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Volume 9-2 final

Intestinal Dysbiosis Review
The Causes of Intestinal Dysbiosis:
Jason A. Hawrelak, BNat (Hons), PhD Candidate and
Stephen P. Myers, PhD, BMed, ND
role in both excluding these macromolecules and Alterations in the bowel flora and its activities
microbes from the systemic circulation and ab- are now believed to be contributing factors to
many chronic and degenerative diseases.
Irritable bowel syndrome, inflammatory bowel
posed to bacterial products – endotoxins,3 hydro- disease, rheumatoid arthritis, and ankylosing
gen sulphide,4 phenols, ammonia, and indoles5 – spondylitis have all been linked to alterations
that can have detrimental effects on both mucosal in the intestinal microflora. The intestinal
and host health.5 The presence of many of these dysbiosis hypothesis suggests a number of
toxic metabolites is directly dependent on the type factors associated with modern Western living
of fermentation that occurs in the bowel. In turn, have a detrimental impact on the microflora of
this fermentation is dependent on the type of bac- the gastrointestinal tract. Factors such as
teria present in the bowel, as well as the substrates antibiotics, psychological and physical stress,
available for fermentation. Diets high in protein6 and certain dietary components have been
and sulfate (derived primarily from food addi- found to contribute to intestinal dysbiosis. If
tives)4 have been shown to contribute greatly to these causes can be eliminated or at least
the production of these potentially toxic products.
attenuated then treatments aimed at
The production and absorption of toxic metabo- manipulating the microflora may be more
(Altern Med Rev 2004;9(2):180-197)
roots extending as far back as Hippocrates. In 400B.C. he stated that, “.death sits in the bowels.” Introduction
and “.bad digestion is the root of all evil.”8 Moremodern proponents of the bowel toxemia theory The gastrointestinal tract (GIT) is one of have included naturopath Louis Kuhne in the late the largest interfaces between the outside world nineteenth century,9 as well as naturopath Henry 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 andestimated to cover approximately 250-400 m2.
Jason A Hawrelak, BNat (Hons) – PhD Candidate in the Over a normal lifetime, approximately 60 tons of field of intestinal micro-ecology, Southern Cross food will pass through the GIT.1 Food is obviously University’s School of Natural and ComplementaryMedicine and the Australian Centre for Complementary extremely important for well-being, but its pas- sage through the GIT can also constitute a threat Correspondence address: School of Natural andComplementary Medicine, Southern Cross University, PO to health. While the GIT functions to digest and absorb nutrients, food also provides exposure to dietary antigens, viable microorganisms, and bac- Stephen P Myers, PhD, BMed, ND – Professor and Head ofthe Australian Centre for Complementary Medicine terial products. The intestinal mucosa plays a dual Page 180 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004
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Metchnikoff in the early twentieth century.11 Louis inflammatory bowel disease (IBD),16,17 as well as Kuhne proposed that excess food intake, or the more systemic conditions such as rheumatoid ar- intake of the wrong types of food, resulted in the thritis (RA)18 and ankylosing spondylitis.19 Thus, production of intestinal toxins. Fermentation of knowledge of the factors that can cause detrimen- these toxins resulted in increased growth of bac- tal changes to the microflora is becoming increas- teria within the bowel and, subsequently, disease.
He believed a predominantly vegetarian andmostly raw diet would prevent build-up of intes- The Importance of Normal GIT
tinal toxins and, hence, would prevent and even Microflora
The microflora of the gastrointestinal tract Only a few years later, Metchnikoff popu- represents an ecosystem of the highest complex- larized the idea that fermented milk products could ity.14 The microflora is believed to be composed beneficially alter the microflora of the GIT. He of over 50 genera of bacteria20 accounting for over believed many diseases, and even aging itself, 500 different species.21 The adult human GIT is were caused by putrefaction of protein in the bowel estimated to contain 1014 viable microorganisms, by intestinal bacteria. Lactic acid-producing bac- which is 10 times the number of eukaryotic cells teria were thought to inhibit the growth of putre- found within the human body.22 Some researchers factive bacteria in the intestines. Thus, yogurt con- have called this microbial population the “mi- sumption was recommended to correct this “au- crobe” organ – an organ similar in size to the liver tointoxication” and improve composition of the (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 evolved into the intestinal dysbiosis hypothesis.
The term “dysbiosis” was originally coined by Metchnikoff to describe altered pathogenic bac- in the body; thus, there are many areas of host teria in the gut.13 Dysbiosis has been defined by health that can be compromised when the micro- others as “.qualitative and quantitative changes flora is drastically altered. The GIT microflora is in the intestinal flora, their metabolic activity and involved in stimulation of the immune system, their local distribution.”14 Thus dysbiosis is a state synthesis of vitamins (B group and K), enhance- in which the microbiota produces harmful effects ment of GIT motility and function, digestion and via: (1) qualitative and quantitative changes in the nutrient absorption, inhibition of pathogens (colo- intestinal flora itself; (2) changes in their meta- nization resistance), metabolism of plant com- bolic activities; and (3) changes in their local dis- pounds/drugs, and production of short-chain fatty tribution. The dysbiosis hypothesis states that the modern diet and lifestyle, as well as the use ofantibiotics, have led to the disruption of the nor-mal intestinal microflora. These factors result in Factors that Can Alter the GIT
alterations in bacterial metabolism, as well as the Microflora
overgrowth of potentially pathogenic microorgan- isms. It is believed the growth of these bacteria in members of the GIT flora, including antibiotic use, the intestines results in the release of potentially psychological and physical stress, radiation, al- toxic products that play a role in many chronic tered GIT peristalsis, and dietary changes. This review will focus exclusively on the interactions of antibiotics, stress, and diet with the gut flora.
substantiates and clarifies the dysbiosis theory.
Altered bowel flora is now believed to play a rolein myriad disease conditions, including GIT dis-orders like irritable bowel syndrome (IBS)15 and Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004 Page 181
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Table 1a. The Effects of Some Selected Antibiotics on GIT Microflora
∇in Lactobacilli and Bifidus; ↑ in Candida; ∇ production of SCFAs29,36,48 No significant change in Lactobacilli, Bifidus or yeasts29,48 ∇ in Bifidus; ↑ in C. difficile29 ∇ in Lactobacilli and Bifidus;↑ in Candida and Clostridia29 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
∇ in Lactobacilli and Bifidus;↑ in C. difficile and Candida; 70% of drug excreted in bile29,48,49 ↑ in Candida and Pseudomonas; ∇ in Lactobacilli29 ∇ in Lactobacilli and Bifidus; ↑ in C. difficile and Candida29,48 No effect on Lactobacilli; ↑ in Citrobacter spp. and Proteus spp.29 ∇ in Bifidus; ↑ in Candida; 30% of drug excreted in bile29,49 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 ◆ Volume 9, Number 2 ◆ 2004 Page 183
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Table 1c. The Effects of Some Selected Antibiotics on GIT Microflora
↑ in yeastcolonization; no effect on Bifidus or Clostridia29,50 ∇ production of SCFAs; ∇ in Bifidus and Lactobacilli29,36,48,49 No significant change in Lactobacilli or Bifidus;↑ in yeast colonization; No significant change in Lactobacilli, yeasts, Bifidus, or SCFA production29,36,48 ∇ in Lactobacilli and Bifidus;↑ in Candida and C. difficile29,48 ∇ in Lactobacilli and Bifidus;↑ in Candida29 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 1d. The Effects of Some Selected Antibiotics on GIT Microflora
change in Bifidus; larger doses ∇ Lactobacilli29,48,51 ↑ in Candida; no change in Bifidus orLactobacilli29,48,52 ↑ in Candida; ∇ in Bifidus and Lactobacilli29,48 No significant change in Bifidus, Lactobacilli, or SCFAs29,48,53 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.
The Impact of Antibiotics on GIT
related to its spectrum of activity, 27pharmacokinetics, dosage,28 and length of Microflora
administration.29 Regarding the spectrum of activity, an antimicrobial agent active against both significant cause of major alterations in normal gram-positive and -negative organisms will have a greater impact on the intestinal flora.27 antimicrobial agent to influence gut microflora is Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004 Page 185
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In terms of pharmacokinetics, the rate of protection from cardiovascular mortality32 and intestinal absorption plays a fundamental role.
Also important is whether the drug is excreted in If an antimicrobial agent severely impacts its active form in bile or saliva. Both of these phar- the microflora, negative repercussions on host 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 organisms, such as fungi or Clostridium difficile.34 intestine will have minor impact on the colonic Overgrowth of these organisms is a frequent cause flora, whereas agents that are poorly absorbed can of antibiotic-associated diarrhea, and overgrowth cause significant changes. Parenteral administra- of C. difficile can develop into a severe life-threat- 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 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 of an antibiotic will also determine the magnitude production of SCFAs post-antibiotic use may be a of impact on the intestinal flora. In general, the causative factor in antibiotic-associated diarrhea.38 greater the dosage and length of administration, Short-chain fatty acids also contribute to host the larger the impact on the microflora.29 Tables health in other ways, such as improving colonic 1a-1d provide an overview of research investigat- and hepatic blood flow,39 increasing the solubility ing the effects of specific antibiotics on GIT mi- and absorption of calcium,40 increasing the absorp- croflora. In general, the trials were conducted on tive capacity of the small intestine,41 and main- healthy humans and involved only a single course of antibiotics. It is possible microfloral alterationsinduced by a particular antibiotic might be more • Increased susceptibility to intestinal severe in individuals with compromised health or pathogens due to the decrease in colonization re- who have been subjected to multiple courses of sistance.43 A decrease in colonization resistance after antibiotic administration has been observed in animal models. Such experiments have shown shown that individuals who had taken only one that disruption of normal microflora decreases the course of antibiotics had significantly lower serum number of pathogens necessary to cause an infec- concentrations of enterolactone up to 16 months tion and lengthens the time of infection.44 post-antibiotic use compared to individuals whohad remained antibiotic-free during the same time period (p<0.05). As serum concentrations of medicinal herbs and phytoestrogen-rich foods.31 enterolactone are dependent on colonic conversion The activity of many medicinal herbs depends on of plant lignans to enterolactone by the intestinal bacterial enzymatic metabolism in the colon. Of microflora (via beta-glycosidation), this study the many enzymes produced by intestinal flora, suggests infrequent antibiotic use has much longer- bacterial beta-glycosidases probably play the most lasting effects on the microflora and its metabolic significant role, as many active herbal constitu- activities than was previously believed.31 This ents are glycosides and are inert until the active negative association between serum enterolactone aglycone is released via enzymatic hydrolysis.45 levels and antibiotic use has clinical importance Herbs such as willow bark (Salix spp.), senna due to recent studies showing correlations between (Cassia senna), rhubarb (Rheum palmatum), high serum enterolactone concentrations and devil’s claw (Harpagophytum procumbens), soy Page 186 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004
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(Glycine max), and red clover (Trifolium pratense) These changes may result in an intestinal environ- would be essentially inactive without this colonic me- ment less conducive to Lactobacilli survival, adher- tabolism.45,46 Based on the results of the above-de- ence, and replication. Alterations in GIT milieu may scribed epidemiological study,31 it can be inferred lead to detachment of Lactobacilli from the intesti- that antibiotic use interferes with microbial beta- nal epithelium and subsequent passage through the glycosidation in the GIT for a considerable period GIT, thus resulting in decreased numbers of repli- post-antibiotic administration, which could signifi- cating Lactobacilli. This would explain the increased cantly impact the efficacy of many phytotherapeutic shedding of Lactobacilli found on the first day of agents prescribed post-antibiotic use.
stress, followed by a dramatic decrease in numbersof Lactobacilli over the next six days.54 The effects of psychological stress on the used sparingly and selected carefully in order to intestinal environment have been studied in Soviet cosmonauts. In general, it was found that on returnfrom space flight there was a decrease in fecal The Effect of Stress on GIT
Bifidobacteria and Lactobacillus organisms (Table Microflora
2). These changes were attributed primarily to stress,although a diet low in fiber may also have contrib- To determine whether psychological stress results in an altered gas-trointestinal environment,Bailey and Coe investigatedchanges in indigenous GITmicroflora in primates after Table 2. Stress-associated Changes to GIT Microflora
maternal separation. GIT mi-croflora was evaluated in 20infant rhesus macaques ages rated from their mothers forthe first time. All infant mon- cal fecal bacterial concentra-tions at baseline. A brief in- Changes in the Lactobacillus fecal flora in Soviet Cosmonauts (log/mL).58 crease in Lactobacilli shed-ding on the first day post-separation (p<0.05) was fol- lowed by a significant decrease in the concentra- Lizko led to a subsequent decline in colonization tion of Lactobacilli in the feces (p<0.001). An in- resistance, which in turn resulted in increased num- verse relationship was also found between the fe- bers of potentially pathogenic organisms. It has cal concentration of shed pathogens (Shigella spp. been found that exposure to psychological stress and Campylobacter spp.) and shed Lactobacilli results in a significant reduction in the production (p= 0.07). The study demonstrates that psycho- of mucin and a decreased presence of acidic mu- logical stress can alter the integrity of indigenous copolysaccharides on the mucosal surface.58 Since both mucin and acidic mucopolysaccharides are Other authors have also theorized the Lac- important for inhibiting adherence of pathogenic tobacilli population responds to stress-induced organisms to the gut mucosa, a decrease in either changes in GIT physiology, such as inhibition of contributes significantly to successful coloniza- gastric acid release,55 alterations in GIT motility,56 or increased duodenal bicarbonate production.57 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004 Page 187
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Lizko states that exposure to stress results explain the increased numbers of organisms in re- in decreased production of immunoglobulin A sponse to increased epinephrine release.63 (IgA). As IgA plays a vital role in the defense In vitro experiments conducted by Ernst and against pathogenic organisms by inhibiting bac- Lyte have demonstrated that several neurochemicals terial adherence and promoting their elimination have the ability to directly enhance the growth of from the GIT, Lizko postulates that any decrease PPMs. The influence of the catecholamines norepi- in IgA secretion would most likely increase intes- nephrine, epinephrine, dopamine, and dopa were tinal colonization by potentially pathogenic 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- specifically the effect of emotional stress on secretory tial pathogens, with Y. enterocolitica65 and E. coli66 IgA (sIgA) levels.60 The study was conducted on involved in GIT infections and P. aeruginosa in gas- children ages 8-12 years (mean age 9.4 years). Ninety trointestinal, respiratory, and urinary tract infections.67 children were included in the trial – half of whom The concentrations of catecholamines used in the ex- had a history of recurrent colds and flu, while the periment were equivalent to those found in plasma.
other half were healthy controls. The results The addition of norepinephrine, epinephrine, dopa- demonstrated that stressful life events correlated with mine, and dopa to the cultures of E. coli resulted in a decreased salivary ratio of sIgA to albumin. The increased growth when compared to non-catechola- ratio of sIgA to albumin controls for serum leakage mine-supplemented control cultures. However, the of sIgA and is thought to give a clearer indication of largest increase in growth was observed with the mucosal immunity than total sIgA concentration. This addition of norepinephrine. Norepinephrine caused result provides additional evidence of the likelihood a large increase in growth of Y. enterocolitica, while of stress effectively decreasing mucosal immunity both dopa and dopamine produced only small, but and, thus, diminishing intestinal colonization significant, increases in growth. Epinephrine dem- onstrated no effect. Norepinephrine also markedly Other studies on college students have found increased the growth of P. aeruginosa, while the other sIgA concentrations decrease during or shortly after catecholamines appeared to have no effect on this examinations.61 Salivary concentrations of sIgA are inversely associated with norepinephrine concentra- In vitro experiments performed by Lyte et tions, suggesting sympathetic nervous system acti- al showed exposure of enterotoxigenic and vation suppresses the production and/or release of enterohemorrhagic strains of E. coli to norepineph- sIgA.60 Thus, frequent suppression of mucosal im- rine resulted in increased growth and the expression munity by the sympathetic nervous system during of virulence factors, such as the K99 pilus adhesin, stressful experiences could increase colonization of which is involved in the attachment and penetration of the bacterium into the host’s intestinal mucosa.
Holdeman et al studied factors that affect Growth of the enterohemorrhagic E. coli was also human fecal flora. They noted a 20-30 percent rise increased, as was its production of Shiga-like toxin- in the proportion of Bacteroides fragilis subsp.
I and Shiga-like toxin-II. The capability of norepi- thetaiotaomicron in the feces of individuals in re- nephrine to enhance both bacterial virulence-associ- sponse to anger or fearful situations. When these situ- ated factors and growth was shown to be non-nutri- ations were resolved, the concentration of these or- tional in nature – in other words, the bacteria did not ganisms in the feces decreased to normal levels.62 use norepinephrine as a food; rather, the effect was This effect may be mediated via epinephrine, which has been shown to stimulate both intestinal motility Additional experiments by Lyte et al dem- and bile flow. As growth of B. fragilis subsp.
onstrated that upon exposure to norepinephrine, E. thetaiotaomicron is enhanced by bile, this may partly coli produces a growth hormone known as an Page 188 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004
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“autoinducer of growth.”69 This autoinducer showed Diet and Intestinal Microflora
a high degree of cross-species activity with other gram-negative bacteria, resulting in increased growth shown to have a significant impact on the content of other organisms. It was later found to stimulate and metabolic activities of the human fecal flora.20 10- to 104-fold increases in the growth of 12 of 15 Some diets promote the growth of beneficial microorganisms, while others promote micro- floral activity that can be harmful to the host.
to result in dramatic and sustained increases incatecholamine levels. This high concentration of Sulfates
catecholamines, and especially norepinephrine, may result in increased growth of PPMs in the sulfite, have been shown to increase the growth intestines.61 The GIT has abundant noradrenergic of PPMs or increase production of potentially innervation and a high amount of norepinephrine harmful bacterial products in the GIT. In the colon is present throughout.71 Studies conducted by is a specialized class of gram-negative anaerobes Eisenhofer et al showed 45-50 percent of the total known as sulfate-reducing bacteria (SRB). SRB body production of norepinephrine occurs in the mesenteric organs.72,73 Lyte suggests spillover of Desulfotomaculum, Desulfovibrio, Desulfo- norepinephrine into the lumen of the intestinal tract bulbus, Desulfobacter, and Desulfomonas.76 The undoubtedly occurs due to the concentration gra- principal genus, however, is Desulfovibrio, which dient present within the mesenteric organs.74 Thus, accounts for 64-81 percent of all human colonic there would be no requirement for an active trans- port system. This spillover effect has previously Sulfate-reducing bacteria utilize a process been demonstrated for serotonin following its re- termed “dissimilatory sulfate reduction” to reduce lease from gut enterochromaffin cells.75 As such, sulfite and sulfate to sulfide.4 The consequence of the GIT represents an area in which neuroendo- this process is the production of potentially toxic crine hormones like norepinephrine coexist with hydrogen sulfide, which can contribute to abdomi- indigenous microflora.74 Thus far, catecholamines nal gas-distension.76 Hydrogen sulfide can also have not been found to induce the growth of gram- damage colonic mucosa by inhibiting the oxida- tion of butyric acid, the primary fuel for The effect of norepinephrine on gut flora enterocytes. Butyrate oxidation is essential for was recently demonstrated in a murine model. The absorption of ions, mucus synthesis, and lipid syn- release of norepinephrine into the systemic circula- thesis for colonocyte membranes.77 This inhibi- tion, caused by neurotoxin-induced noradrenergic tion of butyrate oxidation is characteristic of the neuron trauma, resulted in increased growth of gram- defect observed in ulcerative colitis and leads to negative bacteria within the GIT. The total gram- intracellular energy deficiency, as well as disrup- negative population increased by 3 log units within tion of essential activities.4 Sulfide has also been the cecal wall and 5 log units within the cecal con- shown to cause a substantial increase in mucosal tents inside a 24-hour time period. The predominant permeability, presumably due to the breakdown species of gram-negative bacteria identified was E. of the polymeric gel structure of mucin through To summarize, stress can induce significant Sulfate-reducing bacteria are not present alterations in GIT microflora, including a significant in all individuals and there appears to be consid- decrease in beneficial bacteria such as Lactobacilli erable variation in SRB concentrations depend- and Bifidobacteria and an increase in PPMs such as ing on geographical location, a variation hypoth- E. coli. These changes may be caused by the growth- esized to be connected to dietary differences. Sul- enhancing effects of norepinephrine on gram-nega- fate-reducing bacteria directly compete with tive microorganisms or by stress-induced changes methanogenic bacteria (MB) for vital substrates, Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004 Page 189
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methanogenesis and sulfate reduction appear to be morphology and intermediate metabolism, in- mutually exclusive in the colon. In the presence of crease DNA synthesis, and reduce the lifespan of sufficient amounts of sulfate, SRB have been shown mucosal cells.6 It is also considered to be more to outcompete MB for both hydrogen and acetate; toxic to healthy mucosal cells than transformed whereas, under conditions of sulfate limitation the cells and, thus, may potentially select for neoplas- reverse occurs.78 The amount of dietary sulfate that tic growth.5 Ammonia production and accumula- reaches the colon appears to be the primary factor in tion is also involved in the pathogenesis of portal- determining the growth of SRB. On the other hand, systemic encephalopathy.86 Indoles, phenols, and endogenous sources of sulfate (e.g., sulfated glyco- amines have been implicated in schizophrenia87 proteins, chondroitin sulfate) appear to have little and migraines.88 Indoles and phenols are also thought to act as co-carcinogens5 and may play a Sources of dietary sulfate include preserva- role in the etiology of bladder and bowel cancer.83 tives, dried fruits (if treated with sulfur dioxide), de- The production of these potentially toxic hydrated vegetables, shellfish (fresh or frozen),80 compounds has been found to be directly related packaged fruit juices, baked goods,81 white bread, to dietary protein intake,6 a reduction of which can and the majority of alcoholic beverages.6 It also ap- decrease production of harmful by-products.89 The pears probable that ingestion of foods rich in sulfur- production of these potentially harmful by-prod- containing amino acids encourages both the growth ucts can also be attenuated by the consumption of of SRB and the production of sulfide in the large diets high in fiber89 and/or indigestible starch (both bowel.4 Major amounts of sulfur-containing amino acids are found in cow’s milk, cheese, eggs, meat,and cruciferous vegetables. Consumption of large Diets High In Animal Protein
amounts of these foods may significantly increase In comparison to diets high in overall pro- sulfide production in the colon.77 Research conducted tein, diets especially high in animal protein have in the 1960s found elimination of milk, cheese, and specific effects on intestinal microflora. While not eggs from the diet of ulcerative colitis sufferers re- appearing to dramatically alter the bacterial com- sulted in substantial therapeutic benefit, suggesting position of the flora compared to control diets, that reducing the intake of sulfur-containing amino ingestion of large amounts of animal protein does acids decreases colonic production of sulfide.82 increase the activity of certain bacterial enzymes,90such as beta-glucuronidase, azoreductase, High Protein Diet
nitroreductase, and 7-alpha-hydroxysteroid Consumption of a high-protein diet can also dehydroxylase, in animals91,92 and humans.93 This increase the production of potentially harmful bac- can have important ramifications to the host, as terial metabolites. It has been estimated that in indi- any increase in activity of these enzymes will re- viduals consuming a typical Western diet (contain- sult in increased release of potentially toxic me- ing ~ 100 g protein/day) as much as 12 g of dietary tabolites in the bowel. For instance, bacterial protein per day can escape digestion in the upper azoreductase can reduce the azo bond found in GIT and reach the colon.83,84 This is in addition to many synthetic food-coloring agents, releasing host-derived proteins, such as pancreatic and intesti- substituted phenyl and napthyl amines, some of nal enzymes, mucins, glycoproteins, and sloughed which are known to be potent carcinogens.90 An- epithelial cells.5 Undigested protein is fermented by other example is the action of the bacterial beta- the colonic microflora with the resultant end-prod- glucuronidases. Many xenobiotics are processed ucts of SCFAs, branched-chain fatty acids (e.g., in the liver by a series of reactions that result in isovalerate, isobutyrate, and 2-methylbutyrate), and glucuronic acid conjugation. These glucuronides potentially harmful metabolites – ammonia, amines, are then passed, via the biliary system, to the in- testines. When these compounds reach the colon Page 190 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004
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Table 3. The Effects of Various Diets on GIT Microflora
Effect of ‘Western’ vs. vegetarian or high carb ohy drate diets on the h uman fec al flora (- = no data ; Ψ = a significan t differenc e bet ween 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 nor mal and alter ed stat es. Che mother 1995;41 (suppl 1 ):5-15.
they can be hydrolyzed by beta-glucuronidase pro- High Simple Sugar/Refined Carbohydrate
duced by the microflora, resulting in the release of the original xenobiotic, which then re-enters Kruis et al observed that diets high in simple enterohepatic circulation and is recirculated sev- sugars slow bowel transit time and increase fermen- eral times before eventually being eliminated tative bacterial activity and fecal concentrations of through the feces. If the original xenobiotic is total and secondary bile acids in the colon.95 A con- mutagenic, carcinogenic, or otherwise toxic, this sequence of slower bowel transit time may be an in- process can be detrimental to the host.94 The nu- creased exposure to potentially toxic bowel con- trient calcium D-glucarate exerts its potentially tents.96 The mechanism by which high-sugar diets beneficial effects by inhibiting beta-glucuronidase.
increase bowel transit time is not yet known.95 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004 Page 191
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the diets of various population groups consuming tivity noted in the Kruis study may not be directly different diets were analyzed, the changes noted associated with changes in microflora composi- were not dramatic.93 Only minor changes were tion, but rather be caused by direct exposure of noted among the groups, although these changes the colon to simple sugars. Refined sugars are were considered to be caused by differences in metabolized quickly in the ascending colon; diet.100 Table 3 outlines results of several studies whereas, high-fiber foods, containing substantial comparing the fecal flora of individuals consuming amounts of insoluble fiber, are metabolized more the typical Western diet (high in fat and meat) to slowly, releasing fermentation end-products (e.g., that of individuals eating vegetarian and/or high hydrogen gas and SCFAs) more gradually.97 In general, it appears populations consum- intake does cause alterations in the microflora. It ing the typical Western diet have more fecal has been observed that high sugar intakes increase anaerobic bacteria, less Enterococci, and fewer bile output. Some species of intestinal bacteria yeasts than populations consuming a vegetarian utilize bile acids as food and, hence, any increase or high complex-carbohydrate diet. Although one in their production will result in a competitive study found a significant difference between a advantage for this group of bacteria.63 The changes mixed Western diet and a vegetarian diet, overall observed in bacterial fermentation in this study there appear to be relatively few trends.
may or may not be related to changes in the spe- In spite of these findings, Gorbach argues cies composition of the microflora. Since this was that due to the sheer number of bacteria present in not adequately assessed in this study, the signifi- the stool (approximately 1011 viable bacteria/g) and cance of these results requires further investiga- 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- insufficient, increased fermentation of the ods may be unable to differentiate changes due to protective layer of mucin may occur due to the limited quantity of carbon sources reaching the colon. This may compromise mucosal defense and method to detect changes in human microflora, lead to direct contact between colonic cells and Peltonen et al utilized gas-liquid chromatography bacterial products and antigens. This, in turn, may (GLC) to analyze profiles of bacterial cellular fatty lead to inflammation and increased mucosal acids. This method measures bacterial cellular permeability. Such a situation may encourage the fatty acids present in the stool that accumulate to growth of potentially pathogenic bacteria and form a GLC fatty acid profile, with each peak in perpetuate the inflammatory response.98,99 This the profile representing relative amounts of a par- theory, however, is yet to be supported by direct ticular fatty acid in the stool. Similar bacterial compositions should yield similar fatty acid pro-files, while distinctions can be quantified by the General Dietary Factors
extent to which profiles differ from each other.
The researchers utilized this technique to analyze composition and metabolic activities of GIT the effects of a vegan, raw food diet on the intes- microflora has been the subject of research since tinal microflora. The one-month diet consisted of the late 1960s. It was initially believed that a variety of sprouts, fermented vegetables, fruits, changing the content of the diet (in terms of meat, seaweed, nuts, and seeds. Differences in the GLC fat, carbohydrate, and fiber content) would profile between the test and control groups were statistically significant (p<0.05), as were the dif- composition of the colonic flora. However, when ferences in test group GLC profiles before and Page 192 Alternative Medicine Review ◆ Volume 9, Number 2 ◆ 2004
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during the diet. No significant changes in the fe- Diets can be altered, the effects of stress attenuated, cal flora could be detected in either group using and antibiotics used sparingly, in order to minimize the traditional isolation, identification, and enu- the effects of these factors on intestinal microflora.
meration bacteriological. While GLC may be a If the causes of dysbiosis can be eliminated or at more sensitive method to determine changes in least attenuated, then treatments aimed at fecal flora, it cannot identify particular compo- manipulating the microflora may become more successful and longer-lasting in effect.
Newer techniques such as fluorescence in situ hybridization (FISH) or polymerase chain re- ology techniques will provide definitive answers action assays coupled with denaturing gel elec- to currently unanswered questions regarding the trophoresis102 are more sensitive to minor alter- effects of various factors on the GIT microflora.
ations in microflora and allow for bacterial iden- Older studies that evaluated the effects of differ- tification that would otherwise be impossible to ent dietary regimes on the GIT flora should be re- culture.103 The use of these modern techniques in conducted utilizing modern microbiology tech- future diet studies will shed more light on this niques. These techniques will also provide accu- contentious area. Interestingly, recent research rate information regarding how specific drugs or utilizing the FISH technique has indicated the herbs affect microbial populations in the GIT. This majority of bacteria in the colon are not culturable information will allow far greater precision in both and have yet to be described. This finding sug- gests how little is actually known about the com-position of GIT microflora.104 References
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