Download Literature Review Summary

Literature Review Summary
Small intestinal bacterial overgrowth (SIBO) is defined as an increase in the number of
bacteria to >105 bacteria/mL or an alteration in the type of bacteria in the upper gastrointestinal
tract (proximal jejunum) (1, 2). The etiology of SIBO is often linked to dysfunction in one or
more of the body’s defense mechanisms listed below (1, 2):
1. Dysfunction of the antibacterial/ gastric acid barrier
2. Impairment of systemic/ local immunity
3. Anatomical alterations
4. Motility Disorders
5. Impaired Ileo-caecal valve function
The body has three natural antibacterial mechanisms that protect against SIBO, these are;
gastric acid secretion, pancreatic enzymes and the immune system (1). Compromised function in
any of the three physiological processes allows opportunistic bacteria to overgrow in the small
intestine.
Increased risk of bacterial overgrowth can be a consequence of anatomical alternations to
the GI tract that result in reduced exposure to gastric acid, decreased clearance of bacteria or
detainment of food (2). Small intestinal obstruction, diverticula, fistulae, surgical blind loop and
ileo-caecal resections are all examples of structural abnormalities that can disrupt the normal
flow of food through the digestive tract (1).
More then just anatomical abnormalities can affect our digestive systems motility.
Regular peristaltic waves prevent the attachment and permanent residence of ingested
microorganism (1). The phase 3 contractions of the migrating motor complex (MMC) occur
every 90-120 min during the fasting state to sweep the small bowel of debris and remnant food
(2). An important consideration noted in the literature was that a fasting state must be reached
before the phase 3 contraction can occur (2). Constant snacking prevents the body from ever
reaching the fasting state and can inhibit this defense against bacterial overgrowth. Additionally,
conditions that damage the visceral nervous and muscular systems can compromise motility in
the digestive system and increase the likelihood of SIBO (2). The following conditions affect the
muscular system that controls peristalsis: scleroderma, diabetes mellitus, post-radiation
enteropathy, and small intestinal pseudo-obstruction (1).
The body’s final natural defense mechanism against the development of SIBO is the ileocaecal valve. The ileo-caecal valve separates the distinct bacterial environment of the colon from
that of the small intestine (1). When this valves function is compromised reverse peristalsis can
occur allowing bacteria native to the colon to occupy the small intestine (1).
SIBO commonly develops as a secondary condition in the presence of other health
conditions that compromise the function of the defense mechanisms discussed above. These
include: Crohn’s Disease, short bowel syndrome, non-alcoholic steatohepatitis, liver cirrhosis,
scleroderma, diabetes mellitus, radiation enteropathy, fibromyalgia, lympho-proiferative disease,
metabolic bone disease, acromegaly, hypothyreosis, alcoholism, rosacea, old age (>75 yrs),
celiac disease (those unresponsive to a gluten free diet) and cystic fibrosis (1).
The literature has also shown a clear association between IBS and SIBO. Recent research
suggests that overgrown gut bacteria may play a role in producing the symptoms of IBS. The
studies reviewed found that when breath tests were administered to IBS patients, between 6584% tested positive for SIBO (3, 4, 5, 6). When SIBO was tested using aspiration (duodenal and
jejunal) the positive tests within the IBS patients was significantly less. When duodenal
aspiration was used for diagnosis, 37.5% of IBS patients tested positive for SIBO (7). This study
found that SIBO was much more prevalent in IBS patients in the diarrhea predominant subgroup.
Within the diarrhea predominant subgroup, 60% of IBS-D patients tested positive for SIBO (7).
Contrary to the five studies discussed above, when Posserud et al. evaluated the relationship
between IBS patients and SIBO, using jejunal aspiratation, only 4% of patients tested positive for
SIBO (8). They initially defined a positive test as >105/ml bacteria in the upper gastrointestinal
tract. However, when they reevaluated the results of the jejunal aspirate to a diagnostic criteria of
>103/ml, 43% of the IBS patients tested positive (8).
After diagnosing SIBO, the researchers treated patients with a variety of antibiotics in the
hope of relieving IBS symptoms through treating the bacterial overgrowth. Pimentel et al. found
significant reduction in digestive complaints, specifically diarrhea and abdominal pain when
eradication of SIBO was successful (4). After treatment, 48% percent of the IBS patients who
were successfully treated with antibiotics in this study tested negative for IBS, using the Rome
criteria (4). Positive effects on digestive distress were seen with successful eradication of SIBO.
However, successful antibiotic treatment was not achieved in more than 62% of patients treated
in the reviewed studies. The success rate in one study was as low as 20%, although most studies
successful treated around 50% of the SIBO patients with antibiotics (3,4,5,6). The
ineffectiveness of antibiotics in treating SIBO is thought to be attributed to the large number of
different enteric organisms (5).
The findings in these studies support the use of breath tests to differentiate the
overlapping symptoms of IBS and SIBO, which will ensure proper diagnosis and treatment. One
study specifically stressed the importance of testing and treating SIBO before testing sugar
malabsorption or eliminating sugars from the diet (3). They found that many participants tested
positive for sugar malabsorption before SIBO was treated. They caution health care professionals
to ensure that SIBO is not the causing the malabsorption of sugars.
The proper treatment of SIBO is important to prevent the co-morbidities that can be
caused by bacterial overgrowth (1). These include maldigestion and malabsorption of both
carbohydrates and fat. Poor digestion and absorption of fat may result in deficiencies in fat
soluble vitamins, as well B12 deficiency (1). Bacterial toxins can cause villi atrophy similar to
that seen in celiac disease (1). Other consequences include weight loss, liver lesions, increased
intestinal permeability, protein deficiency and neurological abnormalities (high serum D-lactic
acid) (2). A distinct feature of SIBO is high serum folate and vitamin K (over produced by
bacteria) and low B12 (2).
There are several other clinical tests that can be used to confirm the diagnosis of SIBO.
The gold standard test is jejunal aspiration. However, this test is very invasive and for that
reason is rarely used (2). Breath tests for lactulose, glucose and xylose are less invasive
alternatives to confirm the presence of SIBO (2). Lactulose and glucose breath tests have 6070% sensitivity and 40-80% specificity when compared to the gold standard (jejunal aspiration)
(2). However, breath testing is unable to differentiate between the types of colonizing bacteria.
The treatment of SIBO is complex and individualized. Three guiding principles appeared
several times within the literature (1): 1) treat the underlying disease 2) nutrition support for
malnourishment 3) antibiotic treatment. There is no general consensus on the type, dose and
duration of antibiotic for SIBO treatment. The antibiotic Rifaximin is seen to have the greatest
success in treating SIBO in the reviewed studies (3, 6). Its low GI absorption and effectiveness
on both gram positive and negative, as well as on aerobic and anerobic bacteria make it
particularly effective (1).
Article Summaries
1) Bures J, Cyrany J, Kohoutova D, Forstl M, Rejchrt S, Kventina J, et al. Small intestinal
bacterial overgrowth syndrome. World J Gastroenterol [Internet]. 2010 [cited 2014 Jun
12]; 16 (24): 2978-2990. doi: 10.3748/wjg.v16.i24.2978.
The duodenum and jejunum are sparsely populated with gram-positive aerobes/ facultative
anerobes [<104 organisms per ml). The ileum functions as a transition between this proximal area
of the small intestine and the large bowel, which is densely populated with anaerobic bacteria.
SIBO is an increase in the number and/or alteration in the type of bacteria in the upper
gastrointestinal tract (>105 bacteria/mL). The endogenous defense mechanism for preventing
bacteria growth including:
 Gastric acid secretion
 Intestinal motility
 Intact ileo-caecal valve
 Immunoglobulins (via intestinal secretion)
 Bacteriostatic pancreatic functions
 Biliary secretion
The etiology of SIBO is often associated with
 Disorders of protective antibacterial mechanism:
o Achlorhydria: is the absence of hydrochloric acid in gastric secretions. Which
can be caused by chronic atrophic gastritis or long-term use of proton pump
inhibitors. The hydrochloric acid’s antibacterial function in the stomach is
compromised in both these conditions allowing bacterial growth in the stomach
and duodenum.
** proton pump inhibtors not only decrease the protective acid sections, but can
increase intestinal transit time.
o Exocrine Pancreatic Insufficiency: chronic pancreatitis is complicated by SIBO in
30-40% of cases. The loss of anti-bacterial proteolytic enzymes, abnormal chime
and motility disorders increase prevalence of SIBO.
o Immunodeficiency syndromes such as IgA deficiency and AIDS increase risk of
infections such as SIBO in patients
 Anatomical abnormalities: small intestinal obstruction, diverticula, fistulae, surgical
blind loop, ileo-caecal resections
o Small intestinal obstruction & stagnation (strictures, adhesions, tumors,
diverticula or abdominal surgery) often cause increas susceptibility to SIBO.
Structural abnormalities affect the motility of food through the digestive tract
which can increase the risk of SIBO.
 Motility disorders: scleroderma, autonomic neuropathy in diabetes mellitus, postradiation enteropathy, small intestinal pseudo-obstruction
Conditions that Increase the Prevalence of SIBO
1. SIBO & IBS: There is conflicting hypothesis about the clear relationship between IBS and
SIBO. Believers of the:
 Bacterial hypothesis believe that SIBO is the primary event and IBS the secondary. The
microbial genome for fecal microbiota in those with IBS is different then the healthy
population
 Others believe that IBS is the primary factors, causing motor disturbance, visceral
hypersensitivity and psycho-social dysfunction leading the secondary bacterial
overgrowth- SIBO.
 Others believe that there is a distinction between the two and that they are not
interdependent.
2. SIBO & Crohn’s Disease: SIBO is particularly prevalent in Crohn’s patients who have loss of
the ileo-caecal valve due to a resection. After resections valve function is compromised and
reverse peristalsis can occur causing colonization of the small intestine (SIBO).
3. SIBO & Short Bowel Syndrome: the reduction in absorptive surface area and acceleration
through the GI tract due to the loss of the ileo-caecal valve/ ileal break prevent food from
being properly digested. The undigested food can become a substrate for bacterial
fermentation
4. Non-alcoholic Steatohepatitis: the fatty accumulation in the liver effects the function of bowel
motility and it is thought that exposure to edotoxins may have an effect.
5. Age: elderly subjects have a prolonged orocaecal transit time in comparison with younger
subjects and SIBO has been described among the elderly in the absence of any obvious
predisposing cause (>75 yrs)
6. Liver Cirrhosis: The portal hypertention that occurs in cirrhosis changes the intraluminal
milieu of the gut
7. Scleroderma: this chronic connective tissue disease can manifest pseudo-obstruction leading
to SIBO
8. Autonomic Neuropathy in Diabetes Mellitus: the damage from diabetes causes delayed gastric
emptying and motility disorders- both these consequences increase risk of SIBO
9. Radiation enteropathy: SIBO & lactose intolerance may develop after radiotherapy of the
pelvis
10.
Other Conditions: Fibromyalgia, Lympho-proiferative disease, Metabolic bone disease,
Acromegaly, Hypothyreosis, Alcoholism, Rosacea, Celiac’s who are non-responsive to a
gluten-free diet, Cystic Fibrosis
Bacterial homeostasis is affected by:
 pH
 Peristalsis
 Redox potential
 Bacterial adhesion
 Bacterial co-operation/antagonism
 Diet (amount and composition)
 Nutrient availability
 Drugs/ alcohol
 Stress
Defense mechanism to prevent excess bacterial growth in the small intestine include:






Antegrade peristalsis: prevents the attachment of ingested micro-organisms
Gastric acid & bile: destroy micro-organisms in the stomach before moving into the small
intestine
Proteolytic enzymes: destroy bacteria in the small intestine
Intestinal mucus: traps bacteria
Ileo-caecal valve: inhibits retrograde translocation of bacteria from the colon to the small
bowel
Immune system
Consequences of SIBO:
 Maldigestion and malabsorption (if bacteria metabolize fructose, lactose and sorbitol
malabsorption of saccharides may occur)
 Bacteria can interfere with enzymatic, absorptive and metabolic actions of microorganisms
 Can cause damage to the brush border, effecting the breakdown of disaccharides
 Damage to the mucosa can cause increased permeability and protein losing enteropathy
 Vit B12 deficiencies can manifest from anaerobic micro-organisms consuming this
vitamin
 Protein deficiency can develop if bacteria use intraluminal protein and excessive
ammonia production by bacteria
 Fat malabsorption can also develop if bacteria deconjugate the bile salts. Fat
malabsorption is frequently accompanied by deficiency in fat soluble vitamins
 Bacteria produce toxins as by products  which stimulates the production of proinflammatory cytokines which can cause villi atrophy (similar to the damage in celiac
disease)
Clinical Symptoms:
SIBO can be asymptomatic, however frequently the symptoms include bloating, diarrhea,
malabsorption, weight loss and malnutrition (resembling IBS). In severe cases malabsorption,
liver lesions, skin manifestations, arthralgias and deficiencies (macrocytic anemia, vitamin D,
metabolic bone diseasecan manifest
** A distinct feature of SIBO is normal/ high serum folate and vitamin K levels – caused by
bacterial overproduction.
Another severe complication that can result from SIBO in the case of overgrowth of lactobacilli,
non-absorbed saccharides are fermented in the large bowel to the D-isomer of D-lactic acid. Dlactic acid is absorbed, but the body has no system to metabolize them, elevated serum
concentrations can lead to neurological abnormalities (confusion, cerebellar atazia, slurred
speech and loss of memory).
Principles of Treatment:
Therapy for SIBO is complex and individualized. The three guiding principles to treatment are:
1. Treat the underlying disease
2. Nutritional support for malnourishment
 Ex: enteral nutrition, lactose free diet, reduction of simple sugars
3. Cyclical Gastro-intestinal selective antibiotics

There is no general agreement on the dosing, duration and type of antibiotic. The
use of a broad-spectrum antibiotic is not optimal (antibiotic resistance, diarrhea,
clostridium difficile). Rifaximin is a popular antibiotic for treatment because of its
low GI absorption and because of its effectiveness on gram + and –ve, as well as
both aerobic and anerobic bacteria.
Role of prebiotics and probiotics:
Can strengthen the barrier function of the gut, inhibit pathogens, and reduce the inflammatory
response of the bowel and visceral hypersensitivity. However, their therapeutic effectiveness is
limited, therefore they are not recommended for general clinical use.
2) Bohm M, Siwiec R, Wo J. Diagnosis and management of small intestinal bacterial
overgrowth. Nutr Clin Pract [Internet]. 2013 [cited 2014 Jun 15]; 28 (3):289-299. doi:
10.1177/0884533613485882.
In healthy individuals
 Gram-positive are found in the stomach, duodenum and proximal jejunum <103
CFU/mL overgrowth of gram positive results when failure of the gastric acid
protective mechanism (>105 CFU/mL)
 Gram-negative bacteria are found in the colon. Overgrowth of coliform gram –ve in the
small bowel results in malabsorption, diarrhea, weight loss and nutrition deficiency, also
know as SIBO (>105 CFU/mL)
The distal ileum is the transition zone between the sparsely populated aerobic bacteria in the
small bowel and the densely populated anaerobes in the colon.
Pathophysiology of SIBO can be classified into 4 causes:
1. Failure of gastric acid barrier: gastric acid kills 99% of bacteria in the stomach within
5 min. The failure of this protective mechanism allows bacteria to populate the GI tract.
Proton pump inhibitors, inhibit acid secretion and can increase the pH environment in the
stomach by 2 units. Gastric acid impairment causes overgrowth of gram-positive, which
doesn’t appear to cause clinically significant symptoms/complications.
2. Failure of Small bowel clearance: Small intestinal peristalsis is essential in controlling
small intestine bacterial growth. The phase 3 contractions of the migrating motor
complex (MMC) occurs every 90-120 min during the fasting state to sweep the small
bowel of debris and remnant food. Any condition that affects visceral enteric neurologic
and muscular system can affect this protective mechanism and cause SIBO.
3. Anatomic alteration: structural changes that reduce exposure to gastric acid, ineffective
clearance of bacteria or retain food increase risk of SIBO
4. Impairment of systemic and local immunity
Clinical Manifestations:



Fat malabsorption: bacterial deco junction of bile salts can cause steatorrhea.
CHO malabsorption: occurs as a result of premature digestion by bacteria and impaired
disaccharidase activity due to damage to the brush border
B12 def: can develop in patients with SIBO due to competitive uptake by luminal bacteria
Diagnostic Testing
 Increase in serum folate and simultaneous low B12 is an indirect marker
Breath Testing
Lactulose: lactulose is not absorbed until it reaches the colon and is metabolized by the
resident bacteria of the large bowel- identified by a hydrogen peak 90 minutes after
ingestion. In SIBO there is an early hydrogen peak, before the 90 minute mark. This
indicates the presence of colonic bacteria in the small intestine. A second hydrogen peak
will also be measured at the 90 minute mark when the lactulose is metabolized by the
bacteria native to the large intestine.
Glucose: is rapidly and completely absorbed in the small bowel before reaching the colon
without hydrogen or methane elevation. In SIBO glucose is metabolized by abnormal
small bowel bacteria before being absorbed- producing a hydrogen and methane peak.
Xylose: can be used in a breath test for SIBO- however it is rarely used in practice
because of the exposure to radiation
Lactulose and glucose breath tests when compared with the gold standard of jejunal aspiration
and culture, have sensitivities of 60-70% with specificities of 40-80%. However, breath testing
does not differentiate between types of colonizing bacteria.
False-positive breath tests may occur due to: rapid small bowel transit, oral flora, a high-fibre
diet the day before, recent exercise, those with lung disease and smokers.
3) Nucera G, Gabrielli M, Lupascu A, Lauritano E, Santoliquido A, Cremonini F, et al.
Abnormal breath tests to lactose, fructose and sorbitol in irritable bowel syndrome may
be explained by small intestinal bacterial overgrowth. Aliment Pharmacol Ther
[Internet]. 2005 [cited 2014 Jun 16]; 21: 1391-1395. doi: 10.1111/j.13652036.2005.02493.x.
The purpose of this study was to assess the extent that SIBO may influence the results of
hydrogen sugar breath tests in IBS patients. It is believed that the undiagnosed presence of SIBO
can cause false positives in lactose, fructose and sorbitol hydrogen breath tests in IBS patients.
The study found that 65% of participants (IBS patients) tested positive for SIBO (using the
lactulose breath test). Subjects who tested positive for SIBO were also more likely to test
positive for sugar malabsorption. After treatment of SIBO with antibiotics, a significant
reduction in positive tests for sugar malabsorption was seen. It is important to note that
successful antibiotic treatment of SIBO was only seen in 62% of the population.
These results can be applied in the treatment of IBS by testing to detect SIBO initially, before
testing for sugar malabsorption or eliminating sugars in the diet.
4) Pimentel M, Chow E, Lin H. Eradication of Small Intestinal Bacterial Overgrowth
Reduces Symptoms of IBS. Am J. Gastroenterol [Internet]. 2000 [cited 2014 Jun 6]; 95
(12): 3503-3506. doi:
This study looked at whether SBIO is associated with symptoms of IBS and if treatment of SIBO
reduces intestinal complaints. This study found that of the 202 IBS patients, 157 (78%) had
overgrowth. When successful eradication of SIBO using antibiotics was achieved there was a
significant reduction in the complaints of diarrhea and abdominal pain, no symptom change was
seen in those who eradication was not achieved in. 53% of the group treated with antibiotics
achieved successful eradication and a negative SIBO test. 48 % of the patients successfully
treated with antibiotics after tested negative on the Rome Criteria. There appears to be a higher
prevalence of SIBO in subjects with IBS and successful treatment of SIBO results in significant
improvement in GI complaints, with almost 50% elimination of IBS (as stated by the Rome
Criteria)
5) Pimentel M, Chow E, Lin H. Normalization of Lactulose Breath Testing Correlates with
Symptom Improvement in Irritable Bowel Syndrome: A Double-Blind, Randomized,
Placebo-Controlled Study. Am J. Gastroenterol [Internet]. 2003 [cited 2014 Jul 7]; 98
(2): 412-419. doi: 10.1016/S0002-9270(02)05902-6.
This double blind study looked at the association between SIBO (abnormal lactulose breath test –
LBT) and IBS. The study looked to test the effectiveness of antibiotic treatment to reduce IBS
symptoms. 111 IBS subjects were treated with an antibiotic (neomycin) or a placebo. Of the 111
IBS patients 84% tested positive to a LBT [a positive test indicates SIBO], compared to only
20% of the healthy control population testing positive to LBT. Although antibiotics did improve
symptoms in those who positively tested in the LBT, the antibiotic neomycin was only able to
normalize the breath test (treat SIBO) 20% of the time. The ineffectiveness of antibiotics at
treating all cases of SIBO has thought to be attributed to the large numbers of different enteric
organisms.
When analyzing the type of gas produced in the LBT they found that when it was methane
excreted in the abnormal breath test (over hydrogen) 100% of these participants fell into the
constipation-predominant IBS group. Methane appears to be more common in conditions that
slow gastric transit (diverticulosis & encopresis) and not found in diarrheal conditions (crohn’s
or colitis)
6) Esposito I, de Leone A, Di Gregorio G, Giaquinto S, de Magistris L, Ferrieri A, Riegler
G. Breath test for differential diagnosis between small intestinal bacterial overgrowth
and irritable bowel disease: An observation on non-absorbable antibiotics. World J
Gastroenterol [Internet]. 2007 [cited 2014 Jul 29]; 13(45): 6016-6021.
The aim of this study was to estimate the prevalence of SIBO among patients with an earlier
diagnosis of irritable bowel disease (IBS), and evaluate the effect of non-absorbable antibiotics
in the management of SIBO. Of the 73 IBS patients tested using a lactulose breath test 45.2%
tested positive. After treatment with rifaximin (1200mg/d/7 days) 59.4% of patients tested
negative in the LBT, as well as reduction in digestive symptoms. For the remaining 40.6% of
patients who’s SIBO was not eradicated by rifaximin, ciprofloxacin (500 mg/d/ 7 days) was
used, but it was not effective at treating the bacterial overgrowth. These results support the use of
breath tests by clinicians to distinguish between SIBO and IBS since symptoms are so similar.
Proper treatment for SIBO’s is essential to prevent systemic consequences such as malabsorption
of lipids & lipid soluble vitamins, loss of electrolytes, translocation of bacterial to extraintestinal
tissues.
7) Pyleris E, Giamarellos-Bourboulis E, Tzivras D, Koussoulas V, Barbatzas C, Pimentel
M. The Prevalence of Overgrowth by Aerobic Bacteria in the Small Intestine by Small
Bowel Culture: Relationship with Irritable Bowel Syndrome. Dig Dis Sci [Internet].
2012 [cited 2014 Jul 30]; 57: 1321-1329. doi: 10.1007/s10620-012-2033-7
The purpose of this study was to determine the frequency of SIBO in IBS patients using
duodenal aspirate for diagnosis Other studies have used a positive glucose or lactulose breath test
to diagnose SIBO, the sensitivity and specificity of these breath tests have been under scrutiny
for their accuracy. Additionally, breath tests don’t allow for the identification of the type of
bacteria overgrowing the in small intestine. This study found that 37.5% of participants that met
the criteria for IBS diagnosis also had SIBO (specifically aerobe colonic bacteria). The
prevalence of SIBO was even greater in IBS patients in the diarrhea predominant subgroup, with
60% of IBS-D patients testing positive for SIBO. Although this study confirmed that IBS was the
strongest co-morbidity in SIBO it noted that other co-morbidities linked to SIBO include type 2
diabetes and the use of PPI.
8) Posserud I, Stotzer P, Bjornsson E, Abrahamsson H, Simren M. Small Intestinal
Bacterial Overgrowth in Patients with Irritiable Bowel Syndrome.
Neurogastroenterology [Internet]. 2006 [cited 2014 Jul 30]; 56: 802-808. doi:
10.1136/gut.2006.108712.
The aim of the study was to assess the prevalence of SIBO using small bowel aspirate and in the
IBS patient population. Positive SIBO tests were found in 4% of both IBS patients and the
control group. When the diagnostic criteria for SIBO was reduced from 105/ml to 103/ml 43% of
the IBS patients tested positive for SIBO. They found that mild increased amount of small bowel
bacteria was more common in IBS patients, but findings did not support a significant role of
SIBO as a cause of IBS symptoms.