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Page 180 Alternative Medicine Review
◆ Volume 9, Number 2 ◆ 2004
Intestinal Dysbiosis Review
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Jason A Hawrelak, BNat (Hons) – PhD Candidate in the
field of intestinal micro-ecology, Southern Cross
University’s School of Natural and Complementary
Medicine and the Australian Centre for Complementary
Medicine Education and Research.
Correspondence address: School of Natural and
Complementary Medicine, Southern Cross University, PO
Box 157, Lismore NSW, Australia 2480
E-mail: jhawre10@scu.edu.au
Stephen P Myers, PhD, BMed, ND – Professor and Head of
the Australian Centre for Complementary Medicine
Education and Research.
Abstract
Alterations in the bowel flora and its activities
are now believed to be contributing factors to
many chronic and degenerative diseases.
Irritable bowel syndrome, inflammatory bowel
disease, rheumatoid arthritis, and ankylosing
spondylitis have all been linked to alterations
in the intestinal microflora. The intestinal
dysbiosis hypothesis suggests a number of
factors associated with modern Western living
have a detrimental impact on the microflora of
the gastrointestinal tract. Factors such as
antibiotics, psychological and physical stress,
and certain dietary components have been
found to contribute to intestinal dysbiosis. If
these causes can be eliminated or at least
attenuated then treatments aimed at
manipulating the microflora may be more
successful.
(Altern Med Rev 2004;9(2):180-197)
Introduction
The gastrointestinal tract (GIT) is one of
the largest interfaces between the outside world
and the human internal environment. From mouth
to anus, it forms a nine-meter long tube, consti-
tuting the body’s second largest surface area and
estimated to cover approximately 250-400 m
2
.
Over a normal lifetime, approximately 60 tons of
food will pass through the GIT.
1
Food is obviously
extremely important for well-being, but its pas-
sage through the GIT can also constitute a threat
to health. While the GIT functions to digest and
absorb nutrients, food also provides exposure to
dietary antigens, viable microorganisms, and bac-
terial products. The intestinal mucosa plays a dual
The Causes of Intestinal Dysbiosis:
A Review
Jason A. Hawrelak, BNat (Hons), PhD Candidate and
Stephen P. Myers, PhD, BMed, ND
role in both excluding these macromolecules and
microbes from the systemic circulation and ab-
sorbing crucial nutrients.
2
As mentioned above, the mucosa is ex-
posed to bacterial products – endotoxins,
3
hydro-
gen sulphide,
4
phenols, ammonia, and indoles
5
–
that can have detrimental effects on both mucosal
and host health.
5
The presence of many of these
toxic metabolites is directly dependent on the type
of fermentation that occurs in the bowel. In turn,
this fermentation is dependent on the type of bac-
teria present in the bowel, as well as the substrates
available for fermentation. Diets high in protein
6
and sulfate (derived primarily from food addi-
tives)
4
have been shown to contribute greatly to
the production of these potentially toxic products.
The production and absorption of toxic metabo-
lites is referred to as bowel toxemia.
7
The bowel toxemia theory has historical
roots extending as far back as Hippocrates. In 400
B.C. he stated that, “...death sits in the bowels...”
and “...bad digestion is the root of all evil....”
8
More
modern proponents of the bowel toxemia theory
have included naturopath Louis Kuhne in the late
nineteenth century,
9
as well as naturopath Henry
Lindlahr
10
and Nobel prize laureate Elie
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Alternative Medicine Review
◆ Volume 9, Number 2 ◆ 2004 Page 181
Review Intestinal Dysbiosis
Metchnikoff in the early twentieth century.
11
Louis
Kuhne proposed that excess food intake, or the
intake of the wrong types of food, resulted in the
production of intestinal toxins. Fermentation of
these toxins resulted in increased growth of bac-
teria within the bowel and, subsequently, disease.
He believed a predominantly vegetarian and
mostly raw diet would prevent build-up of intes-
tinal toxins and, hence, would prevent and even
cure disease.
9
Only a few years later, Metchnikoff popu-
larized the idea that fermented milk products could
beneficially alter the microflora of the GIT. He
believed many diseases, and even aging itself,
were caused by putrefaction of protein in the bowel
by intestinal bacteria. Lactic acid-producing bac-
teria were thought to inhibit the growth of putre-
factive bacteria in the intestines. Thus, yogurt con-
sumption was recommended to correct this “au-
tointoxication” and improve composition of the
microflora.
11,12
The bowel toxemia theories eventually
evolved into the intestinal dysbiosis hypothesis.
The term “dysbiosis” was originally coined by
Metchnikoff to describe altered pathogenic bac-
teria in the gut.
13
Dysbiosis has been defined by
others as “...qualitative and quantitative changes
in the intestinal flora, their metabolic activity and
their local distribution.”
14
Thus dysbiosis is a state
in which the microbiota produces harmful effects
via: (1) qualitative and quantitative changes in the
intestinal flora itself; (2) changes in their meta-
bolic activities; and (3) changes in their local dis-
tribution. The dysbiosis hypothesis states that the
modern diet and lifestyle, as well as the use of
antibiotics, have led to the disruption of the nor-
mal intestinal microflora. These factors result in
alterations in bacterial metabolism, as well as the
overgrowth of potentially pathogenic microorgan-
isms. It is believed the growth of these bacteria in
the intestines results in the release of potentially
toxic products that play a role in many chronic
and degenerative diseases.
13
There is a growing body of evidence that
substantiates and clarifies the dysbiosis theory.
Altered bowel flora is now believed to play a role
in myriad disease conditions, including GIT dis-
orders like irritable bowel syndrome (IBS)
15
and
inflammatory bowel disease (IBD),
16,17
as well as
more systemic conditions such as rheumatoid ar-
thritis (RA)
18
and ankylosing spondylitis.
19
Thus,
knowledge of the factors that can cause detrimen-
tal changes to the microflora is becoming increas-
ingly important to the clinician.
The Importance of Normal GIT
Microflora
The microflora of the gastrointestinal tract
represents an ecosystem of the highest complex-
ity.
14
The microflora is believed to be composed
of over 50 genera of bacteria
20
accounting for over
500 different species.
21
The adult human GIT is
estimated to contain 10
14
viable microorganisms,
which is 10 times the number of eukaryotic cells
found within the human body.
22
Some researchers
have called this microbial population the “mi-
crobe” organ – an organ similar in size to the liver
(1-1.5 kg in weight).
23
Indeed, this microbe organ
is now recognized as rivaling the liver in the num-
ber of biochemical transformations and reactions
in which it participates.
24
The microflora plays many critical roles
in the body; thus, there are many areas of host
health that can be compromised when the micro-
flora is drastically altered. The GIT microflora is
involved in stimulation of the immune system,
synthesis of vitamins (B group and K), enhance-
ment of GIT motility and function, digestion and
nutrient absorption, inhibition of pathogens (colo-
nization resistance), metabolism of plant com-
pounds/drugs, and production of short-chain fatty
acids (SCFAs) and polyamines.
14,25,26
Factors that Can Alter the GIT
Microflora
Many factors can harm the beneficial
members of the GIT flora, including antibiotic use,
psychological and physical stress, radiation, al-
tered GIT peristalsis, and dietary changes. This
review will focus exclusively on the interactions
of antibiotics, stress, and diet with the gut flora.
Page 182 Alternative Medicine Review
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Intestinal Dysbiosis Review
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Table 1a. The Effects of Some Selected Antibiotics on GIT Microflora
Agent
Ampicillin
Ampicillin/
Sulbactam
Amoxicillin
Amoxicillin/
clavulanic acid
Azlocillin
Aztreonam
Bacampillicin
Cefaclor
Cefaloridine
Cefazolin
Cefbuperazone
Cefixime
Cefmenoxime
Entero-
bacteria
↓↓
↓
↓
−
↓
↓↓
−
−
−
−
↓↓
↓↓
↓
Entero-
cocci
↓↓
↓
↓
−
↓
↑
−
−
−
−
↓
↓
−
Anaerobic
bacteria
↓↓
↓
↓
−
↓
−
↓
−
−
−
↓↓
↓↓
−
Overgrowth
of resistant
strains
+
+
+
+
+
+
−
+
−
+
−
+
+
Days to
normalization
of flora (post-
administration)
not stated
14
not stated
not stated
29
not stated
14
29
not stated
7
not stated
29
not stated
29
28
14
not stated
Other
∇in Lactobacilli
and Bifidus; ↑ in
Candida; ∇
production of
SCFAs
29,36,48
∇ in Lactobacilli
and Bifidus
29,48
↑ in Candida
29
∇ in Lactobacilli
29
No significant
change in
Lactobacilli,
Bifidus or
yeasts
29,48
∇ in Bifidus;
↑ in C. difficile
29
∇ in Lactobacilli
and Bifidus
29
∇ in Bifidus; ↑ in
C. difficile
29
∇ in Lactobacilli
and Bifidus;↑ in
Candida and
Clostridia
29
Impact on
An overview of some of the research investigating the effects of selected antibiotics on the GIT microflora. ↓↓ = strong
suppression (> 4 log 10 CFU/g feces); ↓ = mild to moderate suppression (2-4 log 10 CFU/g feces); ↑= increase in number of
organisms during therapy; - = no significant change; ∇= decrease; + = positive result; Bifidus= Bifidobacterium spp.
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Table 1b. The Effects of Some Selected Antibiotics on GIT Microflora
Agent
Cefoperazone
Cefotaxime
Cefotetan
Cefotiam
Cefoxitin
Ceftazadime
Ceftizoxime
Ceftriaxone
Cephradine
Cephrocile
Entero-
bacteria
↓↓
↓
↓
↓
↓
↓
↓
↓↓
−
↑
Entero-
cocci
↓↓
↓
↑
−
↑
−
−
↓↓
−
↓
Anaerobic
bacteria
↓
−
↓
−
↓
−
−
↓
−
−
Overgrowth
of resistant
strains
+
−
+
+
+
−
+
+
−
+
Days to
normalization
of flora (post-
administration)
not stated
not stated
29
not stated
not stated
not stated
not stated
not stated
28
not stated
4
Other
∇ in Lactobacilli
and Bifidus;↑ in
C. difficile and
Candida; 70% of
drug excreted in
bile
29,48,49
∇ in Lactobacilli;
↑ in C. difficile
29
↑ in Candida and
Pseudomonas; ∇
in Lactobacilli
29
∇ in Lactobacilli
and Bifidus; ↑ in
C. difficile and
Candida
29,48
∇ in Lactobacilli
29
No effect on
Lactobacilli; ↑ in
Citrobacter spp.
and Proteus
spp.
29
∇ in Bifidus; ↑ in
Candida; 30% of
drug excreted in
bile
29,49
No ↑ in yeast
29
↑ in C. difficile
29
Impact on
An overview of some of the research investigating the effects of selected antibiotics on the GIT microflora. ↓↓ = strong
suppression (> 4 log 10 CFU/g feces); ↓ = mild to moderate suppression (2-4 log 10 CFU/g feces); ↑= increase in number of
organisms during therapy; - = no significant change; ∇= decrease; + = positive result; Bifidus= Bifidobacterium spp.
Page 184 Alternative Medicine Review
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Table 1c. The Effects of Some Selected Antibiotics on GIT Microflora
Agent
Ciprofloxacin
Clindamycin
Doxycycline
Enoxacin
Erythromycin
Imipenem/
cilastatin
Lomefloxacin
Metronidazole
Moxalactam
Norfloxacin
Ofloxacin
Entero-
bacteria
↓↓
−
↓
↓↓
↓
↓↓
↓↓
−
↓↓
↓↓
↓↓
Entero-
cocci
↓↓
↑
↓
−
↓
↓↓
−
−
↑
−
↓
Anaerobic
bacteria
↓
↓↓
−
−
↓
↓↓
−
−
↓↓
−
−
Overgrowth
of resistant
strains
−
+
+
−
+
−
−
−
+
−
−
Days to
normalization
of flora (post-
administration)
7
14
not stated
14
not stated
14
21
29
not stated
14
14
29
Other
↑ in yeast
colonization; no
effect on Bifidus
or Clostridia
29,50
10% of drug
excreted in bile;
∇ production of
SCFAs; ∇ in
Bifidus and
Lactobacilli
29,36,48,49
No effect on
SCFA
production
29,36
↑ in Candida
29
No significant
change in
Lactobacilli or
Bifidus;↑ in yeast
colonization;
∇ production of
SCFAs
29,36,48
∇ in Lactobacilli
and Bifidus
29
No significant
change in
Lactobacilli,
yeasts, Bifidus, or
SCFA
production
29,36,48
∇ in Lactobacilli
and Bifidus;↑ in
Candida and
C. difficile
29,48
∇ in Lactobacilli
and Bifidus;↑ in
Candida
29
Impact on
An overview of some of the research investigating the effects of selected antibiotics on the GIT microflora. ↓↓ = strong
suppression (> 4 log 10 CFU/g feces); ↓ = mild to moderate suppression (2-4 log 10 CFU/g feces); ↑= increase in number of
organisms during therapy; - = no significant change; ∇= decrease; + = positive result; Bifidus= Bifidobacterium spp.
Alternative Medicine Review
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The Impact of Antibiotics on GIT
Microflora
Antibiotic use is the most common and
significant cause of major alterations in normal
GIT microbiota.
27
The potential for an
antimicrobial agent to influence gut microflora is
related to its spectrum of activity,
27
pharmacokinetics, dosage,
28
and length of
administration.
29
Regarding the spectrum of
activity, an antimicrobial agent active against both
gram-positive and -negative organisms will have
a greater impact on the intestinal flora.
27
Table 1d. The Effects of Some Selected Antibiotics on GIT Microflora
Agent
Pefloxacin
Phenoxymethyl-
penicillin
Piperacillin
Pivampicillin
Pivmecillinam
Talampicillin
Temocillin
Tetracycline
Ticarcillin/
Clavulanic acid
Tinidazole
Entero-
bacteria
↓↓
−
↓
−
↓↓
↑
↓↓
−
↓
−
Entero-
cocci
−
−
↓
−
↑
−
−
−
↑
−
Anaerobic
bacteria
−
−
↓
−
↓
−
−
−
−
↓
−
Overgrowth
of resistant
strains
−
−
−
+
+
+
−
+
−
−
Days to
normalization
of flora (post-
administration)
not stated
14
not stated
29
not stated
not stated
not stated
29
not stated
29
not stated
not stated
not stated
Other
No effect on
Candida
29
No significant
change in Bifidus;
larger doses ∇
Lactobacilli
29,48,51
↑ in Candida;
no change in
Bifidus or
Lactobacilli
29,48,52
∇ in Lactobacilli
and Bifidus
29,48
↑ in Candida; ∇ in
Bifidus and
Lactobacilli
29,48
∇ in Lactobacilli
and Bifidus
29
No significant
change in Bifidus,
Lactobacilli, or
SCFAs
29,48,53
Impact on
An overview of some of the research investigating the effects of selected antibiotics on the GIT microflora. ↓↓ = strong
suppression (> 4 log 10 CFU/g feces); ↓ = mild to moderate suppression (2-4 log 10 CFU/g feces); ↑= increase in number of
organisms during therapy; - = no significant change; ∇= decrease; + = positive result; Bifidus= Bifidobacterium spp.
Page 186 Alternative Medicine Review
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In terms of pharmacokinetics, the rate of
intestinal absorption plays a fundamental role.
Also important is whether the drug is excreted in
its active form in bile or saliva. Both of these phar-
macokinetic factors determine the drug’s ultimate
concentration in the intestinal lumen and, hence,
the severity of the microfloral alteration.
27
In gen-
eral, oral antimicrobials well absorbed in the small
intestine will have minor impact on the colonic
flora, whereas agents that are poorly absorbed can
cause significant changes. Parenteral administra-
tion of antimicrobial agents is not free from these
consequences, as some of these agents can be se-
creted in their active forms in bile, saliva, or from
the intestinal mucosa, and result in considerable
alterations in the colonic flora.
30
The dosage and length of administration
of an antibiotic will also determine the magnitude
of impact on the intestinal flora. In general, the
greater the dosage and length of administration,
the larger the impact on the microflora.
29
Tables
1a-1d provide an overview of research investigat-
ing the effects of specific antibiotics on GIT mi-
croflora. In general, the trials were conducted on
healthy humans and involved only a single course
of antibiotics. It is possible microfloral alterations
induced by a particular antibiotic might be more
severe in individuals with compromised health or
who have been subjected to multiple courses of
antibiotics.
Recent epidemiological research has
shown that individuals who had taken only one
course of antibiotics had significantly lower serum
concentrations of enterolactone up to 16 months
post-antibiotic use compared to individuals who
had remained antibiotic-free during the same time
period (p<0.05). As serum concentrations of
enterolactone are dependent on colonic conversion
of plant lignans to enterolactone by the intestinal
microflora (via beta-glycosidation), this study
suggests infrequent antibiotic use has much longer-
lasting effects on the microflora and its metabolic
activities than was previously believed.
31
This
negative association between serum enterolactone
levels and antibiotic use has clinical importance
due to recent studies showing correlations between
high serum enterolactone concentrations and
protection from cardiovascular mortality
32
and
breast cancer.
33
If an antimicrobial agent severely impacts
the microflora, negative repercussions on host
health can result, and include:
• Overgrowth of already-present micro-
organisms, such as fungi or Clostridium difficile.
34
Overgrowth of these organisms is a frequent cause
of antibiotic-associated diarrhea, and overgrowth
of C. difficile can develop into a severe life-threat-
ening infection.
35
• Decreased production of SCFAs, which
can result in electrolyte imbalances and diarrhea.
36
Short-chain fatty acids play a vital role in electro-
lyte and water absorption in the colon.
37
Reduced
production of SCFAs post-antibiotic use may be a
causative factor in antibiotic-associated diarrhea.
38
Short-chain fatty acids also contribute to host
health in other ways, such as improving colonic
and hepatic blood flow,
39
increasing the solubility
and absorption of calcium,
40
increasing the absorp-
tive capacity of the small intestine,
41
and main-
taining colonic mucosal integrity.
42
• Increased susceptibility to intestinal
pathogens due to the decrease in colonization re-
sistance.
43
A decrease in colonization resistance
after antibiotic administration has been observed
in animal models. Such experiments have shown
that disruption of normal microflora decreases the
number of pathogens necessary to cause an infec-
tion and lengthens the time of infection.
44
• Decreased therapeutic effect of some
medicinal herbs and phytoestrogen-rich foods.
31
The activity of many medicinal herbs depends on
bacterial enzymatic metabolism in the colon. Of
the many enzymes produced by intestinal flora,
bacterial beta-glycosidases probably play the most
significant role, as many active herbal constitu-
ents are glycosides and are inert until the active
aglycone is released via enzymatic hydrolysis.
45
Herbs such as willow bark (Salix spp.), senna
(Cassia senna), rhubarb (Rheum palmatum),
devil’s claw (Harpagophytum procumbens), soy
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(Glycine max), and red clover (Trifolium pratense)
would be essentially inactive without this colonic me-
tabolism.
45,46
Based on the results of the above-de-
scribed epidemiological study,
31
it can be inferred
that antibiotic use interferes with microbial beta-
glycosidation in the GIT for a considerable period
post-antibiotic administration, which could signifi-
cantly impact the efficacy of many phytotherapeutic
agents prescribed post-antibiotic use.
Hence, antimicrobial agents should be
used sparingly and selected carefully in order to
minimize the impact on GIT microflora.
47
The Effect of Stress on GIT
Microflora
To determine whether psychological stress
results in an altered gas-
trointestinal environment,
Bailey and Coe investigated
changes in indigenous GIT
microflora in primates after
maternal separation. GIT mi-
croflora was evaluated in 20
infant rhesus macaques ages
6-9 months who were sepa-
rated from their mothers for
the first time. All infant mon-
keys were found to have typi-
cal fecal bacterial concentra-
tions at baseline. A brief in-
crease in Lactobacilli shed-
ding on the first day post-
separation (p<0.05) was fol-
lowed by a significant decrease in the concentra-
tion of Lactobacilli in the feces (p<0.001). An in-
verse relationship was also found between the fe-
cal concentration of shed pathogens (Shigella spp.
and Campylobacter spp.) and shed Lactobacilli
(p= 0.07). The study demonstrates that psycho-
logical stress can alter the integrity of indigenous
microflora for several days.
54
Other authors have also theorized the Lac-
tobacilli population responds to stress-induced
changes in GIT physiology, such as inhibition of
gastric acid release,
55
alterations in GIT motility,
56
or increased duodenal bicarbonate production.
57
These changes may result in an intestinal environ-
ment less conducive to Lactobacilli survival, adher-
ence, and replication. Alterations in GIT milieu may
lead to detachment of Lactobacilli from the intesti-
nal epithelium and subsequent passage through the
GIT, thus resulting in decreased numbers of repli-
cating Lactobacilli. This would explain the increased
shedding of Lactobacilli found on the first day of
stress, followed by a dramatic decrease in numbers
of Lactobacilli over the next six days.
54
The effects of psychological stress on the
intestinal environment have been studied in Soviet
cosmonauts. In general, it was found that on return
from space flight there was a decrease in fecal
Bifidobacteria and Lactobacillus organisms (Table
2). These changes were attributed primarily to stress,
although a diet low in fiber may also have contrib-
uted.
58
The change in microflora observed by
Lizko led to a subsequent decline in colonization
resistance, which in turn resulted in increased num-
bers of potentially pathogenic organisms. It has
been found that exposure to psychological stress
results in a significant reduction in the production
of mucin and a decreased presence of acidic mu-
copolysaccharides on the mucosal surface.
58
Since
both mucin and acidic mucopolysaccharides are
important for inhibiting adherence of pathogenic
organisms to the gut mucosa, a decrease in either
contributes significantly to successful coloniza-
tion by pathogenic organisms.
59
Table 2. Stress-associated Changes to GIT Microflora
During preparation
After short flight
After long flight
L. acidophilus
4.0
1.7
2.9
L. casei
3.5
0
0
L. plantarum
2.6
0.5
0
Changes in the Lactobacillus fecal flora in Soviet Cosmonauts (log/mL).
58
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Lizko states that exposure to stress results
in decreased production of immunoglobulin A
(IgA). As IgA plays a vital role in the defense
against pathogenic organisms by inhibiting bac-
terial adherence and promoting their elimination
from the GIT, Lizko postulates that any decrease
in IgA secretion would most likely increase intes-
tinal colonization by potentially pathogenic
microorganisms (PPMs).
58
A 1997 study assessed the effects of
psychosocial stress on mucosal immunity,
specifically the effect of emotional stress on secretory
IgA (sIgA) levels.
60
The study was conducted on
children ages 8-12 years (mean age 9.4 years). Ninety
children were included in the trial – half of whom
had a history of recurrent colds and flu, while the
other half were healthy controls. The results
demonstrated that stressful life events correlated with
a decreased salivary ratio of sIgA to albumin. The
ratio of sIgA to albumin controls for serum leakage
of sIgA and is thought to give a clearer indication of
mucosal immunity than total sIgA concentration. This
result provides additional evidence of the likelihood
of stress effectively decreasing mucosal immunity
and, thus, diminishing intestinal colonization
resistance.
Other studies on college students have found
sIgA concentrations decrease during or shortly after
examinations.
61
Salivary concentrations of sIgA are
inversely associated with norepinephrine concentra-
tions, suggesting sympathetic nervous system acti-
vation suppresses the production and/or release of
sIgA.
60
Thus, frequent suppression of mucosal im-
munity by the sympathetic nervous system during
stressful experiences could increase colonization of
the intestinal mucosa by PPMs.
Holdeman et al studied factors that affect
human fecal flora. They noted a 20-30 percent rise
in the proportion of Bacteroides fragilis subsp.
thetaiotaomicron in the feces of individuals in re-
sponse to anger or fearful situations. When these situ-
ations were resolved, the concentration of these or-
ganisms in the feces decreased to normal levels.
62
This effect may be mediated via epinephrine, which
has been shown to stimulate both intestinal motility
and bile flow. As growth of B. fragilis subsp.
thetaiotaomicron is enhanced by bile, this may partly
explain the increased numbers of organisms in re-
sponse to increased epinephrine release.
63
In vitro experiments conducted by Ernst and
Lyte have demonstrated that several neurochemicals
have the ability to directly enhance the growth of
PPMs. The influence of the catecholamines norepi-
nephrine, epinephrine, dopamine, and dopa were
assessed on two strains of Enterobacteriaceae –
Yersinia enterocolitica and Escherichia coli, and one
strain of Pseudomonadaceae – Pseudomonas
aeruginosa.
64
All three bacterial species are poten-
tial pathogens, with Y. enterocolitica
65
and E. coli
66
involved in GIT infections and P. aeruginosa in gas-
trointestinal, respiratory, and urinary tract infections.
67
The concentrations of catecholamines used in the ex-
periment were equivalent to those found in plasma.
The addition of norepinephrine, epinephrine, dopa-
mine, and dopa to the cultures of E. coli resulted in
increased growth when compared to non-catechola-
mine-supplemented control cultures. However, the
largest increase in growth was observed with the
addition of norepinephrine. Norepinephrine caused
a large increase in growth of Y. enterocolitica, while
both dopa and dopamine produced only small, but
significant, increases in growth. Epinephrine dem-
onstrated no effect. Norepinephrine also markedly
increased the growth of P. aeruginosa, while the other
catecholamines appeared to have no effect on this
organism.
64
In vitro experiments performed by Lyte et
al showed exposure of enterotoxigenic and
enterohemorrhagic strains of E. coli to norepineph-
rine resulted in increased growth and the expression
of virulence factors, such as the K99 pilus adhesin,
which is involved in the attachment and penetration
of the bacterium into the host’s intestinal mucosa.
Growth of the enterohemorrhagic E. coli was also
increased, as was its production of Shiga-like toxin-
I and Shiga-like toxin-II. The capability of norepi-
nephrine to enhance both bacterial virulence-associ-
ated factors and growth was shown to be non-nutri-
tional in nature – in other words, the bacteria did not
use norepinephrine as a food; rather, the effect was
via an unknown mechanism.
68
Additional experiments by Lyte et al dem-
onstrated that upon exposure to norepinephrine, E.
coli produces a growth hormone known as an
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“autoinducer of growth.”
69
This autoinducer showed
a high degree of cross-species activity with other
gram-negative bacteria, resulting in increased growth
of other organisms. It was later found to stimulate
10- to 10
4
-fold increases in the growth of 12 of 15
gram-negative microorganisms tested.
70
Exposure to stress has been documented
to result in dramatic and sustained increases in
catecholamine levels. This high concentration of
catecholamines, and especially norepinephrine,
may result in increased growth of PPMs in the
intestines.
61
The GIT has abundant noradrenergic
innervation and a high amount of norepinephrine
is present throughout.
71
Studies conducted by
Eisenhofer et al showed 45-50 percent of the total
body production of norepinephrine occurs in the
mesenteric organs.
72,73
Lyte suggests spillover of
norepinephrine into the lumen of the intestinal tract
undoubtedly occurs due to the concentration gra-
dient present within the mesenteric organs.
74
Thus,
there would be no requirement for an active trans-
port system. This spillover effect has previously
been demonstrated for serotonin following its re-
lease from gut enterochromaffin cells.
75
As such,
the GIT represents an area in which neuroendo-
crine hormones like norepinephrine coexist with
indigenous microflora.
74
Thus far, catecholamines
have not been found to induce the growth of gram-
positive bacteria.
70
The effect of norepinephrine on gut flora
was recently demonstrated in a murine model. The
release of norepinephrine into the systemic circula-
tion, caused by neurotoxin-induced noradrenergic
neuron trauma, resulted in increased growth of gram-
negative bacteria within the GIT. The total gram-
negative population increased by 3 log units within
the cecal wall and 5 log units within the cecal con-
tents inside a 24-hour time period. The predominant
species of gram-negative bacteria identified was E.
coli.
74
To summarize, stress can induce significant
alterations in GIT microflora, including a significant
decrease in beneficial bacteria such as Lactobacilli
and Bifidobacteria and an increase in PPMs such as
E. coli. These changes may be caused by the growth-
enhancing effects of norepinephrine on gram-nega-
tive microorganisms or by stress-induced changes
to GIT motility and secretions.
Diet and Intestinal Microflora
The composition of the diet has been
shown to have a significant impact on the content
and metabolic activities of the human fecal flora.
20
Some diets promote the growth of beneficial
microorganisms, while others promote micro-
floral activity that can be harmful to the host.
Sulfates
Sulfur compounds, including sulfate and
sulfite, have been shown to increase the growth
of PPMs or increase production of potentially
harmful bacterial products in the GIT. In the colon
is a specialized class of gram-negative anaerobes
known as sulfate-reducing bacteria (SRB). SRB
include species belonging to the genera
Desulfotomaculum, Desulfovibrio, Desulfo-
bulbus, Desulfobacter, and Desulfomonas.
76
The
principal genus, however, is Desulfovibrio, which
accounts for 64-81 percent of all human colonic
SRB.
Sulfate-reducing bacteria utilize a process
termed “dissimilatory sulfate reduction” to reduce
sulfite and sulfate to sulfide.
4
The consequence of
this process is the production of potentially toxic
hydrogen sulfide, which can contribute to abdomi-
nal gas-distension.
76
Hydrogen sulfide can also
damage colonic mucosa by inhibiting the oxida-
tion of butyric acid, the primary fuel for
enterocytes. Butyrate oxidation is essential for
absorption of ions, mucus synthesis, and lipid syn-
thesis for colonocyte membranes.
77
This inhibi-
tion of butyrate oxidation is characteristic of the
defect observed in ulcerative colitis and leads to
intracellular energy deficiency, as well as disrup-
tion of essential activities.
4
Sulfide has also been
shown to cause a substantial increase in mucosal
permeability, presumably due to the breakdown
of the polymeric gel structure of mucin through
the cleavage of disulfide bonds.
4
Sulfate-reducing bacteria are not present
in all individuals and there appears to be consid-
erable variation in SRB concentrations depend-
ing on geographical location, a variation hypoth-
esized to be connected to dietary differences. Sul-
fate-reducing bacteria directly compete with
methanogenic bacteria (MB) for vital substrates,
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such as hydrogen and acetate. In fact,
methanogenesis and sulfate reduction appear to be
mutually exclusive in the colon. In the presence of
sufficient amounts of sulfate, SRB have been shown
to outcompete MB for both hydrogen and acetate;
whereas, under conditions of sulfate limitation the
reverse occurs.
78
The amount of dietary sulfate that
reaches the colon appears to be the primary factor in
determining the growth of SRB. On the other hand,
endogenous sources of sulfate (e.g., sulfated glyco-
proteins, chondroitin sulfate) appear to have little
impact on SRB levels.
79
Sources of dietary sulfate include preserva-
tives, dried fruits (if treated with sulfur dioxide), de-
hydrated vegetables, shellfish (fresh or frozen),
80
packaged fruit juices, baked goods,
81
white bread,
and the majority of alcoholic beverages.
6
It also ap-
pears probable that ingestion of foods rich in sulfur-
containing amino acids encourages both the growth
of SRB and the production of sulfide in the large
bowel.
4
Major amounts of sulfur-containing amino
acids are found in cow’s milk, cheese, eggs, meat,
and cruciferous vegetables. Consumption of large
amounts of these foods may significantly increase
sulfide production in the colon.
77
Research conducted
in the 1960s found elimination of milk, cheese, and
eggs from the diet of ulcerative colitis sufferers re-
sulted in substantial therapeutic benefit, suggesting
that reducing the intake of sulfur-containing amino
acids decreases colonic production of sulfide.
82
High Protein Diet
Consumption of a high-protein diet can also
increase the production of potentially harmful bac-
terial metabolites. It has been estimated that in indi-
viduals consuming a typical Western diet (contain-
ing ~ 100 g protein/day) as much as 12 g of dietary
protein per day can escape digestion in the upper
GIT and reach the colon.
83,84
This is in addition to
host-derived proteins, such as pancreatic and intesti-
nal enzymes, mucins, glycoproteins, and sloughed
epithelial cells.
5
Undigested protein is fermented by
the colonic microflora with the resultant end-prod-
ucts of SCFAs, branched-chain fatty acids (e.g.,
isovalerate, isobutyrate, and 2-methylbutyrate), and
potentially harmful metabolites – ammonia, amines,
phenols, sulfide, and indoles.
5,77,85
Ammonia has been shown to alter the
morphology and intermediate metabolism, in-
crease DNA synthesis, and reduce the lifespan of
mucosal cells.
6
It is also considered to be more
toxic to healthy mucosal cells than transformed
cells and, thus, may potentially select for neoplas-
tic growth.
5
Ammonia production and accumula-
tion is also involved in the pathogenesis of portal-
systemic encephalopathy.
86
Indoles, phenols, and
amines have been implicated in schizophrenia
87
and migraines.
88
Indoles and phenols are also
thought to act as co-carcinogens
5
and may play a
role in the etiology of bladder and bowel cancer.
83
The production of these potentially toxic
compounds has been found to be directly related
to dietary protein intake,
6
a reduction of which can
decrease production of harmful by-products.
89
The
production of these potentially harmful by-prod-
ucts can also be attenuated by the consumption of
diets high in fiber
89
and/or indigestible starch (both
of which reduce intestinal pH).
83
Diets High In Animal Protein
In comparison to diets high in overall pro-
tein, diets especially high in animal protein have
specific effects on intestinal microflora. While not
appearing to dramatically alter the bacterial com-
position of the flora compared to control diets,
ingestion of large amounts of animal protein does
increase the activity of certain bacterial enzymes,
90
such as beta-glucuronidase, azoreductase,
nitroreductase, and 7-alpha-hydroxysteroid
dehydroxylase, in animals
91,92
and humans.
93
This
can have important ramifications to the host, as
any increase in activity of these enzymes will re-
sult in increased release of potentially toxic me-
tabolites in the bowel. For instance, bacterial
azoreductase can reduce the azo bond found in
many synthetic food-coloring agents, releasing
substituted phenyl and napthyl amines, some of
which are known to be potent carcinogens.
90
An-
other example is the action of the bacterial beta-
glucuronidases. Many xenobiotics are processed
in the liver by a series of reactions that result in
glucuronic acid conjugation. These glucuronides
are then passed, via the biliary system, to the in-
testines. When these compounds reach the colon
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they can be hydrolyzed by beta-glucuronidase pro-
duced by the microflora, resulting in the release
of the original xenobiotic, which then re-enters
enterohepatic circulation and is recirculated sev-
eral times before eventually being eliminated
through the feces. If the original xenobiotic is
mutagenic, carcinogenic, or otherwise toxic, this
process can be detrimental to the host.
94
The nu-
trient calcium D-glucarate exerts its potentially
beneficial effects by inhibiting beta-glucuronidase.
High Simple Sugar/Refined Carbohydrate
Diet
Kruis et al observed that diets high in simple
sugars slow bowel transit time and increase fermen-
tative bacterial activity and fecal concentrations of
total and secondary bile acids in the colon.
95
A con-
sequence of slower bowel transit time may be an in-
creased exposure to potentially toxic bowel con-
tents.
96
The mechanism by which high-sugar diets
increase bowel transit time is not yet known.
95
Table 3. The Effects of Various Diets on GIT Microflora
Microorganisms
Total anaerob es
Total aerob es
Bacteroides spp.
Enterococci
Bifidobact eria
Lactobacilli
Clostridia
Yeasts
American/
Mixed
Western Diet
10.2
a
7.5
a
9.8
a
5.5
a
10.0
a
7.3
a
4.4
a
–
American/
Seventh D ay
Adventist
Vegetarian D iet
–
–
11.7
b
6.5
b
8.1
b
10.0
b
8.6
b
–
English/
Mixed
Western Diet
10.1
a
8.0
a
9.8
a
9.7
a
Ψ
5.8
a
5.7
a
Ψ
9.8
a
9.9
a
Ψ
6.5
a
6.0
a
Ψ
5.0
a
4.4
a
1.3
a
Ψ
Japanese/
Japanese Diet
9.9
a
11.4
b
9.4
a
9.8
b
9.4
a
10.1
b
8.1
a
8.4
b
9.7
a
8.2
b
7.4
a
5.7
b
5.1
a
9.7
b
–
Japanese/
Mixed
Western Diet
11.5
b
9.6
b
11.1
b
8.4
b
9.5
b
4.0
b
9.5
b
–
Ugandan/
Vegetarian D iet
9.3
a
8.2
a
8.2
a
8.2
a
Ψ
7.0
a
7.0
a
Ψ
9.3
a
9.3
a
Ψ
7.2
a
7.2
a
Ψ
4.6
a
4.0
a
3.1
a
Ψ
Indian/
Vegetarian
Diet
9.7
a
8.2
a
9.2
a
7.3
a
9.6
a
7.6
a
5.0
a
–
Effect of ‘Western’ vs. vegetarian or high carbohydrate diets on the h uman fecal flora (- = no data ; Ψ = a significant difference
between gro ups;
a
= log10 mean c ount/g wet weight of f eces;
b
= log10 mean c ount/g dry weight of f eces.)
From: Salminen S, Isolauri E, Onnela T. Gut flora in normal and alter ed states. Chemother 1995;41 (suppl 1):5-15.
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The increase in colonic fermentative ac-
tivity noted in the Kruis study may not be directly
associated with changes in microflora composi-
tion, but rather be caused by direct exposure of
the colon to simple sugars. Refined sugars are
metabolized quickly in the ascending colon;
whereas, high-fiber foods, containing substantial
amounts of insoluble fiber, are metabolized more
slowly, releasing fermentation end-products (e.g.,
hydrogen gas and SCFAs) more gradually.
97
It is possible, however, that high sugar
intake does cause alterations in the microflora. It
has been observed that high sugar intakes increase
bile output. Some species of intestinal bacteria
utilize bile acids as food and, hence, any increase
in their production will result in a competitive
advantage for this group of bacteria.
63
The changes
observed in bacterial fermentation in this study
may or may not be related to changes in the spe-
cies composition of the microflora. Since this was
not adequately assessed in this study, the signifi-
cance of these results requires further investiga-
tion.
Other researchers have postulated that
when intake of dietary carbohydrates is
insufficient, increased fermentation of the
protective layer of mucin may occur due to the
limited quantity of carbon sources reaching the
colon. This may compromise mucosal defense and
lead to direct contact between colonic cells and
bacterial products and antigens. This, in turn, may
lead to inflammation and increased mucosal
permeability. Such a situation may encourage the
growth of potentially pathogenic bacteria and
perpetuate the inflammatory response.
98,99
This
theory, however, is yet to be supported by direct
evidence.
General Dietary Factors
The effect of the overall diet on the
composition and metabolic activities of GIT
microflora has been the subject of research since
the late 1960s. It was initially believed that
changing the content of the diet (in terms of meat,
fat, carbohydrate, and fiber content) would
dramatically alter the bacterial species
composition of the colonic flora. However, when
the diets of various population groups consuming
different diets were analyzed, the changes noted
were not dramatic.
93
Only minor changes were
noted among the groups, although these changes
were considered to be caused by differences in
diet.
100
Table 3 outlines results of several studies
comparing the fecal flora of individuals consuming
the typical Western diet (high in fat and meat) to
that of individuals eating vegetarian and/or high
complex-carbohydrate diets.
In general, it appears populations consum-
ing the typical Western diet have more fecal
anaerobic bacteria, less Enterococci, and fewer
yeasts than populations consuming a vegetarian
or high complex-carbohydrate diet. Although one
study found a significant difference between a
mixed Western diet and a vegetarian diet, overall
there appear to be relatively few trends.
In spite of these findings, Gorbach argues
that due to the sheer number of bacteria present in
the stool (approximately 10
11
viable bacteria/g) and
the enormous variety (around 500 anaerobic spe-
cies, not to mention aerobic and facultative spe-
cies), the classical method of quantifying flora is,
at best, a crude approximation. Thus, these meth-
ods may be unable to differentiate changes due to
variations in diet.
90
In an attempt to create a more sensitive
method to detect changes in human microflora,
Peltonen et al utilized gas-liquid chromatography
(GLC) to analyze profiles of bacterial cellular fatty
acids. This method measures bacterial cellular
fatty acids present in the stool that accumulate to
form a GLC fatty acid profile, with each peak in
the profile representing relative amounts of a par-
ticular fatty acid in the stool. Similar bacterial
compositions should yield similar fatty acid pro-
files, while distinctions can be quantified by the
extent to which profiles differ from each other.
The researchers utilized this technique to analyze
the effects of a vegan, raw food diet on the intes-
tinal microflora. The one-month diet consisted of
a variety of sprouts, fermented vegetables, fruits,
seaweed, nuts, and seeds. Differences in the GLC
profile between the test and control groups were
statistically significant (p<0.05), as were the dif-
ferences in test group GLC profiles before and
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during the diet. No significant changes in the fe-
cal flora could be detected in either group using
the traditional isolation, identification, and enu-
meration bacteriological. While GLC may be a
more sensitive method to determine changes in
fecal flora, it cannot identify particular compo-
nents of the flora.
101
Newer techniques such as fluorescence in
situ hybridization (FISH) or polymerase chain re-
action assays coupled with denaturing gel elec-
trophoresis
102
are more sensitive to minor alter-
ations in microflora and allow for bacterial iden-
tification that would otherwise be impossible to
culture.
103
The use of these modern techniques in
future diet studies will shed more light on this
contentious area. Interestingly, recent research
utilizing the FISH technique has indicated the
majority of bacteria in the colon are not culturable
and have yet to be described. This finding sug-
gests how little is actually known about the com-
position of GIT microflora.
104
In summary, research has shown that con-
sumption of foods rich in sulfur compounds, high
in protein, and/or high in meat may produce detri-
mental effects on the host. These changes may be
mediated through alterations in composition of the
microflora or through increased production of
bacterial metabolites. The impact of a high refined-
carbohydrate intake on the microflora has yet to
be clearly elucidated. Similarly, the relationship
between the overall diet and composition of the
microflora awaits further clarification using mod-
ern microbiological techniques.
Conclusion
Alterations in bowel flora and its activities
are now believed to be contributing factors to
many chronic degenerative diseases. Ample
evidence in the literature exists to confirm
dysbiosis as an important clinical entity. It is
therefore imperative to know what factors play a
causative role in this increasingly common
condition. Antibiotics, psychological and physical
stress, and dietary factors contribute to intestinal
dysbiosis. Armed with knowledge of the factors
that contribute to dysbiosis, clinicians are better
equipped to deal with the causes of this condition.
Diets can be altered, the effects of stress attenuated,
and antibiotics used sparingly, in order to minimize
the effects of these factors on intestinal microflora.
If the causes of dysbiosis can be eliminated or at
least attenuated, then treatments aimed at
manipulating the microflora may become more
successful and longer-lasting in effect.
Future research using molecular microbi-
ology techniques will provide definitive answers
to currently unanswered questions regarding the
effects of various factors on the GIT microflora.
Older studies that evaluated the effects of differ-
ent dietary regimes on the GIT flora should be re-
conducted utilizing modern microbiology tech-
niques. These techniques will also provide accu-
rate information regarding how specific drugs or
herbs affect microbial populations in the GIT. This
information will allow far greater precision in both
dietary and herbal prescribing.
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