1. Roundoc Rx
A Systems Biology Approach to Irritable Bowel Syndrome
Robert Rountree, MD
For far too long irritable bowel syndrome (IBS) has been
viewed by conventional doctors as a purely functional disorder.
For years, mainstream textbooks typically characterized IBS
as a psychosomatic process in which erratic neuronal signals
sent from the brain to the gut resulted in the mix of physical
symptoms that include diarrhea, constipation, and abdominal
pain. The diagnosis has mainly been one of exclusion in which
IBS was the wastebasket term used to describe what was left
after “real” diseases were ruled out. Given that, at that time,
there was no known biologic cause of the disorder, the goal
of treatment was symptom control, and the path to cure was
alleviating patients’ nervous tendencies. In other words, it was
thought that, if the person could just calm down and become
less neurotic, his or her IBS symptoms might just go away.
Fortunately, this attitude is beginning to change. Sophisticated molecular diagnostic techniques have shown that IBS is not
a simple functional disorder. Rather, it is a multifactorial condition with several prominent overlapping subtypes, including
dysbiotic, inflammatory, postinfectious, and neurochemical subtypes.1 Dysbiosis, a disruption in the normal balance of the gut
flora, is increasingly being recognized as a major factor in IBS
development.1–8 Furthermore, in contrast to long-held beliefs,
intestinal biopsies and measurements of cytokines have shown
that chronic low-level inflammation is involved in a significant
percentage of cases.4 IBS can also result from food allergies or
intolerances, inadequate production of hydrochloric acid and/or
digestive enzymes, and dysregulation of chemical messengers in
the gastrointestinal (GI) tract.3,4,9–11
A unifying model based on the concepts of functional medicine that I have discussed in several previous columns is that
certain antecedents, including genetic or lifestyle factors, can
predispose an individual to a health disorder such as IBS.
When the GI tracts of susceptible individuals are exposed to
noxious stimuli—including foods, microbes, damaged tissue,
or toxins—that sets off a complex response pattern involving
visceral hypersensitivity, which then engages a mixture of interacting immune, neurologic, and endocrine pathways. These
pathways are mediated by endogenous chemicals (autacoids,
cytokines, gut peptides, or hormones), which are, in turn, influenced by the person’s diet, hormonal state, and lifestyle. In this
scenario, psychosocial issues are only one of many factors that
can trigger or amplify the symptoms of IBS.
In the late 1800s, Robert Heinrich Hermann Koch, MD,
developed his famous postulates that established the causative
relationship between a pathogenic bacterium and a specific infectious disease. These postulates were tremendously valuable
in helping to diagnose and treat bacterial diseases such as tuberculosis. However, the worldview engendered by Dr. Koch’s
postulates also created limitations in our thinking. It was a
linear model in which a particular disease was thought to be
caused by a single microbe. This model has been greatly challenged by recent scientific advances, especially nucleic acid sequencing of gut microbes, which has enabled identification of
organisms that cannot be cultured in the laboratory.12 Another
challenge to the Koch postulates has come from the realization
that the presence of a potentially pathogenic microbe does not
always translate into a clinical infection, because many people
can be “asymptomatic” carriers, so other host factors must be
involved before that microbe can cause overt disease.
As I described in a previous column, in which I reviewed
current research on the human microbiome, nucleic-acid sequencing techniques have led to the realization that there is
a lot more microbial diversity in the human intestines than
we ever imagined.13 Furthermore, when these techniques are
utilized for individuals with GI disorders such as IBS or inflammatory bowel disease (IBD), a complex picture emerges.
Instead of identifying a single microbe that is responsible for
a person’s condition, scientists have found aberrant patterns in
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the relative amounts of bacteria, archaea, viruses, fungi, and
protozoa that are present.
To comprehend the meaning behind this mosaic, we have to
adopt a systems biology approach that sees the gut microbiome
as a community of living organisms that exerts both positive
and negative influences on the intestinal tract. The question is
which of those influences predominate—the good ones or the
bad ones. We have to think in terms of how imbalances in gut
microbial ecology trigger or amplify disease rather than being
overly focused on the search for a single pathogen.
For example, one study, in which real-time polymerase chain
reaction (PCR) assays were used to evaluate the microbiotic
composition of fecal samples collected from individuals with
the IBS diagnosis, reported positive correlations between the
severity of self-reported IBS symptoms and specific GI bacteria such as Ruminococcus torques 94% phylotype. In contrast, the
amounts of Clostridium cocleatum, Collinsella aerofaciens-like,
and Coprococcus eutactus were significantly reduced.2 Although
the researchers concluded that these types of changes may not
be the cause of IBS, they may be useful as biomarkers of the
disorder.2
People Are What They Eat
Some interesting and unexpected findings are emerging from
gut microbiome studies around the world. For example, the human microbiome is much more fluid than was once thought.
Babies largely acquire their microbiomes from their mothers.
The human gut is colonized at birth and gradually achieves the
size and diversity of an adult microbiome throughout the first
year of life.4 Whereas we once believed that a person’s microbiome would then remain stable—with transient changes caused
by disruptive factors—such as acute infections, antibiotic therapy, or conditions such as small intestinal bacterial overgrowth
(SIBO)—studies have shown that long-term changes in diet,
for example, can alter a person’s microbiomic profile.4,8
There is, in general, a certain mix of bacteria that creates
the ideal digestive environment in the human gut. Although
not yet fully defined, the “normal” human microbiome is the
subject of intensive research projects, such as the Human Microbiome Project, being carried out by the National Institutes
of Health (NIH) and aimed at characterizing the microbial
communities present at various sites on the human body, one
being the GI tract.14
Another is the American Gut, organized by the Human
Food Project.15 One aim of the American Gut project is to
compare the microbiomes of participants with greatly different dietary practices, whether by choice or for medical reasons. This includes carnivores; vegetarians; and people on
gluten-free, low-fat, or low-carbohydrate diets. According to
the website of the American Gut project, starving a mouse or
switching it to a high-fat diet for just 1 day can transform the
animal’s microbiome.
Ongoing research has focused on understanding how the
microbes in the gut communicate, interact with each other,
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and interact with their human host, and in particular the human immune and neuroendocrine systems. In decoding these
microbial “social networks,” researchers have discovered new
molecules that help protect the lining of the intestines from
chemical signals that gut flora use to communicate with each
other, toxic substances produced by the microbiome, and
unique components of the human immune system (such as
immunoglobulin A) that interact with bacteria in the gut.7
Dysbiosis is a situation in which microbial social networks
in the gut have been disrupted; this can interfere with the normal neurochemical signaling pathways in the gut submucosa.
In addition to the growing body of information about dysbiosis and its role in triggering or perpetuating IBS symptoms, we
have also learned more in recent years about the neuronal signaling between the brain and the gut that is believed to have a
role in IBS. The conventional definition of IBS as a functional
disorder implied a primary psychoneurologic basis in which
disordered signals originating in the central nervous system led
to symptoms in the bowel. This brain-to-bowel pathway was
believed to be responsible, at least in part, for the alternating
hyper- and hypomotility, along with the visceral hypersensitivity characteristic of IBS.
However, microanatomical studies have since revealed many
more neuronal connections than were previously thought to
exist in the gut.16 Furthermore, these studies showed that, surprisingly, a greater number of information-gathering neurons
travel from the gut to the brain than in the other direction.
These findings were the basis for a profoundly insightful book
on the neurology of the gut, by Michael Gershon, MD,16 who
referred to the intestinal nervous system as our “second brain.”
The implication of these findings is that the gut is doing more
than simply digesting and assimilating food—the gut is acting
as an environmental sensor that gathers information about the
quality of that food and the types of microbes associated with
it. This information is then “packaged” and communicated
back to the brain.
Could it be that the intestines—and ultimately the central
nervous systems—of people with IBS are just responding to
the presence of microbes or chemical compounds, whether
naturally occurring (such as gluten) or synthetic (such as organophosphates), that are perceived by the sensors in the gut
as being potentially dangerous? In other words, perhaps IBS is
the intestinal equivalent of a canary in the coal mine.
Irritable Gut, Irritable Patient
IBS affects 10%–20% of adults and adolescents worldwide.1,2 Although the mucosa of a person with IBS may look
completely normal during colonoscopy, there is no doubt that,
as the name irritable bowel syndrome implies, the person’s GI
tract is chronically irritated, compromising quality of life and
making the affected patient irritable as well. As previously
mentioned, a patient with IBS may experience symptoms that
range from mild to severe; that fluctuate in intensity; and that
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and bloating, and flatulence. It is well-documented that anxiety and/or depression tend to occur more commonly in individuals with IBS, but whether these are precursors or results of
the disorder has not been clear. In fact, some studies suggest
that imbalances in the gut microbiome may be the cause of
anxiety or depression, rather than the reverse.17
Considering the more-recent studies that have shed light
on the microbiome, dysbiosis, and the neuroanatomy of the
gut, the central issue to focus on now is what is making the
bowel irritable. In some individuals, the irritability results from
cytokine-mediated inflammatory responses triggered by conditionally pathogenic microbes, reactions to certain foods, or
chronic low-level subclinical inflammation in the gut lining
resulting from persistent upregulation of immune cells. These
cytokines travel through the systemic circulation before crossing the blood–brain barrier and influencing the cells of the
central nervous system directly. This scenario has been referred to as cytokine sickness.18
Activated mast cells have been found in the mucosa of individuals without IBS, so this situation is yet another mechanism that may account for subclinical inflammation. Mast
cells release histamine and other inflammatory mediators in
response to environmental triggers. (Note that histamine is
also present in certain foods and that ingesting those foods
can mimic the effects of an allergic reaction.) Given that
chronic subclinical inflammation is found in many people
with IBS, one of the conundrums of this disorder is that conventional anti-inflammatory drugs, such as corticosteroids
or nonsteroidal anti-inflammatories, have little or no effect
on the symptomatology. Perhaps it is because the underlying
problem is an intrinsic defect in the way the neurons in the
gut process inflammatory signals, such as disordered secretion of the neurotransmitter serotonin, 90% of which is produced by enterochromaffin cells in the gut. Enterochromaffin
cells produce serotonin in response to noxious stimuli. This
local increase in serotonin stimulates gut motility by activating enteric neurons, which results in expulsion of the irritant.
Excessive serotonin production can cause hypermotility or
diarrhea, while inadequate production can result in constipation. Yet another possibility could be that dysbiotic microbes
or food components are stimulating the overproduction of
signaling molecules that affect gut motility. Some of the
numerous signaling molecules that have been shown to be
disrupted in irritable bowel syndrome include autacoids (serotonin, histamine, eicosanoids, substance P) and neuroendocrine peptides (CCK, VIP, NPY, somatostatin).19,20
To sum up, the integrative medicine community views IBS
not as a purely functional disorder, but rather as a dysfunction
of the GI tract that is triggered by reactions to foods, toxins,
and traumas in the context of chronic dysbiosis and intrinsic
visceral hypersensitivity. A disruption in the normal balance
of the gut flora is the primary ongoing pathologic phenomenon, which results in the activation of inflammatory-signaling pathways. These phenomena underlie the constellation of
symptoms experienced by patients with IBS. However, as disturbing and disruptive as these symptoms may be—and there
is no denying that some patients suffer quite a lot—there is no
reason to believe that IBS predisposes such patients to a more
serious or potentially life-threatening disorder or cancer.
Don’t Skimp on the Diagnosis
The initial approach to IBS remains one of excluding more
serious causes of persistent intestinal symptoms. To begin with,
it is important to rule out IBD, celiac or gluten sensitivity, and
lactose intolerance, all of which would require a different treatment approach than IBS. A complete blood count, C-reactive
protein testing, erythrocyte sedimentation rate, a complete
metabolic panel, and a thyroid-function profile should all be
part of the typical workup. Tests for infectious agents should
include a screen for typical bacterial pathogens and Clostridium difficile toxin; protozoa such as Giardia lamblia, Entamoeba histolytica, and Blastocystis hominis; and also overgrowth of
pathogenic yeasts, primarily Candida species.
For patients with recurrent bloating, especially when it occurs soon after eating, a hydrogen/methane breath test can be
helpful for diagnosing SIBO, a problem that is either comorbid
with IBS or—for some individuals—the primary cause of IBS.
Fecal calprotectin and/or lactoferrin are excellent biomarkers
for differentiating between IBS (in which the levels are usually
low) and IBD, infectious enteritis, or cancer. Although both
tests have utility by themselves, combining the two provides
more sensitivity and specificity. Patients with long-term symptoms, especially if bleeding is present, or if fecal calprotectin
levels are elevated, should undergo colonoscopy to rule out the
presence of ulcerative or cancerous lesions.
Symptomatic Treatment
If no alternative diagnoses appear to be relevant and a patient is considered to have IBS, that is where integrative and
mainstream medicine begin to diverge in their approach to
patient management. Symptom control to ease patients’ discomfort and improve their daily lives is certainly desirable,
but does not solve the underlying problems and should not be
considered the beginning and end of treatment. Conventional
symptomatic treatment focuses mainly on medications, such
as loperamide to alleviate diarrhea, polyethylene glycol powder
or lubiprostone for constipation, anticholinergics or other antispasmodics for abdominal pain and cramps, and, if warranted,
tricyclic and other antidepressants or anxiolytics.
One of the most effective and extensively studied herbal
remedies for IBS-related pain and spasms is enterically coated
peppermint (Mentha x piperita) oil, which is typically dosed at
1–2 capsules three times per day. Another well-studied liquid
phytotherapeutic formulation marketed as STW 5 (Iberogast,®
Medical Futures, Inc., Richmond Hill, Ontario* [see next page
footnote]), which contains a combination of nine herbs, including peppermint leaf, German chamomile (Matricaria recutita),
caraway (Carum carvi), licorice (Glycyrrhiza glabra), lemon
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balm (Melissa officinalis), milk thistle (Silybum marianum), angelica (Angelica archangelica), celandine (Chelidonium majus),
and clown’s mustard (Iberis amara) plant can be very helpful for
patients with IBS.21 In a meta-analysis, 1 mL of this preparation, taken three times per day, for 1 month significantly reduced
a range of symptoms associated with IBS.21 I have prescribed
this formulation for many years in my clinical practice, and have
found it particularly useful for alleviating dyspepsia, abdominal
pain, and spasms associated with IBS.
Preliminary research has shown that artichoke (Cynara
scolymus) leaf extracts can decrease IBS symptoms, including dyspepsia, pain, cramping, bloating, and constipation.22
Several small studies have shown that 2–5 mg of melatonin
at bedtime can reduce overall symptoms and improve quality
of life for people with IBS.23 Numerous anecdotal reports
indicate that 5-hydroxytryptophan (5-HTP; a precursor to
the biosynthesis of serotonin and melatonin) can be beneficial for certain patients with IBS, especially those who are
constipation-predominant.
Going Beyond Just the Symptoms
In contrast to symptomatic treatment, the concept of looking
at ways to correct the imbalance in the microbiome is still a fairly radical notion. This approach can encompass a comprehensive
stool analysis to assess an individual’s gut flora; using probiotics
to repopulate the bowel with healthy bacteria; and prebiotics to
support the growth of the existing, desired microbial species.
I like to view this approach of correcting the microbiome
as being analogous to improving the conditions of a garden in
which the plants are not growing well. Identifying the source
of the problem and restoring the health of the soil or removing
offending pathogens is essential before the plants can thrive
again. In a garden, the problem may be with the pH of the
soil, an unhealthy mix of bacteria, or fungal overgrowth, for
example. Similarly, a microbiome/probiotic approach aims to
restore the proper balance of the gut flora.
The Four Rs—a Therapeutic Blueprint
The most comprehensive and well–thought-out approach to
treating IBS, in my opinion, is the 4-R strategy outlined by
the Institute for Functional Medicine.24 The four Rs refer to
Remove, Repair, Replace, and Reinoculate.
Remove
Remove is the first “R.” Remove potential sources of noxious stimuli that may be contributing to the person’s symptoms. This includes two main steps: (1) Look for pathogens
that can be treated, such as harmful bacteria and parasites. (2)
*Although the author sometimes sells this product in his clinic pharmacy, he has no financial interest in this product or the company that
manufactures it.
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Try to identify foods or food groups that the individual’s digestive system cannot tolerate.
One source of controversy in the Remove component of
the 4-R approach involves whether or not to try an aggressive,
empirical course of antimicrobial therapy to “wipe the slate
clean,” even when no specific pathogen is detected in a stool
analysis. Because rifaximin is poorly absorbed systemically,
many practitioners consider it to be the antibiotic of choice in
this situation, especially for patients with symptoms consistent
with SIBO, such as chronic bloating, flatulence, and abdominal cramps after eating. The antibiotic neomycin, which is also
not absorbed systemically, can be added to rifaximin for severe
cases. A typical course of treatment with one or both antibiotics for 10–14 days can potentially clear the gut of the fermenting bacteria and, presumably, allow it to be repopulated with a
healthy microbial mix.
A study of individuals undergoing upper GI endoscopy
found that 19.4% had SIBO and > 67% of that group had
IBS.3 SIBO was present in 37.5% of patients with IBS, in
60% of these patients with predominantly diarrhea symptoms, and in 27.3% of these patients without diarrhea. In
another study, persons who were Rome I criteria positive for
IBS underwent a lactulose hydrogen breath test to assess for
SIBO.6 Antibiotics were administered after a positive breath
test. SIBO was detected in 78% of the patients who had IBS.
Among patients who were SIBO-positive, were treated with
antibiotics, and had follow-up testing, IBS symptoms, such
as diarrhea and abdominal pain, were significantly reduced
among the patients in whom SIBO was eradicated, compared to those in whom it was not. Furthermore, 48% of the
patients in whom SIBO was eradicated no longer met the
Rome I criteria for IBS.
Unfortunately, although it is generally well-tolerated, rifaximin is extremely expensive (well over $700 for a course
of treatment), so that puts a major limitation on its use. In
addition, some researchers question the wisdom of using a
broad-spectrum antibiotic to correct a condition in which
there may already be a decrease in microbial richness and diversity. The risk of allergic reactions or other side effects from
the antibiotics should also be considered. Without a clear and
powerful strategy to restore that diversity, it is possible that
the SIBO or dysbiosis could rebound after the person stops
taking the drug.
An alternative to empirical antibiotic therapy is to use herbal
antimicrobials to eliminate suspected bacterial overgrowth or
imbalances. Typical options include berberine, garlic (Allium
sativum), and oil of oregano (Origanum vulgare). Their advantage is that they appear to suppress pathogenic strains without wiping out healthy flora. This is based on observations of
people who have taken berberine or garlic for long periods of
time (months or years) without developing evidence of a disrupted microbiome.
With respect to the second part of Remove—identifying offensive foods that might trigger symptoms—the best approach
is to start the patient on an elimination diet. While certain
blood tests are available to test for food sensitivities, these tests

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tend to be fraught with difficulties. Instead, have patients start
as simple a diet as possible—preferably just some rice and
lightly steamed nonflatulence-producing vegetables.
For people with particularly severe symptoms, I sometimes recommend bowel rest for a few days using an oligoantigenic plant protein powder. When these patients are
free of symptoms, they can begin to add back in one type of
food at a time. For a comprehensive description of elimination diets, I would refer readers to the excellent review by
Kathie Madonna Swift, MS, RD, LDN, and Irina Lisker,
BA, MD(Cand) that appeared in the October 2012, issue
of this journal.25
A body of evidence has grown to support dietary management of GI symptoms, such as those linked to IBS, by restricting rapidly fermentable, short-chain carbohydrates. Some
people do not absorb these carbohydrates well, especially in
the small intestine, so they are fermented by bacteria, leading
to distention of the bowel wall and irritation of the gut. The
Fermentable Oligo-, Di- and Mono-saccharides and Polyols
(FODMAP) approach, developed by Peter Gibson, MD, and
Susan Shepherd, BAppSci, MNut & Diet, PhD (at Monash
University in Melbourne, Australia), restricts global intake of
carbohydrates, including fructose; lactose; and fructo- and galacto-oligosaccharides; and polyols such as sorbitol, mannitol,
xylitol, and maltitol.26
A strict trial of the FODMAP diet is recommended for
6–8 weeks initially, and with good dietary compliance, this approach can produce a reduction of symptoms and durable efficacy.27 Details regarding the implementation of this diet were
provided by Ms. Swift and Ms. Lisker in their review.25
Repair
The second “R” is Repair. The notion of Repair is based on
the presumption that, if dysbiosis is present, with disruption of
the intestinal environment, then damage to the gut mucosa is
likely to have occurred. Even once we remove the stimulus, the
injury to the gut wall may persist for a very long time, so active
repair measures are necessary. In celiac disease, for example, the
damage can be quite severe, characterized by flattening of the
villi lining the intestinal mucosa. This may not resolve for years
after removal of gluten from the diet.
The nutrient with the strongest research base to support its
capabilities to repair the gut wall is l-glutamine. It is a primary fuel for enterocytes and can stimulate healthy enterocyte
proliferation. Therapeutic administration of l-glutamine has
been shown in animal studies to promote epithelial recovery
in the injured small intestine.28 A typical dose of l-glutamine
is 3–15 g daily.
Another good therapeutic option is the short-chain fatty acid
butyrate, which is formed by bacterial fermentation of certain
fibers. No one would want to take butyrate orally, though—
this is the chemical that gives stool its delightful aroma—so
instead we provide its precursors in the form of short-chain
fructo-oligosaccharides (FSO) or inulin. The bacteria in the
gut then produce the butyrate by fermentation. A caveat with
using these prebiotics is that they can initially cause bloating
and flatulence. For that reason, the initial dose should be low—
~ 0.5–1.0 tsp daily—and increased very slowly to ~ 1 tbsp daily
as tolerated. If the person has SIBO, then FOS should probably be avoided.
Replace
The third “R” is Replace, which involves the use of digestive
enzymes and hydrochloric acid with pepsin. Given the popularity of proton-pump inhibitors (PPIs) for treating a whole
range of upper GI tract symptoms, mainstream practitioners
may challenge the need for giving a person hydrochloric acid.
The belief is that overproduction of stomach acid is the culprit
rather than underproduction of this acid. In my experience,
that is simply not so. Hypochlorhydria can actually be very
common, especially among elderly patients, and can compromise the ability to break down proteins and prevent the
overgrowth of fermenting bacterial strains. This situation can
also lead to SIBO, a condition that commonly occurs in people
taking PPIs.
For patients with chronic flatulence and bloating, I recommend a commercial formulation of betaine hydrochloric acid
empirically, to be taken with food (at the end of a meal), and
see if it helps. A typical dose is 5–20 grains per meal. When
this approach does help, the effect can be remarkable. If it does
not, then no harm is done. In addition, the added stomach
acid can actually help rebalance the small intestine gut flora by
helping sterilize the food and limit the bacteria that contribute
to fermentation in the small intestines.
Digestive enzymes can be derived from pancreatin, fungi
(typically Aspergillus niger), or fruits such as pineapple (bromelain), or papaya (papain). Pancreatin—which contains a combination of amylase, lipase, and protease—is very potent and
helps people digest a wide range of foods. It is most effective
in the high pH of the small intestine. Fungal- and plant-based
enzymes are much less potent than pancreatin, but offer the
advantage of being active across a wide pH range. Perhaps the
best studied plant-based enzyme is a-galactosidase. It was initially promoted to decrease flatulence production after eating
legumes, but it is actually helpful for enhancing digestion of a
wide range of vegetables.
Dose ranges can vary greatly, and I have found that I generally need to recommend much higher amounts of these products
than are called for on the product labels. These products can be
quite effective if people use enough of them, but they are too often underdosed. I have not seen any negative effects from using
higher doses than those given by the manufacturers. A combination of traditional pancreatin and fungal-based enzymes may be
the best option for individuals with particularly poor digestion.
Reinoculate
The final “R” is Reinoculate. This involves giving prebiotics
(dietary fibers such as inulin, FOS, and larch (Larix gmelinii)
arabinogalactans that are fermented by host bacteria) and
probiotics (live microorganisms) to deliver “good” bacteria to
the gut, along with supporting the growth of existing good
bacteria. Commonly recommended probiotics for IBS are
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Lactobacillus spp., Bifidobacteria spp., and Propionibacterium.29
Theoretically, probiotics should be the ideal way to restore a
healthy and diverse gut microbiome. They may improve the
immune profile in the gut, leading to improved oral tolerance.
In some studies their use has been associated with normalization of altered, proinflammatory cytokine ratios4,5,30 and
reduced IBS symptoms.
However, there are also a number of negative studies that
have been unable to demonstrate benefit. Simply put, after
years of prescribing a wide range of probiotic strains at different doses for people with IBS, the best thing I can say
is that the results are inconsistent and unpredictable. In my
experience, probiotics help some of the people some of the
time, but the same bacterial strains do not work for everyone,
and it often takes 1–3 months of consistent use before the
benefits become evident. I still believe that probiotics should
be included as a standard part of the treatment regimen for
IBS, but determining which strain to use and at what dose is
largely a matter of trial and error. My best recommendation is
to always select probiotic strains that are backed by published
clinical studies.
Given that probiotics have such a strong potential, why have
they not proven to be more effective for addressing IBS? It
may be that they do not provide the precise mix of bacterial
strains needed to reinoculate the microbiome in order to restore its healthy ecology. In contrast to the hit-or-miss effects
of commercial probiotics, there is an intervention that is increasingly gaining recognition and that has been shown to introduce a completely new, healthy microbiome. This approach
essentially reconstitutes a person’s gut flora, in many cases after
a single dose. The therapy is called a fecal microbiota transplant (FMT), or human probiotic infusion.30
As described in a detailed review article by Sala Horowitz,
PhD, in the April 2013 issue of this journal, FMTs have been
used most often in difficult-to-treat cases of C. difficile infection and less frequently in IBD.30 Some practitioners have
also been using this approach for more-severe cases of IBS.
Interestingly, in April 2013, the U.S. Food and Drug Administration declared that FMT would be classified as an unapproved biologic drug that could not be used without obtaining
an investigational new drug application. However, there was
such a strong outcry against this regulation from both doctors
and patients that the FDA backed away from its ruling a few
months later.
If the goal is to repopulate the bowel with a healthy microbiome, replacing the entire ecosystem of the gut via an FMT
may turn out to be the most effective approach—not just for
C. difficile, but also for a wide range of chronic intestinal disorders, including IBS. The main challenge at present lies in
finding an extremely healthy donor with presumably normal
gut flora. As I mentioned, we still do not know what exactly
that looks like, so for now, recipients typically rely on family
members as donors. If a person does not have bowel-related
symptoms; has a negative screen for stool pathogens; does
not have hepatitis B or C, or HIV infection; is not exceptionally overweight; and is otherwise generally healthy, he or
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she could be a potential donor. This opens the door to future research into identifying ideal and perhaps standardized
“universal” donors based on extensive microbiome testing.
Another possibility would be to pool samples from multiple
donors to create a “broad-spectrum” and highly diverse source
material. Researchers have been experimenting with enterically coated capsules containing purified extracts of donated
fecal material, which may help to overcome the “yuck” factor
associated with this treatment.
Conclusion
In the future, making the diagnosis of IBS will require a
detailed map of a patient’s microbiome—a qualitative and
quantitative analysis of the microbial contents of the patient’s GI tract. The task at hand is for researchers to establish a composite view of the “normal” microbial diversity
and colonization in the human gut. This will provide the
information needed to differentiate a healthy and rich microbial profile from one that is pathologically imbalanced.
It will also help determine the influences of genetics, geography, diet, disease, medications (especially antibiotics),
environmental toxins, and other factors on microbiome profiles, so that we can design personalized interventions to
restore balance and diversity.
Just as genomic, bioinformatic, and other next-generation
molecular and computational tools are revolutionizing many
aspects of diagnostics, therapeutics, and personalized medicine,
so too will these tools dramatically change our understanding
of the microbiome and the way we approach poorly defined
disorders such as IBS.
The sophisticated techniques and tools driving these research discoveries and their clinical applications continue
to evolve and yield more detailed and complete views of the
microbiome and to decrease in cost so they are more broadly
accessible. Concurrently, they are becoming easier to use and
the results are becoming more readily interpretable, creating
new opportunities for diagnosing IBS, defining the underlying
dysbiosis, and monitoring the course of the disorder and the
effectiveness of treatment.
n
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Robert Rountree, MD, practices family medicine in Boulder, Colorado.
To order reprints of this article, e-mail Karen Ballen at: Kballen@liebertpub.com
or call (914) 740-2100.
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