
of cerebral functional defects and their effect on fitness to
drive. Dig Dis Sci 1981; 26: 622630.

Medical Hypotheses (2003) 61(2), 307313

312 Solga

6. Hamster, W. Neuropsychologie der latenten

portosystemischen Enzephalopathie. Hebilitationsschrift,
Medizinische Fakultat der Eberhard-Karls-Universistat
Turbingen, Turbingen, 1982.
7. Groenweg M., Qeuro J. C., De Bruijn I. et al. Subclinical
hepatic encephalopathy impairs daily functioning.
Hepatology 1998; 28: 4549.
8. Conn H. O. Quantifying the severity of hepatic
encephalopathy. In: H. O. Conn, Bircher (eds). Hepatic
Encephalopathy: Syndromes and Therapies. East Lansing, MI:
Medi-Ed Press, 1993: 1326.
9. Burne R., Chen Y. Bacterial ureases in infectious diseases.
Microb Infect 2000: 533542.
10. Nomura F., Ohnishik K., Terabayshi H. et al. Effect of
intrahepatic portal-systemic shunting on hepatic ammonia
extraction in patients with cirrohsis. Hepatology 1994; 20:
14781481.
11. Schmidt-Nielsen K. Animal Physiology, 4th Edn. Cambridge:
Cambridge University Press, 1994. p. 387.
12. Collins C. M., DOrazio S. E. Bacterial ureases: structure,
regulation of expression and role in pathogenesis. Mol
Microbiol 1993; 9(5): 907913.
13. Mobley H. L., Hausinger R. P. Molecular biology of
microbial ureaes. Microbiol Rev 1995; 59(3): 451480.
14. Thompson A., Visek W. J. Some effects of induction of
urease immunity in patients with hepatic insufficiency. Am J
Med 1963; 35: 804809.
15. LeVeen H. H., LeVeen E. G., LeVeen R. F. Awakenings to the
pathogenicity of urease and the requirement for continuous
long term therapy. Biomed Pharmacother 1994; 48: 157166.
16. Nielsen A. E. Kemiske Data. Kobenhavn: F.A.D.Ls Forlag,
1976.
17. Clausen M. R. Production and oxidation of short-chain fatty
acids in the human colon. Danish Med Bull 1998; 45(1): 51
75.
18. Mortensen P. B., Holtug K., Bonnen H., Clausen M. R. The
degradation of amino acids, proteins, and blood to shortchain fatty acids in the colon is prevented by lactulose.
Gastroenterology 1990; 98: 353360.
19. Dheeraj L., Gorbach S., Levitan R. Intestinal microflora in
patients with alcholic cirrhosis: urea-splitting bacteria and
neomycin resistance. Gastroenterology 1972;(62): 275279.
20. Hansen B. A., Vilstrup H. Increased intestinal hydrolysis of
urea in patients with alcoholic cirrohsis. Scand J
Gastroenterol 1985;(20): 346350.
21. Yang C. Y., Chang C. S., Chen G. H. Small-intestinal
bacterial overgrowth in patients with liver cirrohsis,
diagnosed with glucose H2 or CH4 breath tests. Scand J
Gastroenterol 1998; 33(8): 867871.
22. Lockwood A. H., Yap E. W., Wong W. H. Cerebral ammonia
metabolism in patients with severe liver disease and
minimal hepatic encephalopathy. J Cereb Blood Flow Metab
1991; 11: 337341.
23. Haussinger D., Kircheis G., Fischer R., Schliess F., vom Dahl
S. Hepatic encephalopathy in chronic liver disease: a clinical
manifestation of astrocyte swelling and low grade cerebra
edema? J Hepatol 2000; 32: 10351038.
24. Blei A. Baillieres Clin Gastroenterol 2000; 14(6): 959974.
25. Yurdaydin C., Walsh T. J., Engler H. D. et al. Gut bacteria
provide precursors of benzodiazepine receptor ligands in a
rat model of hepatic encephalopathy. Brain Res 1995; 679:
4248.
26. Zieve L., Doizaki W. M., Zieve J. Synergism between
mercaptans and ammonia or fatty acids in the production of

Medical Hypotheses (2003) 61(2), 307313

27.

28.

29.
30.
31.

32.

33.

34.

35.

36.

37.
38.

39.
40.

41.

42.

43.

44.

45.

coma: a possible role for mercaptans in the pathogenesis of

hepatic coma. J Lab Clin Med 1974; 83: 1628.
Dagenais M. H., Bernard D., Marleau D. et al. Surgical
treatment of severe postshunt hepatic encephalopathy.
World Surg 1991; 15: 109114.
Uribe M., Campollo O., Vargas F. Acidifying enemas (lacitiol
and lactose) vs. nonacidifying enemas (tap water) to treat
acute portal-systemic encephalopathy: a double-blind,
randomized clinical trial. Hepatology 1987; 7: 639643.
Clausen M. R., Mortensen P. B. Lactulose, disaccharides and
colonic flora. Drugs 1997; 53(6): 930942.
Jenkins D., Kendall C. W., Vuksan V. Inulin, oligofructose,
and intestinal function. J Nutr 1999; 129: 1431S1433S.
Gibson G. R., Roberfroid M. B. Dietary modification of the
human colonic microbiota-introducing the concept of
prebiotic. Nutrition 1995; 125: 14011412.
Rycroft C. E., Jones M. R., Gibson G. R., Rastall R. A. A
comparative in vitro evaluation of the fermentation
properties of prebiotic oligosaccharides. J Appl Microbiol
2001;(91): 878887.
Salminen S., Salminen E. Lactuluose, lactic acid bacteria,
intestinal microecology and mucosal protection. Scand
Gastroenterol 1997; 222: 4548.
Uribe M., Conn H. O. Dietary management of portalsystemic encephalopathy. In: H. O. Conn, A. Bircher (eds).
Hepatic Encephalopathy: Syndromes and Therapies.
Bloomington, IL: Medi-Ed Press, 1994: 331349.
Herlong H. F., Maddrey W. C., Walser M. The use of ornithine
salts of branched-chain ketocids in portal-systemic
encephalopathy. Ann Intern Med 1980; 93: 545550.
Sushma S., Dasarathy S., Tandon R. K., Jain S., Gupta S.,
Bhist M. S. Sodium benzoate in the treatment of acute
hepatic encephalopathy: a double-blind randomized trial.
Hepatology 1992; 16: 138144.
Warren S. E., Mitas J. A., Swerdlin A. H. Hypernatremia in
hepatic failure. JAMA 1980; 243: 12571260.
Lost S., Sonne J., Dossing M., Andreasen P. B. Metronidazole
pharmokinetics in patients with hepatic encephalopathy.
Scand J Gastroenterol 1987; 22: 117123.
Gerber T., Schomerus H. Hepatic encephalopathy in liver
cirrhosis. Drugs 2000; 60(6): 13531370.
Gibson G. R., Wang X. Regulatory effects of bifidobacteria
on the growth of other colonic bacteria. Appl Bacteriol 1994;
77(4): 412420.
Madsen K. L., Cornish A., Soper P. Probiotic bacteria
enhance murine and human intestinal epithelial barrier
function. Gastroenterology 2001; 121: 580591.
Kanauchi O., Fujiyama Y., Mitsuyama K. et al. Incresed
growth of bifidobacterium and eubacterium by germinated
barely foodstuff, accompanied by enhanced butyrate
production in healthy volunteers. Int J Mol Med 1999; 3(2):
175179.
Adachi Y., Moore L. E., Bradford B. U., Gao W., Thurman R.
G. Antibiotics prevent liver injury in rats following longterm exposure to ethanol. Gastroenterology 1995; 108(1):
218224.
Nanj A. A., Khettry U., Sadrzadeh S. M. H. Lactobacillus
feeding reduces endotoxemia and severity of experimental
alcoholic liver disease. Proc Soc Exp Biol Med 1994; 205:
243247.
Yang S. Q., Lin H. Z., Lane M. D., Clemens M., Diehl A. M.
Obesity increases sensitivity to endotoxin liver injury:
implications for the pathogenesis of steatohepatitis. PNAS
1997; 94(6): 25572562.

2003 Elsevier Science Ltd. All rights reserved.

Probiotics can treat hepatic encephalopathy

46. Enomoto N., Ikejima K., Bradford B. U. et al. Hepatology:

microcirculation and pathogenesis of alcoholic liver injury.
Role of Kupffer cells and gut-derived endotoxins in
alcoholic liver injury. J Gastroenterol Hepatol 2000;
15(suppl): D20D25.
47. Yang S. Q., Lin H., Diehl A. M. Fatty liver vulnerability to
endotoxin-induced damage despite NF-kappaB induction
and inhibited caspase 3 activation. Am J Physiol Gastrointest
Liver Physiol 2001; 281(2): G382G392.
48. Li Z., Yang S. Q., Lin H. Z. et al. Probiotics and anti-TNF
antibodies inhibit inflammatory activity and improve nonalcoholic fatty liver disease in ob/ob mice. Abstract DDW
2002, in review.
49. Hida M., Aiba Y., Sawamura S. et al. Inhibition of the
accumulation of uremic toxins in the blood and their
precursors in the feces after oral administration of Lebenin,
a lactic acid bacteria preparation, to uremic patients
undergoing hemodialysis. Nephron 1996; 74: 349355.
50. Simenhoff M. L., Dunn S. R., Zollner G. P. et al.
Biomodulation of the toxic and nutritional effects of small
bowel bacterial overgrowth in end-stage kidney disease
using freeze-dried Lactobacillus acidophilus. Miner
Electrolyte Metab 1996; 22(13): 9296.
51. Rolfe R. D. The role of probiotic cultures in the control of
gastrointestinal health. J Nutr 2000; 130(2s suppl): 396s
402s.
52. Gionchetti P., Rizzello F., Venturi A., Campieri M. Probiotics
in infective diarrhea and inflammatory bowel diseases. J
Gastroenterol Hepatol 2000; 15: 489493.
53. Seeff L., Lindsay K. L., Bacon B. R., Kresina T. F., Hoofnagle
J. H. Complementary and alternative medicine in chronic
liver disease. Hepatology 2001; 34(3): 595603.
54. Ferenci P. Hepatic encephalopathy; treatment. In: J. W. D.
McDonald, A. K. Burroughs, B. G. Feagan (eds). Evidence
Based Gastroenterology and Hepatology. London: British
Medical Journal-Books, 1999: 443455.
55. Ferenci P., Lockwood A., Mullen K., Tarter R., Weissenborn
K., Blei A. Hepatic encephalopathy-definition,

2003 Elsevier Science Ltd. All rights reserved.

56.

57.

58.

59.

60.

61.

62.

63.

313

nomenclature, diagnosis, and quantification. Final Report of

the Working Party at the 11th World Congress of
Gastroenterology, Vienna, 1998. Hepatololgy 2002; 35:
716721.
Macbeth W., Kass E., McDermott W. Treatment of hepatic
encephalopathy by alteration of intestinal flora
with Lactobacillus acidophilus. Lancet 1965; 1:
399403.
Read A. E., McCarthy C. F., Heaton K. W., Laidlaw J.
Lactobacillus acidophilus (Enpac) in treatment of hepatic
encephalopathy. BMJ 1966; 1: 12671269.
Loguerico C., Abbiati R., Rinaldi M., Romano A., Del
Vecchio Blanco C., Coltori M. Long-term effects of
Enterococcus faecium SF68 versus lactulose in the
treatment of patients with cirrhosis and grade 12 hepatic
encephalopathy. J Hepatol 1995; 23: 3946.
Loguercio C., Del Vecchio Blanco C., Coltorti M.
Enterococcus lactic acid bacteria strain SF68 and lactulose in
hepatic encephalopathy: a controlled study. J Int Med Res
1987; 15(6): 335343.
Venturi A., Gionchetti P., Rizzello F. et al. Impact on the
composition of the faecal flora by a new probiotic
preparation: preliminary data on maintenance treatment of
patients with ulcerative colitis. Aliment Pharmacol Ther
1999; 13: 11031108.
Brigidi P., Vitali B., Swennen E., Bazzocchi G., Matteuzzi D.
Effects of probiotic administration upon the composition
and enzymatic activity of human fecal microbiota in
patients with irritable bowel syndrome or functional
diarrhea. Res Microbiol 2001; 152: 735741.
Bianchi-Salvadori B., Vesely R., Ferrari A., Canzi E.,
Casiraghi C., Brighenti F. Behaviour of the pharmaceutical
probiotic preparation VSL#3 in human ileostomy effluent
containing its own natural elements. New Microbiol 2001;
24(1): 2333.
Madsen K. L., Cornish A., Soper P et al. Probiotic bacteria
enhance murine and human intestinal epithelial barrier
function. Gastroenterology 2001; 121: 580591.

Medical Hypotheses (2003) 61(2), 307313