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NAFLD (non-alcoholic fatty liver disease)





Non-Alcoholic Fatty Liver Disease

The liver is the second largest organ in your body.
The liver performs many jobs. It processes what you
eat and drink into energy and nutrients your body
can use. The liver also removes harmful substances
from your blood.

Non-alcoholic fatty liver disease (NAFLD) is the build up of extra fat in liver cells
that is not caused by alcohol. It is normal for the liver to contain some fat.
However, if more than 5% - 10% percent of the livers weight is fat, then it is
called a fatty liver (steatosis).


NAFLD tends to develop in people who are overweight or obese or have
diabetes, high cholesterol or high triglycerides. Rapid weight loss and poor eating
habits also may lead to NAFLD.However, some people develop NAFLD even if
they do not have any risk factors. NAFLD affects up to 25% of people in the
United States.

NAFLD may cause the liver to swell (steatohepatitis). A swollen liver may cause
scarring (cirrhosis) over time and may even lead to liver cancer or liver failure.

NAFLD often has no symptoms.
When symptoms occur, they may include fatigue, weakness, weight loss, loss of
appetite, nausea, abdominal pain, spider-like blood vessels, yellowing of the skin
and eyes (jaundice), itching, fluid build up and swelling of the legs (edema) and
abdomen (ascites), and mental confusion.

NAFLD is initially suspected if blood tests show high levels of liver enzymes.
However, other liver diseases are first ruled out through additional tests. Often,
an ultrasound is used to confirm the NAFLD diagnosis.


There are no medical treatments yet for NAFLD. Eating a healthy diet and
exercising regularly may help prevent liver damage from starting or reverse it in
the early stages.

See a doctor who specializes in the liver regularly

Talk to your doctor about ways to improve your liver health
Lose weight, if you are overweight or obese
Lower your cholesterol and triglycerides
Control your diabetes
Avoid alcohol

There are ways to prevent NAFLD:

Maintain a healthy weight

Eat a healthy diet
Exercise regularly
Limit alcohol intake
Only take medicines that you need and follow dosing recommendations.

The more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH).
NASH causes the liver to swell and become damaged. NASH tends to develop in
people who are overweight or obese, or have diabetes, high cholesterol or high
triglycerides. However, some people have NASH even if they do not have any
risk factors.
Most people with NASH are between the ages of 40 and 60 years. It is more
common in women than in men. NASH often has no symptoms and people can
have NASH for years before symptoms occur.
NASH is one of the leading causes of cirrhosis in adults in the United States. Up
to 25% of adults with NASH may have cirrhosis.

Leaky gut and the liver: A role for bacterial

translocation in nonalcoholic steatohepatitis
Gut flora and bacterial translocation (BT) play important roles in
the pathogenesis of chronic liver disease, including cirrhosis and
its complications. Intestinal bacterial overgrowth and increased

bacterial translocation of gut flora from the intestinal lumen

predispose patients to bacterial infections, major complications and
also play a role in the pathogenesis of chronic liver disorders.
Levels of bacterial lipopolysaccharide, a component of gramnegative bacteria, are increased in the portal and/or systemic
circulation in several types of chronic liver disease. Impaired gut
epithelial integrity due to alterations in tight junction proteins may
be the pathological mechanism underlying bacterial translocation.
Preclinical and clinical studies over the last decade have suggested
a role for BT in the pathogenesis of nonalcoholic steatohepatitis
(NASH). Bacterial overgrowth, immune dysfunction, alteration of
the luminal factors, and altered intestinal permeability are all
involved in the pathogenesis of NASH and its complications. A
better understanding of the cell-specific recognition and
intracellular signaling events involved in sensing gut-derived
microbes will help in the development of means to achieve an
optimal balance in the gut-liver axis and ameliorate liver diseases.
These may suggest new targets for potential therapeutic
interventions for the treatment of NASH. Here, we review some of
the mechanisms connecting BT and NASH and potential
therapeutic developments.
Bacterial translocation (BT) and the derangement of gut flora are
of substantial clinical relevance to patients with chronic liver
disease and cirrhosis[1,2]. Intestinal bacterial overgrowth and
increased bacterial translocation of gut flora from the intestinal
lumen predispose patients to bacterial infections and major
complications[3,4]. Furthermore, levels of bacterial
lipopolysaccharide (LPS), a component of gram-negative bacteria,
are increased in the portal and/or systemic circulation in several
types of chronic liver disease. Bauer et al[5-7] have demonstrated
this phenomenon in cirrhosis. Impaired gut epithelial integrity due
to alterations in tight junction proteins may be the pathological
mechanism underlying bacterial translocation. Over the last

decade, increased gut permeability and increased LPS levels have

been described in patients with alcoholic and nonalcoholic
steatohepatitis (NASH)[8,9]. Increased serum LPS levels and
activation of proinflammatory signaling cascades have been
suggested to be important for disease progression in these
settings[10]. Some potential mechanisms to explain the association
between BT and liver disease associated with lipid accumulation
and the development of NASH are reviewed here. These
mechanisms may suggest new targets for potential therapeutic
interventions for the treatment of NASH.

(sndrome de intestino permeable)



Leaky gut can be a difficult diagnosis to establish for a number of reasons:
It's associated with a wide range of seemingly unconnected symptoms; it
has a lot of different causes; there's no specific test to confirm it; and
evidence tying it to other conditions can be murky. As a result, theres a fair
amount of skepticism in the mainstream medical community about the
legitimacy of leaky gut as a diagnosis. But as the evidence that this is
indeed a real and recognizable condition grows, opinions are slowly
changing. That's a good thing, because leaky gut is likely to emerge as one

of the most significant medical concepts of our time.

How Leaky Gut Affects You
Our digestive lining serves an important barrier function. It's like a net
with very small holes that allows only certain substances that are small
enough to go through, while keeping out larger undesirable particles. With
leaky gut, also known as increased intestinal permeability, the net becomes
damaged, resulting in bigger holes that allow more things to pass through
that ordinarily couldnt.
The barrier function becomes compromised, so that bacteria, viruses,
undigested food particles and toxic waste products can leak from the inside
of your intestines through the damaged digestive lining into your
bloodstream, where they're transported throughout your body and can
trigger your immune system to react. The end result is inflammation in
various parts of your body, leading to a wide variety of symptoms like
bloating, cramps, fatigue, food sensitivities, flushing, achy joints, headache
and rashes.
With leaky gut not only is the digestive lining more porous and less
selective about what can get in, but normal absorption can also be affected.
Nutritional deficiencies may develop as a result of damage to the villi - the
finger-like projections in the small intestine that are responsible for
absorbing nutrients.
Multiple food sensitivities are another hallmark of leaky gut, because
partially digested particles of protein and fat may leak through the
intestinal wall into the bloodstream and cause an allergic response.
Increased intestinal permeability may potentially cause or worsen a
number of other conditions, including Celiac disease, inflammatory bowel
disease (IBD, which includes Crohns disease and ulcerative colitis),
irritable bowel syndrome (IBS), arthritis, psoriasis, eczema and asthma.


So what causes leaky gut or increased intestinal permeability?
There's still much to be learned, but diet, chronic stress, certain
medications and bacterial imbalance seem to play important roles. Eating
a diet high in refined sugar can lead to overgrowth of yeast
species, which has been associated with leaky gut.
Preservatives and chemicals in processed foods can damage
the lining, and so can consumption of gluten a protein found
in wheat, rye and barley.
Chronic stress can lead to a weakened immune system, affecting your
ability to fight off invading bacteria and viruses and worsening the
symptoms of leaky gut. Medications like aspirin and non-steroidal anti
inflammatories (NSAIDs) that can damage the lining of your gut, as well as
antibiotics that kill off your essential good bacteria are also associated with
increased intestinal permeability. In fact, an imbalance between beneficial
and harmful species in your gut called dysbiosis is one of the leading
theories about what causes increased intestinal permeability. Excessive
alcohol consumption, infection with parasites, radiation and chemotherapy
can damage the lining of the intestine and are also risk factors.
In addition to bloating and digestive distress, a lot of the patients I see with
leaky gut have a combination of other symptoms like food allergies, chronic
sinus infections, achy joints, fatigue, brain fog or unexplained rashes.
Typically theyve been to multiple doctors trying to make sense of their
symptoms, and conventional tests and imaging studies have been
unrevealing. There can be a feeling of hopelessness and despair, because
the symptoms seem so unrelated.

When you think of leaky gut not so much as a disease, but as a mechanism
by which a number of different conditions can develop, it starts to make
sense. A leaky gut is the pathway for how toxins enter the body through the
GI tract and create all kinds of mayhem once they're in, sort of like party
crashers who slip through security and proceed to make a mess of the
What Tests Are Available for Leaky Gut?
Leaky gut is a clinical diagnosis, and while there's no specific test that can
tell you with 100% certainty that you have it, a positive Intestinal
Permeability Test is strongly associated with the condition. This
test measures the ability of two non-metabolized sugar molecules
mannitol and lactulose to get through the digestive lining.
Mannitol is a small molecule that normally passes through easily and
serves as a marker of how well nutrients are being absorbed. Lactulose is a
larger molecule that doesn't normally pass through very well and serves as
a marker for whether there are large holes in the lining. To perform the
test, the patient mixes pre-measured amounts of lactulose and mannitol
and drinks it. The test measures the amount of lactulose and mannitol
recovered in a 6-hour urine sample.
Low levels of both mannitol and lactulose indicate malabsorption. Elevated
levels of both lactulose and mannitol suggest general increased intestinal
permeability, consistent with leaky gut. Permeability to lactulose may be
increased, suggesting leaky gut, while permeability to mannitol may be
decreased, suggesting malabsorption of small molecules. The
lactulose/mannitol ratio is a useful value; an elevated ratio indicates that
the effective pore size of the gut lining has increased, allowing larger,
possibly harmful molecules to gain access to the body.

Are There Any Solutions?

Theres no miracle cure for treating leaky gut, but there are things you can
do if youre suffering from it that can help heal inflammation and restore
the integrity of your gut lining.
An anti-inflammatory diet that eliminates refined sugars, dairy,
gluten, alcohol and artificial sweeteners some of the biggest

offenders when it comes to inflammation can be very helpful.

Consuming lots of anti-inflammatory essential fatty acids in fish and nuts,
and filling up on green leafy vegetables, high-fiber and fermented foods
that help to promote the growth of good bacteria is also crucial.
A robust probiotic that contains large amounts of good bacteria can help
heal a damaged intestinal lining by restoring balance in the gut flora.
Supplements like glutamine have been shown in some studies to help with
intestinal injury after chemotherapy and radiation and may be beneficial in
leaky gut.
Most people will notice improvement within 6 weeks, although it may take
several months and even years to heal a damaged intestinal lining in
extreme cases of leaky gut. Because were still learning about leaky gut,
many of the treatment guidelines are drawn more from anecdotal
observation than from rigorous scientific studies. But theyre sensible
recommendations that can lead to improvements in your overall health,
whether or not you have increased intestinal permeability.
Leaky gut is one of those diagnoses that bridges the gap between
conventional and alternative medicine, between what we can see and touch
and what we can feel in our bodies. I refuse to believe that the hundreds of
patients I see in my office with unusual and seemingly unrelated
complaints are crazy, or just stressed out.
I believe them when they say they feel like they're being poisoned, or that
they think there's a connection between all their symptoms, even though
they don't know what it is. My hunch is that as our knowledge grows, the
theories behind leaky gut will become the foundation for lots of diseases
that are widely prevalent in our society, and millions of people will be in a
better position to find relief from their suffering.

The normal gut has a mucous lining that serves as a barrier between
the food we eat and the blood stream. Nutrients from digested food
normally and properly cross this border to enter the blood stream.
When this lining is irritated, by foods you are allergic to, or asprin and
similar non-steroidal anti-inflammatories, then undigested food

particles and other large molecules escape from the gut into the
blood stream. The immune system reacts, sending white blood cells
to attack them. This overactivity of the immune system can contribute
to ailments like joint pain, head-aches, fibromyalgia, Autism, Chrons
disease and ulcerative colitis. More Information on Leaky Gut.

Testing in order to know if you have gluten sensitive genes. So that
you get a definitive answer so you can make a definitive decision as
to not to ingest any gluten (no grain foods) for the rest of your life, so
that you can completely repair and heal your gut lining so that
no impurities end up contaminating your precious blood stream.
Measure intestinal damage and intestinal inflammation. A simple
urine test can measure the permeability of your intestinal lining.
In addition, chew your food at least 25-50 times per bite.
This makes it easier for the digestive enzymes to do their job. Take
digestive enzymes 1-2 hours after meals. Get tested for food allergies
or do an allergy elimination diet, and take these food allergies
seriously. Avoid anti-inflammatory medicines like Motrin. Use instead,
natural ones like MSM, curcumin, boswellia and bromelain. For
arthritis try glucosamine, chondroitin, and niacinamide. Take friendly
bacteria and treat any infections in the gut, like candida or bacterial
overgrowth. Try L-glutamine, an amino acid that is fuel for the
intestinal cells. L-glutamine may help repair these cells and relieve
leaky gut. But if you are sensitive to MSG, then avoid this, as
glutamine converts to MSG.


Clean the Colon to Check Candida
By Andrew Gutauskas and Monica O'Kane
The diet of the average North American consists of food that is over processed, low in fiber, and
high in refined sugar. We also consume large amounts of red meat, dairy products, and wheat.
According to a 1977 Journal of American Medical Association article, this kind of diet results in
fewer "friendly" bacteria in the intestinal tract. Furthermore, many of us eat too much, too often,
and we mix too many different kinds of food at the same meal.
These and other factors can cause a thick coat of mucus and impacted food residue, which
combines to form on the walls of the large intestine. Not only does this encrusted matter
contribute to further dysfunction of the colon, but, according to Bernard Jansen, D.C., in his boldly
illustrated book, Tissue Cleansing through Bowel Management, disease actually begins here
because toxins are absorbed to cause malnutrition of our body cells while absorption of nutrients
is prevented.
Candida albicans, a normal inhabitant of a healthy colon, prefers to live in this toxic filth where it
is warm, putrid, and lacking in oxygen. Consequently, this family of yeast does well in most
colons. In many cases, as noted by Trowbridge and Walker in The Yeast Syndrome, they become
so prolific that they escape the confines of the intestinal tract and cause havoc throughout the
rest of the body.
According to a research pioneer, C. Orian Truss, MD, in a paper published in a 1978 issue of The

Journal of Orthomolecular Psychiatry, Candida albicans proliferates in the intestines because of

several factors, including stress, lowered immune system, antibiotic overuse, oral contraceptives,
and use of cortisone or prednisone. It can change from the harmless non-invasive, sugar
fermenting yeast like organism to the mycelial, or fungal, form with long, root like structures that
can penetrate the membrane lining of the digestive tract.
If an individual can restore proper colon hygiene, the Candida will, instead, retreat to their former
subdued state. Dr. David Soil, a University of Iowa biologist reported in a 1985 Science magazine
article that Candida albicans is capable of changing from benign to virulent and change back to
benign. In many cases, when the Candida returns to the benign form, the immune system will
clear Candida from the rest of the body. Without paying close attention to the restoration of proper
colon cleanliness, the immune system will be forced to continually battle Candida and its toxins.
So a clean colon is essential in the battle against Candida, and the accumulation of filth here can
be decreased, if not eliminated, with proper dietary modifications. First, adapt these nutritional
Eliminate refined sugar and refined, bleached, chemically treated flour;

Eliminate meats treated with synthetic hormones or chemicals;

Eliminate hydrogenated fats (such as that which exists in peanut butter, baked goods, margarine,

Reduce fats (use those rich in Omega-3 --fish and olive oils);

Eat fresh and raw vegetables**** For more complete diet recommendations, see the
WholeApproach Diet Pages
Eat nothing unless it will spoil or rot, but eat it before it does so. At the grocery store, shop at the
outer fringes of the building, avoiding canned, packaged products. Exercise regularly.
Next, eliminate colon toxicity. This can be accomplished by using two natural agents, Psyllium
and Bentonite. Neither one is absorbed into the system, but rather, each absorbs and then expels
toxic materials in the feces.
Psyllium (pronounced "silly-um") is a seed, grown commercially in India. Its husk is used as a
bulk forming laxative in numerous products, and Constance Kies, PhD, in a 1982 issue of
Prevention wrote, "As it absorbs water in the digestive tract, the Psyllium expands, stimulating
and speeding up elimination." Psyllium also looks as though it is a cholesterol fighter, as Kies
found in an experiment with healthy volunteers whose cholesterol levels dropped, on average,
from 193 to 168 when they added Psyllium to their customary diets.
Gastroenterologist Jack D. Welsh, MD at the University of Oklahoma Health Sciences Center,
noted in the June, 1982 edition of the American Journal of Clinical Nutrition that Psyllium entirely
prevented the expected gas pain and nausea. If Psyllium seed powder is added to the husk
powder in the proper ratio, the preparation becomes an intestinal cleanser. The Psyllium seed
fragments are very hard; they tend to scrape away at the toxic plaguing on the walls and clean it
away over a period of months.
Bentonite, a volcanic ash, acts toward toxic material as fly paper does with flies when processed
into a very fine liquid suspension. The unique properties of Bentonite were reported in the
Medical Annals of the District of Columbia in June of 1961 by Frederick Damrau, MD, who
established that Bentonite adsorbs toxins, bacteria, and viruses both in laboratory dishes and in
humans. Because Bentonite, itself, is not absorbed, whatever it adsorbs is removed in the feces.
This includes miscellaneous intestinal poisons and toxins generated by Candida albicans.
The restoration of proper colon hygiene using this method takes anywhere from three to 24
months, depending on the age and condition of the individual. Caprylic acid can be added to help

reduce the Candida albicans. Its anti fungal properties were the subject of a 1961 Japanese study
at the Niigata University School of Medicine and were reported in the Japanese Journal of
Microbiology: "....the fungicidal effect of Caprylic acid on C. albicans was exceedingly powerful." It
was also noted in journal, "Caprylic acid exhibits the most remarkable fungiastatic and fungicidal
properties of all the normal saturated fatty acids with even numbered carbon atoms studied. The
fungicidal activity of Caprylic acid depends upon the concentration of the acid, the period of
contact, and the pH of the media."
Traditional Caprylic acid preparations exist as capsules or tablets, but the one we prefer is liquid
Caproyl. This was designed to take advantage of other health benefits of oleic acid from Safflower
oil and to interact with the Psyllium to amplify its fungicidal effects far beyond what Caprylic acid
has traditionally offered. We recommend that liquid Caprylic acid be mixed with the Psyllium
powder, Bentonite, and water to be taken orally once or twice daily.

As the Psyllium gel presses up against the intestinal walls, some unique and beneficial things
the liquid Caprylic acid is released into the intestinal wall at a rate determined by the gel, not by
the intestinal pH conditions, which vary widely among individuals. Consequently, results are
predictable; consistent, and favorable. Caprylic acid is slowly released through the entire length of
the intestinal tract.

As the gel rubs itself against the intestinal wall, it acts as a paint brush in delivering the liquid
Caprylic acid to the intestinal wall. Not a square millimeter of wall is missed through the entire
length of the intestines.

Because the Candida albicans micro-organisms are buried deep into the toxic accumulations on
the intestinal walls, access to them is difficult. But the bulking action of the gel forcibly rubs liquid
Caprylic acid into the filth and onto the Candida.
Liquid Caprylic acid, dispersed in a Psyllium gel, will rid most people of major yeast symptoms in
three to eight weeks. If these people really want to improve their health, however, or merely stay
well, they will need to continue to eradicate the originating site and cause of the problem. They
will need to clean up their intestinal environment.

While other colon cleansers may be touted, we know that over a period of many months, using
the Psyllium/Bentonite mixture once or twice daily and adding the liquid Caprylic acid every fourth
week for five consecutive days will clean out a colon and keep the Candida in check.




Leaky Gut - The syndrome linked to

autoimmune diseases

"Leaky gut" syndrome

Hyperpermeability or "leaky gut"
syndrome is the name given to a
very common disorder in which
the cells lining the intestines
become "leaky" due to
inflammation. The abnormally large spaces present between the
cells of the gut wall allow the entry of toxic material into the
bloodstream that would normally be eliminated.
The gut becomes leaky in the sense that bacteria, fungi,
parasites, undigested protein, fat and toxic waste normally not
absorbed into the bloodstream in the healthy state, pass through
a damaged, hyperpermeable gut membrane. This can be verified
by special gut permeability urine tests or microscopic
examination of the lining of the intestinal wall.

Common causes of leaky gut

Infections - fungal overgrowth, parasitic infections

Drugs like NSAIDS, chemotherapeutic agents

Crohn's disease or Ulcerative Colitis
Celiac disease
Chronic alcoholism
Strenuous exercise
Food allergies

Leaky gut and the connection to autoimmune

Leaky gut syndrome is almost always associated with
autoimmune disease. In fact, reversing symptoms of
autoimmune disease depends on healing the lining of the
gastrointestinal tract. Any other treatment is just symptom
suppression. An autoimmune disease is defined as one in which
the immune system makes antibodies against its own tissues.
Diseases in this category include lupus, alopecia areata,
rheumatoid arthritis, polymyalgia rheumatica, multiple
sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren's
syndrome (dry eyes & dry mouth), vitiligo, thyroiditis,
vasculitis, Crohn's disease, ulcerative colitis, urticaria
(hives), type 1 diabetes and Raynaud's syndrome.
Fortunately doctors are beginning to realize the essential role
that the gut plays in these disease. Understanding the leaky gut
phenomenon helps us see why allergies and autoimmune
diseases develop and how to design therapies to restore
intestinal integrity and reverse leaky gut.

Inflammation is a key trigger for leaky gut

Inflammation causes the spaces between the cells of the gut wall
to become larger than usual. Then protein molecules are
absorbed before they have a chance to be completely broken
down. The immune system starts making antibodies against
these larger molecules because it recognizes them as foreign,
invading substances. Antibodies are made against these proteins
derived from previously harmless foods. The immune system
becomes hyperstimulated and over-reactive to substances that
are not necessarily supposed to be dangerous.
Human tissues have proteins & antigens very similar to
those on foods, bacteria, parasites, candida or fungi. The
antibodies created by the leaky gut phenomenon against these
antigens can get into various tissues and trigger an inflammatory
reaction in that tissue when the corresponding food is consumed
or the microbe is encountered. Autoantibodies are thus created
and inflammation becomes chronic. If this inflammation occurs
in a joint, autoimmune arthritis (rheumatoid arthritis)
develops. If it occurs in the brain, myalgic encephalomyelitis
(chronic fatigue syndrome) may be the result. If it occurs in
the blood vessels, vasculitis (inflammation of the blood
vessels) is the resulting autoimmune problem... and so on.
If the antibodies end up attacking the lining of the gut itself,
the result may be colitis or Crohn's disease. If it occurs in
the lungs, asthma is triggered on a delayed basis every time
the individual consumes the food which triggered the production
of the antibodies in the first place. It is easy to see that practically
any organ or body tissue can become affected by food allergies
created by the leaky gut. Because the foods can trigger delayed

reactions, it can often be very hard to pinpoint the triggering


Leaky gut may cause increase risk of infection

and sensitivity to environmental chemicals
This ongoing inflammation also damages the protective coating
of antibodies normally present in a healthy gut called IgA. Since
IgA helps us ward off infections we become less resistant to
viruses, bacteria, parasites and candida. These microbes are
then able to invade the bloodstream and colonize almost any
body tissue or organ. In the clinic we often find patients with
leaky gut or autoimmune disease also have microbial infections
ongoing in the gut.
Not only can leaky gut create food allergies as the proteins we
consume are activating antibodies, but the microbes in the gut
can cross over into the blood stream creating a toxic burden that
overwhelms the liver's ability to detoxify. Often in severe cases of
leaky gut, patients will develop sensitivities to perfume, cigarette
smoke or other environmental chemicals. Common complaints
are also "brain fog", confusion, poor focus/concentration, or
memory loss.

Leaky gut also causes malabsorption and

nutritional deficiencies
Finally, leaky gut may contribute to a long list of mineral
deficiencies because of the ongoing inflammation and damage to

carrier proteins. The most common are iron deficiency, vitamin

B12 deficiency, magnesium deficiency which can lead to
fatigue, neuropathies or muscle pain. Zinc deficiency due to
malabsorption can result in hair loss or baldness as occurs
in alopecia areata. Copper deficiency can occur in an identical
way leading to high blood cholesterol levels and osteoarthritis.
Further, bone problems develop as a result of the malabsorption
of calcium, boron, silicon and manganese.

Common Disorders of the

Intestinal Tract: Intestinal
Permeability/Leaky Gut
In this section we will take a hard look at the most common
disorders of the intestinal tract, with a focus on the
physiologic mechanisms that lead to these disorders and
how they can be corrected with natural compounds and
dietary changes. We will start this section by examining the
literature on a topic that is gaining a lot of attention in
gastroenterology research as well as the field of immunology:
intestinal permeability or leaky gut. Lets start by
explaining exactly what this condition refers to.

What is Leaky Gut?

The lining of the gastrointestinal
(GI) tract is composed of small
epithelial cells that lie side-by-side
each other forming tight junctions.

These tight junctions act as a barrier between the interior of

the body (blood/circulatory system) and the exterior of the
body (the lumen of the GI tract). There are two primary
functions of the epithelial lining of the GI tract: the first is
to absorb small micromolecules, such as digested food
particles, which are used as fuel sources and other processes
for the body. These micronutrients are absorbed directly into
the epithelial cells or between the cells and enter the
bloodstream after passing through the gut-associated
lymphoid tissue (GALT), the underlying intestinal immune
system. The GALT serves as a containment system,
preventing potentially harmful antigens from reaching
systemic circulation.

A more attentive analysis of the anatomic and functional

arrangement of the gastrointestinal tract, however,

suggests that another extremely important function of this

organ is its ability to regulate the trafficking of
macromolecules between the environment and the host
through a barrier mechanism.[275]
The second function of the epithelial lining of the GI tract, is
to act as a barrier and prevent the absorption of larger
macromolecules which should not normally penetrate
through the intestinal barrier. When the tight junctions (TJs)
of the intestinal mucosa are compromised, they become
widened and permeable to large undigested food
compounds, toxins and bacteria. This is known as intestinal
permeability or leaky gut. The larger compounds of
absorbed yet undigested proteins are reacted against by the
immune system of the gut, called the GALT (gut-associated
lymphoid tissue). This reaction then promotes exaggerated
immune responsiveness and intestinal inflammation.

Think of the cells of your intestinal lining, where absorption

of micromolecules takes place, as bricks which sit side by

side along the basement membrane. These bricks are held
together by proteins that form the tight junctions (TJs),
which act as the mortar between the bricks. Micronutrients
are absorbed into the epithelial cells and transported
through the cells and basement membrane where they enter
the bloodstream. If the mortar starts to break down, you
get penetration of foreign molecules through the intestinal
barrier which can then enter the bloodstream (hence the
term leaky gut). Sometimes the epithelial cells, or bricks
themselves, start to break down allowing passage of toxins
through the cells (transcellular passage) into the blood.
These foreign molecules may include undigested food
molecules, toxins or bacteria.

Intestinal Permeability Leads to

Systemic Inflammation
(san jose functional medicine)

If anything penetrates through this gastrointestinal barrier

that is foreign, the immune system is activated to eliminate
or destroy these unwelcome molecules. This activation of the
immune system leads to an inflammatory response. If you
look at the anatomy of the intestinal lining, it is mostly
immune cells with a thin layer of epithelial cells protecting it.
If that epithelial layer gets breached, there is no question
there will be an inflammatory immune response. So it is no

surprise to see systemic inflammation and risk of

autoimmunity when there is breach of this thin epithelial
lining. Increases in inflammatory responses increase risk
of all chronic disease, including depression and
neurodegenerative diseases, cardiovascular disease, bone
loss, autoimmune disease, inflammatory bowel disease and
chronic pain. A persons intestinal barrier integrity will
influence their inflammatory load and their potential for
deteriorating mechanisms throughout the body.

with Leaky Gut
The following conditions have been associated with leaky gut

Autoimmune disorders
Multiple food sensitivities
Multiple chemical sensitivities
Chronic fatigue syndrome
Heart failure
Chronic inflammatory conditions
Chronic pain
Inflammatory bowel
Chronic yeast overgrowth syndromes
Brain fog

Intestinal Permeability
and Autoimmune
There is a growing amount of evidence establishing the
connection between intestinal permeability and the
development of autoimmune disease. This review paper was
published in 2009 in the prestigious Annals of New York
Academy of Science. This journal is one of the top-rated
most powerful scientific journals available:
There is growing evidence that increased intestinal
permeability plays a pathogenic role in various
autoimmune diseases. Therefore, we hypothesize that loss
of intestinal barrier function is necessary to develop

Basically, what this paper is saying, is

that the research is pointing to
intestinal permeability, or leaky
gut, as a precondition for the
development of all autoimmune
disease, such as type I diabetes,
rheumatoid arthritis (RA), lupus (SLE),
multiple sclerosis (MS), Lou Gehrigs
disease (ALS), Hashimotos
hypothyroidism, Graves disease, Crohns
disease, ulcerative colitis, Celiac disease, and hundreds of
other diseases.

Heres another paper supporting this discovery:

Together with the gut-associated lymphoid tissue and the
neuroendocrine network, the intestinal epithelial barrier,
with its intercellular tight junctions, controls the
equilibrium between tolerance and immunity to non-self
antigens. When the finely-tuned trafficking of
macromolecules is dysregulated in individuals, both
intestinal and extraintestinal autoimmune disorders can

One of the
hallmarks of a
is immune
tolerance to
This prevents
our immune
system from
attacking ones
own tissue of
the body. We
are born with
an immune
system that is
able to differentiate self-tissue from foreign pathogens and
does not attack self-tissue under normal circumstances. One
of the things the research is showing is once these tight
junction proteins get compromised, there is such immune
zealousness and activation, this whole immune self-

tolerance is lost and the immune system is prone to

attacking self-tissue. When this occurs, any tissue is up for
grabs for autoimmune destruction. The type of tissue that is
targeted for destruction determines the type of autoimmune
disease that develops.

Symptoms of Intestinal
Symptoms of intestinal permeability vary significantly and
have a varied presentation. There is a spectrum of severity of
intestinal permeability from mild to severe forms. Here is a
list of the most common symptoms associated with intestinal

Poor Digestion
Food Sensitivities
Chronic Pain
Brain Fog/Poor Memory

People with intestinal permeability will often react to certain

types of foods, especially common food allergens such as

wheat and dairy. Gluten sensitivity is very common with
these patients. Digestive abnormalities such as gas, bloating
and food sensitivities are common symptoms of leaky gut.
On the other side of the scale are people who never have
intestinal symptoms but have other symptoms of chronic
inflammation such as chronic pain, depression, brain fog or
fatigue. They are too tired or in too much pain to go to the
gym and exercise on a regular basis. When we see patients
that present with these symptoms, we have to consider
intestinal permeability issues.

Common Imbalances Associated

with Leaky Gut
There are a number of common imbalances that often occur
together with leaky gut. These include:

Bacterial/yeast overgrowth/dysbiosis (imbalance of
beneficial and pathogenic bacteria)
Intestinal lining degeneration/impaired intestinal immune
Immune activation/immune dysregulation/autoimmunity
Food sensitivities

Mechanisms Leading to Leaky Gut

There are many different environmental and dietary factors

that may damage the epithelial lining of the GI tract,

including a diet high in refined sugar, intake of food
allergens, such as wheat and dairy, alcohol use, use of
medications such as antibiotics or NSAIDs, such as
ibuprofen and aspirin, stress, chronic infections, nutrient
deficiencies, hormonal deficiencies (thyroid, estrogen or
testosterone) and metabolic disturbances, such as diabetes
or pre-diabetes.[277-286] All of these factors have been
shown to contribute to intestinal permeability. Alterations in
intestinal physiology may affect the integrity of the intestinal
epithelium tight junction protein structures. These
mechanisms basically include physiological shifts that
induce greater ongoing catabolism (breakdown) versus
anabolism (buildup) of the epithelial mucosa. Additionally,
systemic inflammation, which occurs in autoimmune
conditions, promotes leaky gut. So this becomes a vicious
cycle of leaky gut, leading to systemic inflammation, leading
to further leaky gut.

What are the Causes of

Leaky Gut?

Diet (refined sugar, wheat, dairy, etc.)

Medication (antibiotics, NSAIDs, etc.)

Infection (bacterial, viral, parasitic)
Hormonal Imbalances (thyroid, estrogen, testosterone, etc.)
Neurologic Issues (stroke, brain injury, etc.)
Metabolic Issues (diabetes, pre-diabetes, etc.)

of Intestinal
There is currently no
drug available to treat
intestinal permeability
and most doctors have not even heard of it. However, this
may change in the near future because drug companies are
now working on drugs that modulate gut permeability.
There is currently a tight junction regulator being
developed, intended for the treatment of patients with celiac
disease which has just recently passed Phase IIb human drug
trial development and will start Phase III clinical trials for
the assessment of the oral drugs efficacy and safety.[287]
Once this drug is approved, doctors, or at least
gastroenterologists, will become more familiar with
intestinal permeability. However, at present, these drugs
appear to be limited to approval for the treatment of this one
particular intestinal autoimmune disorder (celiac disease).
So patients with intestinal permeability with diagnoses of
other autoimmune conditions (or any other condition) will
not be able to get drug treatments for the foreseeable future.

There are several tests that have been developed, and more on the
way, that can tell you if you have some degree of leaky gut.
1. There is a urine test that involves first swallowing a
carbohydrate that will only make it across your intestinal lining
and into your blood and urine if your gut is leaky.

2. It is also possible to identify leaky gut by checking for IgG and IgA
antibodies to food in a blood test and this test is often preferable
because it gives us two pieces of information:
Whether or not there is leaky gut; and
Which foods you can avoid to help heal the leaky gut (if its there).
You can order a food sensitivity test here and complete it at home.
3. A blood test that measures zonulin as well as a substance called
actomyosin which is released when intestinal cells are damaged.
4. A breath test which, like the lactulose-mannitol test, involves first
swallowing sugar mixed in water, and then breathing into tubes which
will identify a gas (carbon dioxide) that is only produced if your gut is
I can help you with determining which test is best for you:
please make an appointment!
Note: Leaky gut cannot be found with an endoscopy or colonoscopy,
and does not show on standard bloodwork, so it is missed by most

Clinical Management of Intestinal

Permeability in Functional
Fortunately, intestinal permeability usually responds very
well to dietary and supplement intervention and can often be
well-managed through these interventions alone. The
treatment of leaky gut should include an aggressive program
designed to break the vicious cycle of leaky gut.

This involves a restricted dietary regimen and nutritional

supplements that have been shown to help

reduce intestinal inflammation and help repair the intestinal

lining. The dietary program may need to be conducted for an
extended period of time for more progressed
cases, depending on the factors involved in
promoting leaky gut. One of the things that
will create variables for how long this will
take are the mechanisms involved that are
causing the leaky gut. If the person is still
consuming alcohol or consuming
inflammatory foods or has hormonal
deficiencies or has blood sugar issues, this
will take longer to correct. There will be some people that
will have chronic leaky gut for the rest of their life, such as
severe autoimmune conditions and people with systemic
inflammatory conditions.

Compounds Shown
to Repair the
Intestinal Lining
There are various plant compounds, vitamins and minerals
that have been shown in the literature to have a restorative
effect on a damaged intestinal barrier. These include the
following: L-glutamine [288-292], deglycyrrhinized licorice
[293-303], N-acetyl glucosamine [304-307], aloe leaf extract
[308-312], spanish moss [313-317], marshmallow extract

[318-321], methylsulfonylmethane (MSM) [322-325],

gamma oryzanol [326-330], slippery elm bark [331-334],
german chamomile [335-337], marigold flower extract [338341], glutathione [342-347], zinc carnosine [348], vitamin D

Regarding intestinal permeability, zinc

carnosine caused an approximate threefold
increase in gut integrity and repair[348]
VDR (vitamin D receptor) plays a critical role
in mucosal barrier homeostasis by preserving
the integrity of junction complexes and the
healing capacity of the colonic epithelium. Therefore,
vitamin D deficiency may compromise the mucosal barrier,
leading to increased susceptibility to mucosal damage and
increased risk of IBD (inflammatory bowel disease).[349]

There is growing appreciation of the

importance of the pleiotropic hormone
vitamin D in the development of
tolerance, immune system defenses,
and epithelial barrier integrity [350]
1,25(OH)2D3 (vitamin D) may play a
protective role in mucosal barrier homeostasis by
maintaining the integrity of junction complexes and in
healing capacity of the colon epithelium. 1,25(OH)2D3 may
represent an attractive and novel therapeutic agent for the
adjuvant therapy of IBD (inflammatory bowel

NSAID-induced enteropathy refers to intestinal damage that
occurs from the use of non-steroidal anti-inflammatory
drugs (NSAIDs). Examples of NSAIDs are ibuprofen
(Advil, Motrin), naproxen (Aleve, Naprosyn),
Celebrex and aspirin. The use of NSAIDs, including
aspirin, is common in the treatment of pain, inflammation,
and fever. Additionally, low-dose aspirin is used routinely in
the prevention of heart attack and stroke. These drugs, both
through prescription and over-the-counter (OTC) use, are
the most widely used class of medications in the United
States.[352] Not surprisingly, NSAID use increases among
the elderly. In a survey of people 65 years of age and older,
70% used NSAIDs at least once weekly, and 34% used them
at least daily! The prevalence of at least weekly aspirin usage
was 60%![353] More than 111 million NSAID prescriptions
were written in 2004.[354]

Much of this usage comes from

pain conditions, such as arthritis
and related musculoskeletal
complaints. In 1990, the
estimated prevalence of selfreported arthritis in the U.S. was
37.9 million cases, or 15% of the
population! By 2020, it is
projected that 59.4 million will be
affecteda 57% increase from 1990![355] As the incidence of
arthritis complaints increases, the use of prescription and

OTC NSAIDs is also expected to increase.[356] However, the

use of NSAIDs does not come without risks. The most
common risk of NSAID use is damage to the stomach
(gastropathy) and intestinal lining (enteropathy). Irondeficient anemia is a common first sign of NSAIDenteropathy (due to internal bleeding), and serious
complications can include massive bleeding, perforation and
strictures, sometimes leading to death.[357]

The prevalence and clinical significance of NSAIDenteropathy continues to be greatly under-recognized.

NSAID-induced enteropathy and bleeding occur more
frequently than NSAID induced gastropathy. Significant
small intestinal damage and bleeding can be observed in
about 70% of chronic NSAID users, and in the majority of
patients the injury is sub-clinical.[357]
Wow! Significant damage to the small damage occurs in
70% of chronic NSAID users! This information should be
more widely publicized! These medications should be clearly
labeled and doctors should be warning their patients about
the risks associated with these drugs with every prescription.
On top of that, in most cases the injury is subclinical
(meaning it does not cause any symptoms or signs)!

If the injury is subclinical, it cant be very

serious, right? Unfortunately, thats not the
even minor and subclinical injury to the
intestinal mucosa can result in significant,
though delayed, metabolic consequences, which may
seriously affect the health of an individual. [358]
With improvements in the detection of NSAID-induced
damage in the small intestine, it is now clear that this
injury and the associated bleeding occurs more frequently
than that occurring in the stomach and duodenum, and can
also be regarded as more dangerous.[357]

It is common practice in primary care

and pain management to prescribe
acid-suppressing medications (PPIs
such as omeprazole) together with
NSAIDs in order to protect the
intestinal tract and reduce risk of GI adverse effects.
However, recent research indicates that this can worsen the
damage to the GI tract.
Moreover, recent studies suggest that commonly used
drugs for protecting the upper gastrointestinal tract (i.e.,
proton pump inhibitors) can significantly worsen NSAIDinduced damage in the small intestine.[357]
The frequent use of PPIs can exacerbate NSAID-induced
small intestinal injury by altering intestinal microbiota.
Thus, the use of PPI is considered to be an independent risk

factor associated with NSAID-associated



Mechanism of
of NSAIDs to Gut
How do NSAIDs
cause damage to
the gut? Lets take
a more in-depth look at how NSAIDs injure the gut lining.
This may be a bit technical for some readers but others will
find this informative. NSAIDs cause topical injury to the
mucosal lining of the GI tract and systemic effects
(throughout the body) by inhibiting the COX enzymes
resulting in prostaglandin depletion. COX (cyclooxygenase)
is an enzyme that is responsible for the production of
prostaglandins and thromboxane. Prostaglandins are lipid
compounds that have a wide range of hormone-like effects in
the body. Tissue prostaglandins are produced via two
distinct enzyme-dependent pathways: a COX-1 and a COX-2

The COX-1 pathway is the

predominant constitutive
(replenishing) pathway;
prostaglandins derived from this
enzyme mediate many effects, most
notably aiding in gastroduodenal protection, renal
perfusion, and platelet activity. The COX-2 pathway, in

contrast, is inducible by inflammatory stimuli and primarily

mediates effects through prostaglandins which result in
inflammation, pain, and fever. NSAIDs work by blocking
these two important enzymes throughout the body.
Inhibition of the COX-1 pathway blocks production of
prostaglandins that play an important protective role in the
stomach by increasing mucosal blood flow, stimulating the
synthesis and secretion of mucus critical for the mucosal
lining, and promoting proliferation of the epithelial lining.
Secretion of mucus and epithelial proliferation are critical
aspects to gut health in order to prevent intestinal
permeability or leaky gut!

The inhibition of these prostaglandins by NSAIDs impairs

these protective factors, resulting in a gastric lining that is
more susceptible to acid, pepsin, and bile salts and more
permeable to toxic intestinal compounds (affect intestinal
permeability). A major consequence of prostaglandin
depletion is to create an environment that is conducive to
peptic ulcer formation, bleeding and serious GI
complications. Since prostaglandins are essential to both the
maintenance of intact GI defenses and normal platelet
function, NSAIDs, including aspirin, promote ulcer
formation as well as bleeding.[356] This is why NSAIDs are
also considered a major risk factor for intestinal

Selective COX-2 Inhibitors

What about the newer class of NSAIDs, known as the
selective COX-2 inhibitors or coxibs, such as Celebrex?
Arent they safer for the gut than the other NSAIDS? In the
1990s, a tremendous amount of research was focused on
understanding the physiology and pharmacology of these
two distinct COX enzymes, largely fueled by the interest of
several large pharmaceutical companies in the notion that
selective inhibitors of COX-2 would provide all of the antiinflammatory activities of NSAIDs without the major adverse
effects on the GI lining.[357]

However, as the science of COX-2 caught up with the

marketing of COX-2, it became evident that the delineation
of functions of the two COX enzymes was not so clear-cut as
had been proposed and heavily promoted. COX-1

contributes significantly to inflammation while COX-2

contributes significantly to many physiological functions,
including mucosal defense.[357]
So we now know that these selective COX-2 inhibitor
medications, which were touted as safe for the stomach and
GI tract by the pharmaceutical companies, are not safe for
the gut either.

Management of NSAIDInduced Enteropathy
There is no known drug treatment for NSAID-induced
enteropathy, other than the withdrawal of use of NSAIDs.
Some doctors may still recommend the use of PPIs in these
cases, however, as we have seen, recent literature has shown
that the use of PPIs increases intestinal damage, rather than
alleviates it.
Moreover, recent studies suggest that commonly used
drugs for protecting the upper gastrointestinal tract (i.e.,
proton pump inhibitors) can significantly worsen NSAIDinduced damage in the small intestine.[357]

Clinical Management of NSAIDInduced Enteropathy in

Functional Medicine

As we have seen from the previous

section on natural compounds used
in the treatment of intestinal
permeability, various plant
compounds, vitamins and minerals
have been shown in the literature to
have a restorative effect on a damaged intestinal lining.[288351] Many of the compounds that are used to treat intestinal
permeability or gastric and duodenal ulcers are also used to
in the treatment for NSAID-induced enteropathy. The
reason for this is because these compounds have a
restorative effect on the mucosal epithelial lining of the GI
tract. In other words, they help the GI tract regenerate
healthy epithelial cells which make up the GI lining.

As you may have noticed, in addition to NSAID-induced

enteropathy, NSAIDs are a risk factor for both gastric and
duodenal ulcers and intestinal permeability. This is because
NSAIDs cause damage to the epithelial lining that lead to all
of these conditions which are closely related. They are all
mediated by damage to this epithelial lining. In fact, one of
the methods used to study the effects of drug or plant

compounds on a damaged gastric or intestinal mucosal

lining is to give rats high-dose NSAIDs to induce this
mucosal damage.[293-295,299] In addition to these plant
compounds used for the treatment of damage to the gastric
and intestinal lining, the omega-3 polyunsaturated fatty
acids (n-3 PUFAs) found in

fish oils (EPA and DHA) have been found to

have a significant protective effect on the GI
lining against NSAID-induced GI damage.
[359] In fact, a large gastroenterology medical journal just
recently published an article claiming that, due to the
protective effects of these fatty acids, the next generation of
NSAIDs will include these omega-3 fatty acids in the drug.
Because n-3 PUFAs have been proven to attenuate
cytotoxicity, inhibit lipid-raft-associated harmful signaling,
and relieve oxidative stress relevant to NSAIDs, n-3 PUFA
based NSAIDs will be next-generation GI-safe

Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) affects as many as 5%-20% of

individuals worldwide and has a significant impact on
quality of life. IBS symptoms range from diarrhea to
constipation, or a combination of the two, with abdominal
pain or discomfort and gas or bloating, referred to as
abdominal distension. The degree of symptoms varies in
different patients from tolerable to severe, and the time
pattern and discomfort varies immensely from patient to
patient. Some patients complain of daily symptoms, while
others report intermittent symptoms at intervals of weeks or

[360,361] There are no biomarkers

used in the diagnosis of IBS so
diagnosis is based on assessment of
symptoms.[362,363] IBS is divided
into subtypes, depending on
symptoms such as diarrheapredominant IBS (IBS-D), constipation-predominant IBS
(IBS-C) and mixed diarrhea and constipation-predominant
IBS (IBS-M).[364,365] IBS is not known to be associated
with the development of serious disease or with excess
mortality. However, IBS causes a reduced quality of life with
the same degree of impairment as major chronic diseases.
[366,367] The annual costs in the United States, both direct
and indirect, for the management of patients with IBS are
estimated at $15-30 billion.[368,369]

What Causes IBS?

The pathogenesis of IBS seems to be multifactorial, with the
following factors most likely playing a central role in the
pathogenesis of IBS: heritability and genetics, diet, gut flora,
low-grade inflammation, and disturbances in the
neuroendocrine system (NES) of the gut, which includes the
enteric nervous system (ENS).[360,361] One hypothesis
published recently in a worldwide gastroenterology journal

proposes that the cause of IBS is an altered NES of the gut, which accounts for
abnormal GI motility, secretions and sensations.[360] All of these abnormalities are
characteristic of IBS. The researchers propose that alterations in the NES could be the
result of one or more of the following causative factors of IBS: genetic factors, diet,
intestinal flora, or low-grade inflammation.[360] Lets take a look at each of factors
that are believed to contribute to the development of IBS.

IBS: Heritability and Genetics

Genetics appear to play a role in IBS. Up to 33% of patients
with IBS had a family history of IBS compared to 2% of the
controls in one study.[370] In another study of a family
cluster, a significant association was reported between
having a first degree family member with bowel symptoms
and presenting with IBS. In contrast, those who reported
having a spouse with bowel symptoms were no more likely to
have IBS symptoms than the general population.[371] It was
also shown that the prevalence of IBS was 17% in the
relatives of patients compared to 7% in the relatives of
spouses.[372] Another study showed that patients with IBS
were more likely to present a family history of IBS than
controls (33.9% and 12.6%, respectively).[373]

IBS: Diet
Most patients with IBS believe that their diet has a
significant influence on their symptoms and they are
interested in finding out which foods they should avoid.[374377] There is some evidence supporting dietary influence on
IBS symptoms. In one study, about 60% of IBS patients
reported a worsening of symptoms following specific food
ingestion: 28% within 15 min after eating and 93% within 3
hrs.[377] Many IBS patients report specific foods as triggers,
most commonly implicating dairy and wheat products, but
other foods as well such as onion, peas and beans, hot spices,
cabbage, certain meats, smoked products, fried food and

The reaction of IBS patients to certain food items has been

attributed to a number of short-chain carbohydrates called
FODMAPs that are poorly digested and absorbed so that a
significant portion of the ingested carbohydrates do not get
digested properly and enter the small intestine and colon.
Once there, these unabsorbed carbohydrates provide a
substrate for bacterial fermentation with the production of
gas and distension of the intestinal tract and an increase in

intra-abdominal pressure (IAP). This leads to abdominal

discomfort or pain. [360] Sound familiar? This is the same
mechanism described earlier that lead to GERD and as we
will see, also occurs in small intestinal bacterial overgrowth

FODMAPs include fructose, lactose, fructans, galactans and
sugar alcohols, such as sorbitol, maltitol, mannitol, xylitol
and ismalt. Fructose and lactose are present in apples, pears,
watermelon, honey, fruit juices, dried fruits, milk and dairy
products. Polyols are used in low calorie food products.
Galactans and fructans are present in common dietary food,
such as wheat, rye, garlic, onions, legumes, cabbage,
artichokes, leeks, asparagus, lentils, inulin, soy, brussel
sprouts and broccoli.[379]

IBS: Fiber
A deficiency in dietary fiber was once widely believed to be
the primary cause of IBS.[380] Although increasing the
amount of dietary fiber continues to be a standard
recommendation for patients with IBS, clinical practice has
shown that increased fiber intake in these patients increases
abdominal pain, bloating and distension.[380] In one study,
IBS patients assigned to fiber treatment showed persistent
symptoms or no improvement in symptoms after treatment
compared to patients taking the placebo or a low-fiber diet
but these patients were using common bran types of fiber.
[380] It is noteworthy that the role of FODMAPs and fiber
on IBS symptoms is associated with the intestinal flora. The
presence of gut bacteria that break down FODMAPs and
fiber and produce gas, such as Clostridia spp., can cause
distension of the small and large intestine with abdominal
discomfort or pain and lead to small intestinal bacterial
overgrowth (SIBO).[381,382]

IBS: Intestinal Flora

Most bacteria in the GI tract exist in the colon. The colon of
each individual contains between 300 and 500 different
species of bacteria, and each person has his own unique
intestinal flora.[360] The intestinal flora is affected by
several factors, such as diet, climate changes, stress, illness,
aging and medications, such as acid-suppressing medication
and antibiotic treatment.[383] The intestinal flora in IBS
patients has been found to differ considerably from that of
healthy controls, as IBS patients have fewer Lactobacillus
and Bifidobacterium spp. than healthy subjects.[384] These
bacteria bind to epithelial cells and inhibit pathogen binding
as well as enhancing barrier functioning.[385] Furthermore,
these bacterial species do not produce gas upon fermenting
carbohydrates, which is an effect that would be amplified as
they also inhibit the Clostridia spp.[385] Probiotics have
been shown to decrease colonic fermentation and stabilize
the colonic microbiota, and several studies on probiotics
have shown improvements in flatulence and abdominal
distension, with a reduction in the composite IBS symptom

A recent systematic review with meta-analysis published in a

worldwide gastroenterology journal examined the efficacy of

probiotics in the treatment of IBS. A total of 1,793 patients
were included in the meta-analysis. Distension, bloating,
and flatulence were evaluated using an IBS severity scoring
system in three trials (two studies) to compare the effect of
probiotic therapy in IBS patients with placebo. The review
concluded the following:
Probiotics reduce pain and symptom severity scores. The
results demonstrate the beneficial effects of probiotics in
IBS patients in comparison with placebo.[388]

IBS: Low-Grade Inflammation

Low-grade systemic inflammation appears to play a role in
the development of IBS. In a subset of IBS patients, GI
symptoms appear following gastroenteritis, with about 25%
of patients showing diarrhea-predominant IBS (IBS-D)
symptoms 6 months post- infection and approximately 10%
developing persistent symptoms.[389-392] Post- infectious
(PI)-IBS has been reported after viral, bacterial, protozoa
and nematode infections[383], with the incidence of PI-IBS
varying between 7% and 31%.[389-392] One study showed

that 6% to 17% of sporadic IBS patients believed that their

symptoms began with an infection.[383] Following infection,
the initial inflammatory response shows an increase in
certain types of lymphocytes (white blood cells) and
macrophages.[389] These changes rapidly decrease in most
subjects but a small number of patients with persistent
symptoms continue to have signs of infection.[393]

There are several pieces of evidence showing that

inflammation and immune cells affect the neuroendocrine
system (NES) of the gut, which controls and regulates GI
motility and sensitivity. [394] There is also evidence of IBS
patients having increased intestinal permeability and gut
barrier issues than in the non-IBS population.[395-396]
For a more in-depth perspective on the neuroendocrine
system (NES) of the gut and the brain-gut axis and how
abnormalities of the NES and the brain-gut axis may
contribute to IBS, click on: The Neuroendocrine System of
the Gut and the Brain-Gut Axis

IBS: Is SIBO the Culprit?

Some researchers now believe that irritable bowel syndrome
(IBS) may be caused by bacterial overgrowth in the small
intestine (SIBO).[487] An article was published in JAMA in
2004 proposing that small intestinal bacterial overgrowth
(SIBO) might explain the symptoms of altered gut motility,
visceral hypersensitivity, abnormal brain-gut interaction and

immune activation seen in IBS.[487] This is supported by

multiple lines of evidence. First, SIBO is found in up to 78%84% of IBS patients undergoing lactulose breath testing
indicating bacterial overgrowth.[488,489] Second, the
distribution of inflammatory mediators and/or inflammatory
cells have been shown to be disturbed in a percentage of
patients with IBS.[490]
It is thought that SIBO may contribute to many of the clinical
manifestations of IBS through bacterial fermentation and
stimulation of a gut immune response, characterized by
release of inflammatory mediators (such as interleukins and
tumour necrosis factor-) which may affect motility,
secretion and sensation.[487,491] Additionally,
postinfectious IBS, which occurs in 4%-31% of patients after
an episode of acute gastroenteritis[492], also supports a
causative role of bacteria in IBS.[493]

Conventional Treatment of IBS

A wide range of medications (prokinetics, antispasmodics,
sedatives, tranquilizers, laxatives, fecal bulking agents,
probiotics and antibiotics) along with lifestyle and diet
modifications have been proposed for this highly prevalent
condition; however to date there is no definite effective cure
for this state.[494]
Conventional treatment options for IBS include
pharmacological drugs aimed at symptomatic relief of the
primary symptoms involved in IBS, namely pain, diarrhea
and constipation.[494] In addition, antibiotic drugs such as
rifaximin are recently being used to treat IBS due to evidence
of bacterial overgrowth in this condition.[495] Treatment
for abdominal pain include antispasmodics, which
encompass several different drug classes (smooth-muscle
relaxants, antimuscarinics, anticholinergics) and other
agents (pinaverium, trimebutine).

The anticholinergic properties of these agents restrict their

usefulness in clinical practice.[494] Other drugs used for
abdominal pain include opioid receptor agonists (exogenous
opioids), GLP-1 (glucagon-like peptide 1) and membrane
stabilizers (ketotifen). Membrane stabilizers act by blocking
mast cell degranulation.[496] The number of mucosal mast
cells has been studied and found positively correlated to
abdominal pain.[497]

Treatment for diarrhea-predominant IBS (IBS-D) include

anti-diarrheals (loperamide), 5-HT3 antagonists or
serotonin-blockers (alosetron, cilansetron, ramosetron),
anti-inflammatory drugs (mesalamine) and antibiotic drugs
(rifaximin). The potential use of antibiotics in IBS treatment
has been supported by a growing body of evidence showing
the important role that intestinal bacterial overgrowth plays
in the development of IBS. Various lines of evidence suggest
that small intestinal bacterial overgrowth (SIBO) may lead to
many of the symptoms seen in IBS, such as altered gut
motility, visceral hypersensitivity, abnormal brain-gut
interaction and immune activation seen in IBS.[494,498]
The American Task Force systematic review of IBS
treatments concludes that rifaximin has shown improvement
of global IBS symptoms and bloating in trials included in
their analysis.[499]

Treatment for constipation-predominant IBS (IBS-C)

include laxative-based treatments (osmotic agents, and stool
softeners), prokinetics (drugs to stimulate movement of
bowels), prosecretory agents (drugs that augment intestinal
secretion, thus acting as a stool lubricant and facilitating its
evacuation, such as lubiprostone and linaclotide), serotoninboosting drugs (serotonin receptor modulators and 5-HT4
agonists such as tegaserod) and bile acid modulators (CDC
and elobixibat). Bile acid modulators have been used to treat
constipation disorders based on the observation of increased
incidence of diarrhea in patients taking bile acids for
gallstones or cholestatic liver diseases.[500]

However, these drugs have limited effects in their use due to

their symptomatic approach and risk of various side effects.

Pharmacologic treatments for IBS-C have largely been

unsatisfactory, mainly due to the multifaceted and poorly
understood pathophysiology of this disorder.[501]
The multifactorial pathogenesis of the disease and the illdefined drug targets make the goal of manufacturing a
universal drug for IBS-C a hard one to attain.[500]

Evidence of the long-term benefit of pharmacological

treatment has been sparse, and new drugs that have proven
to be effective have raised issues concerning safety.[502,503]
These agents have limited usefulness as most of them are
directed toward the symptoms of IBS, rather than the
underlying causes of this condition, with the possible
exception of antibiotic therapy. Alternative therapies, such
as cognitive behavioral therapy and gut-directed
hypnotherapy, have been used with good results.[504] A
more efficient approach would be to address the underlying
factors that appear to be related to the development of IBS,

such as excess carbohydrate consumption, food sensitivities,

insufficient HCl and pancreatic enzyme production, balanced
intestinal flora, low-grade intestinal inflammation and the
brain-gut axis. This is exactly how we approach IBS in the
functional medicine model.

Clinical Management of IBS in

Functional Medicine
Clinical management of IBS in the functional medicine
model starts with a thorough evaluation of the gut. This may
include a comprehensive stool analysis in addition to a stool
microbiology assay, assessing for dysbiosis and ruling out
pathogenic bacterial, fungal or parasitic infection. A
comprehensive stool analysis can provide a great deal of
information about gut function including markers of protein
and fat digestion, pancreatic function, and production of
short-chain fatty acids such as butyric acid which are
important for colon health.

A stool analysis can also assess for inflammatory gut

conditions such as inflammatory bowel disease (ie: ulcerative
colitis and Crohns disease) without undergoing intestinal
biopsy and rule out GI bleeding. Assessment of related gut
conditions, such as intestinal permeability and small
intestinal bacterial overgrowth should be considered in
conditions involving gas and bloating. Routine blood
chemistry is usually done to assess inflammatory markers
and assess other organ function that impact the gut such as

thyroid function. Food sensitivity testing and nutritional

analysis to assess for nutrient deficiencies should be
considered as well.

Management of IBS can vary greatly from person to person

depending on the findings of the stool analysis as well as
other conditions that may impact stomach and GI health
such as intestinal permeability and food sensitivity.
Treatment goals in the functional medicine model are to
eliminate pathogenic infection, restore balance to the gut
flora, and restore normal function of the stomach and GI
tract (normal secretion of HCl and pancreatic enzymes,
normal digestion of food and normal motility/movement of
the intestines). This can normally be attained through the
use of herbal anti-microbial compounds, probiotics and
digestive enzyme therapy. Assessment of related organ
function (particularly the thyroid, immune system, liver and
brain) should be conducted to assess for imbalances in these
organ systems as well (see Gut Connections with Other

Most IBS patients suffer from some degree of dysbiosis, so

the use of probiotics and prebiotics are often employed to
restore gut flora balance. Several specific bacterial probiotic
strains have been shown to improve symptom severity and
abdominal pain in IBS patients in numerous studies.
[462,466-479] There are some species that in clinical trials
appear to be more effective than others, such as
Bifidobacterium species (B. infantis 3564 and B. bifidum
MIMBb75) [470,474,476] and Lactobacillus species
(Lactobacillus acidophilus-SDC 2012, 2013, L.
paracasei B2106, L. plantarum 299V, and L. rhamnosus
GG).[469,473,475] These probiotics appear to be effective in
reducing abdominal pain and discomfort in adults and in
children. Several studies have also suggested that
combinations of different probiotic strains, such as VSL3# or
mixtures of Bifidobacterium and Lactobacillus species, are
able to decrease abdominal pain and discomfort in patients
with IBS.[466,478,479]

Addressing low-grade inflammation and intestinal

permeability through gut-restorative and anti-inflammatory
botanicals as well as dietary intervention is also important in
IBS. There are a wide variety of compounds shown to repair
the damaged intestinal lining, improve gut barrier integrity
and decrease low-grade inflammation in the GI tract as
described in the Intestinal Permeability section above.[288351]

Dietary compounds can induce immune responses in the GI

tract and contribute to low-grade inflammation, particularly
in gut permeability issues, therefore food sensitivity testing
can be of value in IBS patients. This involves assessing for
levels of IgA and IgG antibodies to various foods in the blood
through a lab that offers specialized food sensitivity testing.
Elimination of these foods from the diet is important when
trying to repair a leaky gut or improve IBS symptoms.
Lastly, assessing for small intestinal bacterial overgrowth
(SIBO) and implementing a specific-carbohydrate diet (SCD)
and/or low FODMAP diet in these cases is also important to
reduce bacterial fermentation causing gas, bloating,
abdominal discomfort and improve bowel regularity. We
will learn more about the assessment of SIBO and how this
condition is managed in the next section.

Small Intestinal Bacterial

Small intestinal bacterial overgrowth (SIBO) is defined as the
presence of excessive bacteria in the small intestine. SIBO is

frequently found to be the cause of chronic diarrhea and

malabsorption. Patients with SIBO may also suffer from
unintentional weight loss, nutritional deficiencies, and
osteoporosis.[505] A common misconception is that SIBO
affects only a limited number of patients, such as those with
an anatomic abnormality of the gastrointestinal (GI) tract or
those with a motility disorder. However, the recent literature
shows that SIBO may be more prevalent than previously
thought. This apparent increase in prevalence may have
occurred partly due to readily available diagnostic tests
which have improved our ability to diagnose SIBO.[505]

Prevalence of SIBO
Only limited data are available regarding the prevalence of
SIBO in healthy populations but age appears to be an
important risk factor. In a study of 294 non-hospitalized
older adults in which 34 younger adults (mean age 33.6
years) served as healthy controls, the prevalence of SIBO, as
determined by glucose breath test, was 5.9% in the control
group versus 15.6% in the older group.[505] Healthy elderly
volunteers from the United Kingdom had a 14.5% prevalence
rate for SIBO based on a positive glucose breath test.[505]

Small bowel bacterial overgrowth is an

important and under-recognized clinical
syndrome in the elderly. It is the most
common cause of malabsorption among
older adults[506]

Irritable bowel syndrome (IBS) is another known risk factor

for SIBO. Studies have shown that up to 78% to 84% of
patients who met the Rome I criteria for IBS had an
abnormal lactulose breath test suggestive of SIBO compared
to 20% of healthy volunteers.[507,508] In summary,
although data are limited, the prevalence rates of SIBO
appear to be consistently higher in patients with IBS.
However, it is also common in children with chronic
gastrointestinal symptoms and abdominal pain.

Similar to adults with irritable bowel

syndrome, there is a significantly higher
prevalence of SIBO in children with
chronic abdominal pain[509]
SIBO may be more common in children
with gastrointestinal symptoms and
apparent carbohydrate malabsorption

than previously recognized[510]

Prevalence of SIBO in Various


3% of patients with celiac disease

66% of patients with celiac disease with persistent GI
15% of elderly population
53% of patients with antacid medication use
78% of patients with IBS
33% of patients with chronic diarrhea
34% of patients with chronic pancreatitis
90% of alcoholics [505]

Causes of SIBO
SIBO can result from failure of the gastric
acid barrier, failure of small intestinal
motility, anatomic alterations or
impairment of systemic and local

In the intact intestine, small intestinal
bacterial overgrowth is prevented by the
actions of gastric acid, pancreatic enzyme
activity, small intestinal motility, and the
ileocecal valve[512]

Intestinal bacterial overgrowth develops when the normal

homeostatic mechanisms that control gut bacterial
populations are disrupted. The two most common
conditions that predispose to bacterial overgrowth are
diminished gastric acid secretion (hypochlorhydria) and
decreased small intestinal motility (sluggish bowels). Lets
take a brief look at how these conditions lead to SIBO.

SIBO: Low Gastric Acid

As discussed in Common Stomach Disorders:
Hypochlorhydria, gastric acid suppresses the growth of
ingested bacteria, thereby limiting bacterial counts in the
stomach and upper small intestine. Diminished acid
production (hypochlorhydria) is a risk factor for bacterial
overgrowth simply because there is less acid available to
prevent bacteria from growing. As discussed in the
hypochlorhydria section, there are a number of factors that
can lead to this condition, including colonization with H.
pylori, stress and as a consequence of aging.[505] SIBO can
also result from PPI use in the treatment of GERD.

A prospective study of 47 outpatients treated with either

omeprazole (20 mg/day) or cimetidine (800 mg/day) found
that bacterial overgrowth was present in 53% of patients who
received omeprazole (PPI), compared to only 17% who
received cimetidine (a weaker acid-suppressing medication).
[513] In another study, 20 patients treated with 4 weeks of
omeprazole had a significant increase in duodenal bacterial
counts (compared to baseline) as measured by endoscopic
aspiration.[514] These studies clearly show the importance
of stomach acid production in preventing bacterial

SIBO: Motility Disorders

Normal GI motility involves a complex, tightly coordinated
series of events designed to move material through the GI
tract. During periods of fasting, a migrating motor complex
(MMC) develops approximately every 90-120 minutes to
sweep residual debris through the GI tract. Several studies
have demonstrated that abnormalities in the MMC may
predispose to the development of SIBO.[515-517] There are
a number of conditions that can lead to decreased motility
including hypothyroidism, age-related enteric nervous
system degeneration, brain injury leading to poor vagal tone,
neurodegenerative disease, chronic pancreatitis and chronic

Small bowel motility disorders predispose to the

development of SIBO simply because bacteria (and any
undigested food which the bacteria need to flourish) may not

be effectively swept from the small intestine into the colon

for elimination. Gastroparesis, a chronic disorder of delayed
gastric emptying, can also lead to SIBO due to stasis of food
and bacteria in the upper GI tract. Patients with
chronic renal failure have neuropathic-like motor
abnormalities in the small intestine and are more likely to
develop bacterial overgrowth as well.[518] In addition,
neuropathic processes, such as chronic intestinal pseudoobstruction (CIP), and myopathic processes, such as
scleroderma and polymyositis, are likely to be associated
with SIBO.[519]

SIBO: Underlying Conditions

There are various underlying conditions that can lead to
alterations in the amount of gastric acid available to
neutralize bacteria or lead to motility disorders via an altered
migrating motor complex (MMC) which predispose to
bacterial overgrowth. SIBO can also result from anatomical
defects leading to bacteria pooling and scarring of intestinal
wall from chronic inflammation. Below is a list of some of
these conditions that appear to be risk factors for SIBO.

Underlying Conditions that

Predispose to SIBO

Hypochlorhydria: lack of acidity to neutralize bacteria and

pH homeostasis of small intestine
Proton pump inhibitor use for gastric reflux: lack of acidity
to neutralize bacteria and pH homeostasis of small intestine
Hypothyroidism: lack of thyroid hormone activation of vagal
motor nuclei and migrating motor complex
Age-related enteric nervous system degeneration: lack of
brainstem vagal motor nuclei to stimulate enteric nervous
Brain injury leading to poor vagal tone: lack of brainstem
vagal motor nuclei to stimulate enteric nervous system
Neurodegenerative disease: alpha synuclein or Lewy body
infiltration of intestinal migrating motor complex
Chronic pancreatitis: neuropathic destruction of migrating
motor complex from oxidative stress

Chronic diabetes: neuropathic destruction of migrating

motor complex from oxidative stress
Abdominal anatomical disturbances: anatomical location for
bacteria pooling
Fistula: anatomical location for bacteria pooling
Diverticula: anatomical location for bacteria pooling
Postsurgical alteration: damage of ileocecal valve or
promotion of anatomical location for bacteria pooling
Scleroderma: scarring of intestinal wall from chronic
Celiac disease: scarring of intestinal wall from chronic
Significant immunodeficiency: immunodeficiency to regulate
to regulate enteric bacterial populations of small intestine
Radiation-induced enteropathy: oxidative damage to
migrating motor complex of intestines [520]

Hypothyroidism and SIBO

Hypothyroidism is a major risk factor for the development of
bacterial overgrowth in the small bowel. Thyroid hormone is
critical for normal activity of the enteric motor complex and
vagal motor complex that regulate intestinal motility and
ileocecal valve control. Low levels of thyroid hormone in the
gut leads to decreased thyroid hormone activation of enteric
and vagal motor complex and decreased intestinal motility.
It also leads to decreased vagal activation of gastric acid
production which prevents bacterial overgrowth. In
summary, hypothyroidism leads to the following:

Decreased ileocecal valve control of trafficking bacteria from

large intestine to small intestine
Decreased gut motility leading to bacteriostasis in small

Decreased vagal activation of HCl release leading to inability
to suppress bacterial growth
All of these dysfunctions lead to SIBO as well as the following
Bacterial disruption in the small intestinal lumen
Interference with thyroid medication absorption
Decreased thyroid response on receptor sites

SIBO and Irritable Bowel

There is a significant amount of interest in the connection
between SIBO and IBS and in particular, the role of SIBO in

the development of IBS. First, many IBS symptoms are

nonspecific (bloating, distention, cramping, abdominal
discomfort) and can mimic symptoms of SIBO.[521] Delayed
transit, disordered motility, or abnormalities in the MMC, all
of which can occur in IBS patients, could potentially
predispose these patients to SIBO.[522] Additionally,
studies show a high prevalence of SIBO in IBS patients. In an
uncontrolled study, Pimentel and colleagues found that 157
of 202 patients (78%) who met the Rome I criteria for IBS
had an abnormal lactulose breath test suggestive of SIBO.
[507] A blinded, randomized study found that 84% of
patients who met Rome I criteria for IBS had an abnormal
lactulose breath test consistent with SIBO, compared to 20%
of healthy volunteers,[508] while another group reported a
SIBO prevalence rate of 65% in 98 consecutive IBS patients.

Another line of evidence in support of SIBO contributing to

IBS is evidence of IBS symptoms improving when treated for
bacterial overgrowth. In the above study which showed 78%
of IBS patients having SIBO, these patients were then treated
with antibiotics. Of the 47 patients that had follow-up testing
after antibiotic treatment, 25 of the 47 subjects (53%) had
eradication of their bacterial overgrowth. Those that had the

SIBO condition eradicated revealed a statistically significant

improvement in IBS symptoms of diarrhea and abdominal
pain compared to those that failed to eradicate SIBO. 48% of
the patients who eradicated SIBO no longer met criteria for
IBS.[507] The researchers concluded the following:

Small intestinal bacterial overgrowth is

associated with irritable bowel syndrome.
Eradication of the overgrowth eliminates
irritable bowel syndrome by study criteria
in 48% of subjects.[507]

SIBO, IBS and GERD: Common

The overlap of shared symptoms between SIBO and IBS, the

high incidence of SIBO in IBS and the high percentage of

elimination of IBS in the eradication of SIBO is compelling
evidence that SIBO is a contributing factor in a large
percentage of IBS patients.[507,487-489] Additionally,
research has shown a high incidence of IBS in patients with
GERD. A study performed at the GI Motility Center at
Cedars-Sinai Medical Center in 2002 found that 71% of
GERD patients tested positive for IBS double the
percentage seen in non-GERD patients examined. The
researchers concluded:

There is a higher prevalence of IBS in

subjects with GERD compared with
subjects without GERD.[524]

Based on these findings that most IBS patients have SIBO

and most GERD patients have IBS, we would expect to see a
high prevalence of SIBO in GERD patients. This is consistent
with some of the most recent literature that is starting to
examine this connection. In the largest retrospective cohort
study done to date, risk factors for SIBO were assessed and
correlated with diagnosis of small intestinal bacterial
overgrowth (SIBO). Diagnostic testing for SIBO was

performed using the D-xylose breath test (XBT). The XBT

was performed on 932 patients with symptoms of bloating,
abdominal pain, abdominal distension, weight loss, diarrhea,
and/or constipation based on a clinical suspicion for SIBO.
In the 932 subjects studied, 513 had a positive XBT. Medical
records of the 932 patients who completed the XBT were
reviewed. The researchers found a significant correlation
between a documented history of GERD (P = 0.04) or peptic
ulcer disease (PUD) (P 0.01) and a positive XBT indicating
SIBO.[525] Recall from the previous sections on GERD and
peptic ulcer disease (PUD), both of these conditions have
been associated with low stomach acid production
(hypochlorhydria) which explains the high incidence of
SIBO, as this is a known cause of SIBO. The researchers
made the following remarks that might explain the results of
the study:

Many of these (SIBO and PUD) patients

are placed on lifelong acid suppression
therapy, often using high-potency
pharmacotherapies (ie: PPIs). A less acidic
gastric milieu could create an environment
more conducive to SIBO.[525]

Based on the above studies, it is evident that

hypochlorhydria induces SIBO and there appears to be a
significant correlation between GERD, IBS and SIBO. Taken
together, these data support the theory presented earlier in
the Hypochlorhydria section above that hypochlorhydria
induces GERD and may be involved in the pathophysiology
of IBS as well. Which begs the question: Why are acidsuppressing medications, such as PPIs, being used in the
treatment of GERD?

SIBO, GERD and the Use of Proton

Pump Inhibitors
If hypochlorhydria induces both GERD and SIBO, we would
expect to see a higher prevalence of SIBO in GERD patients
with increased suppression of stomach acid production by
PPI therapy. This is consistent with the current literature on
PPI use in GERD patients and risk of SIBO. In one study, two
groups of patients with GERD were studied. One group was
given omeprazole (PPI) and the other group acted as a
control group and were not given omeprazole. 37% of the
PPI-treated group of GERD patients developed SIBO within
3 months compared to 10% of the GERD patients not treated
with the PPI.[526] The researchers concluded the following:

Proton pump inhibitor therapy in patients

with GERD results in a high prevalence of
gastric bacterial overgrowth. These

findings may have implications in the

of gastroesophageal mucosal injury.[526]

Another more recent larger study confirmed the earlier

results that the use of PPIs was associated with increased
risk of SIBO. In this study, glucose hydrogen breath tests
(GHBTs) were used to assess for SIBO. These GHBTs were
given to 450 consecutive patients (200
with gastroesophageal reflux disease (GERD) who received
PPIs for an average of 36 months; 200 with irritable bowel
syndrome (IBS) with no PPI treatment for at least 3 years;
and 50 healthy control subjects that had not received PPIs
for at least 10 years).

SIBO was detected in 50% of patients using PPIs, 24.5% of

patients with IBS, and 6% of healthy control subjects. There
was a statistically significant difference between GERD
patients using PPIs and those with IBS or healthy control
subjects (P < .001). The prevalence of SIBO increased after 1
year of treatment with PPIs.[527] The researchers concluded
the following:

SIBO, assessed by GHBT, occurs

significantly more frequently among long
term PPI users than patients with IBS or
control subjects.[527]
A large meta-analysis conducted in 2013, which reviewed all
the studies available showing a correlation between the use
of PPIs and risk of SIBO, concluded the following:

Use of proton pump inhibitors (PPIs)

could predispose individuals to small

intestinal bacterial overgrowth (SIBO) by

altering the intraluminal environment and
bacterial flora[528]

Disruptions to Normal Physiology

Caused by SIBO
Small intestinal bacterial overgrowth causes various
disruptions to normal physiology which lead to a wide range
of symptoms and signs, such as increased gas formation
leading to abdominal distension and bowel irregularity,
constipation and diarrhea (as a result of fermentation of
undigested food in GI tract); protein deficiency and
ammonia production (as a result of excess intestinal bacteria
leading to bacterial competition with host for protein);
nutrient malabsorption (as a result of enterotoxin
production from excess gram-negative intestinal bacteria

and damage to brush border mucosa); fat malabsorption (as

a result of excess intestinal bacteria metabolizing bile salts to
unconjugated or insoluble compounds, leading to
impairment of bile salt micelle complex and fat

production of lithocholic acid and enteric nervous system

degeneration (as a result of excess bacteria in small intestine
metabolizing bile salts to unconjugated or insoluble
compounds); and destruction of intestinal tight junctions,
systemic inflammation and destruction of intestinal
migrating motor complex (as a result of excess bacteria in
small intestine leading to enterotoxin production from gramnegative bacteria and destruction of intestinal tight
junctions). Destruction of intestinal tight junctions leads to
lipopolysaccharide (LPS) translocation and activation of
hepatic macrophages leading to release of hepatotoxic
factors and increased systemic and local intestinal

Summary of Disruptions to
Normal Physiology Caused by


Increased gas formation leading to abdominal distension and

bowel irregularity, such as constipation and diarrhea (as a
result of fermentation of undigested food in GI tract)

Protein deficiency and ammonia production (as a result of

excess intestinal bacteria leading to bacterial competition
with host for protein)
Nutrient malabsorption (as a result of excess enterotoxin
production from gram-negative intestinal bacteria and
leading to damage to brush border mucosa)
Fat malabsorption (as a result of excess intestinal bacteria
metabolizing bile salts to unconjugated or insoluble
compounds, leading to impairment of bile salt micelle
complex formation and fat malabsorption)
Production of lithocholic acid and enteric nervous system
degeneration (as a result of excess intestinal bacteria
metabolizing bile salts to unconjugated or insoluble
Destruction of intestinal tight junctions, systemic
inflammation and destruction of intestinal migrating motor
complex (as a result of enterotoxin production from excess
gram-negative intestinal bacteria and destruction of

intestinal tight junctions)

Destruction of intestinal tight junctions leads to
lipopolysaccharide (LPS) translocation and activation of
hepatic macrophages leading to release of hepatotoxic
factors and increased systemic and local intestinal

Assessment of SIBO
The diagnosis of SIBO is controversial.
There is substantial disagreement in the
literature regarding which test is the most
appropriate in either the clinical or
research setting. Two tests are commonly
employed: bacterial culture and breath

Two tests are commonly used to assess for SIBO: bacterial

culture and breath tests. The most direct method of assessing
the bacterial population of the gut is to perform bacterial
colony counts of small bowel contents on
aspiration; however, the cost of endoscopy and the invasive
nature of this procedure with its low but measurable risk,
makes this approach less than ideal. There are also several
technical hurdles which make this test impractical in many

cases. First, many bacterial species do not grow in routine

culture media, and quantitative culture may underestimate
the bacterial population. Additionally, there are multiple
problems inherent in performing this procedure including
contamination of the endoscope and catheter as the
instrument is passed through the GI tract, difficulty
aspirating a sufficient sample, and other issues such as
proper specimen handing which affects accurate sampling.

For these reasons, hydrogen breath tests are the most

common diagnostic tool for SIBO since they are noninvasive,
cheap, simple and safe. These tests are based on the
measurement of hydrogen and methane in breath samples.
These gases are produced by bacteria as a consequence of
carbohydrate fermentation after oral ingestion of glucose
and lactulose, and pass through the blood circulation where

they are expelled in the lungs. The diagnosis of SIBO is

established on the increase of hydrogen and methane gases
with respect to the baseline sample. Unfortunately, breath
tests have not yet been standardized, in terms of substrate
concentration, duration of tests, time intervals of breath
sampling and cut-off values.[529] As a result, hydrogen
breath tests are still not well-accepted as a specific test for
SIBO in the field of gastroenterology.[505] However,
hydrogen breath tests remain the most common diagnostic
tool for SIBO.

Although not without shortcomings,

hydrogen breath testing provides the
simplest non-invasive and widely available
diagnostic modality for suspected SIBO.
Diagnostic accuracy of hydrogen
breath testing in SIBO can be maximized
by careful patient selection for testing,
proper test preparation, and
standardization of test performance as
well as test interpretation.[530]

Conventional Treatment of SIBO

Conventional treatment aimed at correcting the underlying
cause of SIBO primarily includes surgical and drug therapies.
Surgical revision of altered small bowel anatomy may be
beneficial in patients with SIBO secondary to small bowel
diverticulosis, fistulas, or strictures. Medications should be
reviewed to determine if they are playing a role in the
development of symptoms. Prokinetic drugs (to increase
intestinal peristalsis) are used in cases of dysmotility or
gastroparesis. The mainstay of conventional treatment for
SIBO remains antibiotic therapy. A variety of antibiotics
have been used in the treatment of SIBO, most with little
supporting evidence. Ideally, antibiotic therapy would be
based on bacterial culture and sensitivity data. However, this
approach is impractical in the clinical setting and treatment
is thus directed at likely organisms based on reports of
culture data from SIBO patients.[505] Early antibiotics used
in the treatment of SIBO included tetracycline and its
derivatives and other broad-spectrum antibiotics such as
amoxicillin/clavulanate, ciprofloxacin, and doxycycline.
However, these recommendations were based on
uncontrolled data.[505] More recently, antimicrobials such
as Rifaximin and metronidazole have shown efficacy in
improving hydrogen breath test results and symptoms of
SIBO. [531-533]

The optimal duration of antibiotic therapy is not known, and

most trials employed a 7- to 10-day course. However, one of
the drawbacks to the use of antibiotics in the treatment of
SIBO is recurrence of SIBO and the need for additional
courses of antibiotics. In fact, one trial demonstrated an
average duration of symptom improvement of only 22 days,
which translates into a need for at least 12 courses
(presuming 7 days) of antibiotics per year to provide
persistent symptom relief.[534]

Glucose breath test positivity recurrence

rate was high after antibiotic
Patients with evidence of GBT positivity
recurrence showed gastrointestinal
symptoms relapse thus suggesting SIBO
Inadequate or incomplete response to
antibiotic therapy is common[536]

Clinical Management of SIBO in

Functional Medicine
In the functional medicine model, we address the underlying
causes that lead to this condition as well as the
pathophysiology involved in bacterial overgrowth using
botanical and other natural compounds. As we learned
earlier, SIBO is prevented by the following physiologic

Actions of gastric acid

Pancreatic enzyme activity
Small intestinal motility
Normal activity of the ileocecal valve
Therefore, it is important to assess these bodily functions in
the individual and support them when deficient. As
discussed earlier, the most common causes of this condition
are hypochlorhydria (low stomach acid) and decreased
intestinal motility (sluggish bowels).

Hypochlorhydria and pancreatic enzyme deficiency can

usually be addressed by supplementing with hydrochloric
acid (HCl) and pancreatic enzymes. Discontinuation of PPI
therapy in the treatment of GERD is also important in the
treatment of SIBO and this can be accomplished by
supporting gastric acid levels and pancreatic enzyme levels
which as we have seen are at the root cause of both GERD
and SIBO. There are a number of factors that can contribute
to decreased intestinal motility as discussed above, such as
hypothyroidism and decreased vagal activation, so assessing
for these underlying conditions and addressing these causes
when present is important. Thyroid hormone levels must be
normalized prior to addressing the bacterial overgrowth.
Decreased vagal activation can be supported by providing
the patient exercises to increase vagal output, such as
gargling with water throughout the day and promoting the
gag reflex. Coffee enemas can also be used to induce
activation of enteric motility and activate the brain-gut axis.


As discussed above, there are a number of physiologic

imbalances that take place in SIBO, including increased gas
formation leading to abdominal distension and bowel
irregularity, constipation and diarrhea, protein deficiency
and ammonia production, nutrient malabsorption, fat
malabsorption, production of lithocholic acid and enteric
nervous system degeneration, destruction of intestinal tight
junctions, systemic inflammation and destruction of
intestinal migrating motor complex, lipopolysaccharide
(LPS) translocation and activation of hepatic macrophages.
All of these conditions should be assessed and supported
when indicated. This can be done with herbal/botanical and
nutritional compounds shown in the literature to support
these physiologic imbalances in most cases. In some cases of
severe or chronic SIBO, anti-microbial therapy is indicated.
Nutritional support, particularly in those patients with
weight loss or vitamin and mineral deficiencies, is an
important component of SIBO treatment. Supplementation
and maintenance of vitamin B12 and fat-soluble vitamins,
with correction of calcium and magnesium deficiencies, are
key components of treatment.

Probiotics and SIBO

Recent studies have shown that patients with bacterial
overgrowth conditions can benefit from the use of probiotics
although further studies are needed to define the role of
probiotic therapy in SIBO. A randomized, double-blind,
placebo-controlled study on 22 patients with proven
bacterial overgrowth and chronic diarrhea showed
improvement in frequency of symptoms after 15 days and 21
days and the effect was sustained at 7 days and 15 days after
withdrawal.[537] The strains used were Lactobacillus casei
and L. acidophillus strains (LC). A significant decrease in
hydrogen gas concentration was noted in hydrogen breath
testing at 7 days (p < 0.005) at 15 days, and 21 days (p <
0.0001) with these probiotics and at 7 days after withdrawal.
The researchers concluded the following:

In summary, this study provides evidence

that LC are effective for treatment of
bacterial overgrowthrelated chronic
diarrhea, and suggest that probiotics must
be used with continuity.[537]

In another randomized study of 50 patients with chronic

abdominal distension and diagnosis of SIBO made by a
lactulose hydrogen breath test, the effects of probiotics were
compared to metronidazole, a common antimicrobial
medication used to treat SIBO. The probiotic administered to
the treatment group contained Lactobacillus casei,
Lactobacillus plantarum, Streptococcus faecalis, and
Bifidobacterium brevis (Bioflora) for 5 days. The population
was divided into two treatment groups of 25 patients in each
group. Both groups went on the same diet, which consisted
in reduced consumption of alcohol, legumes, dairy products
and leafy green vegetables. 13 subjects (52%) receiving
metronidazol and 20 (82%) receiving the probiotic showed
improvement in symptoms after the treatment. The probiotic
group showed a statistically significant difference in
symptoms (P = 0.036).[538] The researchers concluded:

Based on this pilot study results, we can

suggest that the probiotic herein used has
a higher efficacy than metronidazole in the

early clinical response of patients with

chronic abdominal distension and
Other studies have shown the following:

In uncomplicated cases, symptom-free

condition could be reached with probiotics,
whereas in long lasting, chronic small
intestinal bacterial overgrowth, antibiotic
treatment should be considered[539]
Decontamination of the small intestine is more successful
when probiotics are prescribed (both after antibiotics and
independently), which suppress the opportunistic flora,
protect the mucous coat, improve digestion and arrest

Dietary Intervention and SIBO

Diet is critical in the bacterial overgrowth patient since many

of the overgrowth problems result directly from incomplete

carbohydrate digestion and absorption. Some types of
carbohydrates such as sugars (fructose, lactose, galactose,
etc.), grains (including gluten and gluten-free grains, rice
and corn products), dairy (lactose and casein), legumes
(galactans) and certain fruits (high-fructose) and vegetables
(high-fructan, high starch vegetables) induce bacterial
overgrowth. Therefore, eliminating these foods from the diet
is an important part of recovering from bacterial overgrowth.
For a more detailed list of the specific-carbohydrate diet
(SCD) we recommend, please read the upcoming article on
SIBO in part 8 of the Successful Aging series.

More Disorders of the Intestinal

Tract coming summer 2015
Related Articles:
Functions of Gastrointestinal Tract
Gut Connections with Other Organs
The Neuroendocrine System of the Gut and the Brain-Gut