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com/1007-9327office World J Gastroenterol 2010 June 28; 16(24): 2978-2990

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doi:10.3748/wjg.v16.i24.2978 © 2010 Baishideng. All rights reserved.
TOPIC HIGHLIGHT
Marcela Kopacova, Associate Professor, MD, PhD, Series Editor
Small intestinal bacterial overgrowth syndrome
Jan Bures, Jiri Cyrany, Darina Kohoutova, Miroslav Förstl, Stanislav Rejchrt, Jaroslav Kvetina, Viktor Vorisek,
Marcela Kopacova
Jan Bures, Jiri Cyrany, Darina Kohoutova, Stanislav Rejchrt, SIBO is defined as an increase in the number and/or
Marcela Kopacova, 2nd Department of Medicine, Charles Uni- alteration in the type of bacteria in the upper gastro-
versity in Praha, Faculty of Medicine at Hradec Kralove, Univer- intestinal tract. There are several endogenous defence
sity Teaching Hospital, Sokolska 581, 500 05 Hradec Kralove, mechanisms for preventing bacterial overgrowth: gastric
Czech Republic
acid secretion, intestinal motility, intact ileo-caecal valve,
Miroslav Förstl, Institute of Clinical Microbiology, Charles
University in Praha, Faculty of Medicine at Hradec Kralove, immunoglobulins within intestinal secretion and bacte-
University Teaching Hospital, Sokolska 581, 500 05 Hradec riostatic properties of pancreatic and biliary secretion.
Kralove, Czech Republic Aetiology of SIBO is usually complex, associated with
Jaroslav Kvetina, Institute of Experimental Biopharmaceu- disorders of protective antibacterial mechanisms (e.g.
tics, Joint Research Centre of Czech Academy of Sciences and achlorhydria, pancreatic exocrine insufficiency, immuno-
PRO.MED.CS Praha a.s., Heyrovskeho 1207, 500 03 Hradec deficiency syndromes), anatomical abnormalities (e.g.
Kralove, Czech Republic small intestinal obstruction, diverticula, fistulae, surgical
Viktor Vorisek, Institute of Clinical Biochemistry and Diagnos- blind loop, previous ileo-caecal resections) and/or motil-
tics, Charles University in Praha, Faculty of Medicine at Hradec
ity disorders (e.g. scleroderma, autonomic neuropathy
Kralove, University Teaching Hospital, Sokolska 581, 500 05
in diabetes mellitus, post-radiation enteropathy, small
Hradec Kralove, Czech Republic
Author contributions: Bures J, Cyrany J, Kohoutova D, Förstl intestinal pseudo-obstruction). In some patients more
M, Rejchrt S, Kvetina J, Vorisek V and Kopacova M contributed than one factor may be involved. Symptoms related to
equally to this work. SIBO are bloating, diarrhoea, malabsorption, weight
Supported by The Research Project MZO 00179906 from the loss and malnutrition. The gold standard for diagnosing
Ministry of Health, Czech Republic, and by Research Grant SIBO is still microbial investigation of jejunal aspirates.
GACR 305/08/0535, Czech Republic Non-invasive hydrogen and methane breath tests are
Correspondence to: Jan Bures, Professor, MD, PhD, 2nd most commonly used for the diagnosis of SIBO using
Department of Medicine, Charles University in Praha, Faculty of glucose or lactulose. Therapy for SIBO must be com-
Medicine at Hradec Kralove, University Teaching Hospital, So-
plex, addressing all causes, symptoms and complica-
kolska 581, 500 05 Hradec Kralove,
Czech Republic. [email protected] tions, and fully individualised. It should include treat-
Telephone: +420-495-834240 Fax: +420-495-834785 ment of the underlying disease, nutritional support and
Received: January 13, 2010 Revised: February 19, 2010 cyclical gastro-intestinal selective antibiotics. Prognosis
Accepted: February 26, 2010 is usually serious, determined mostly by the underlying
Published online: June 28, 2010 disease that led to SIBO.
© 2010 Baishideng. All rights reserved.
Abstract Key words: Bacterial overgrowth; Breath test; Hydrogen;

Methane; Small intestine
Human intestinal microbiota create a complex polymi-
crobial ecology. This is characterised by its high popula-
Peer reviewers: Antonio Gasbarrini, MD, Professor, Depart-
tion density, wide diversity and complexity of interaction. ment of Internal Medicine, Gemelli Hospital, Catholic University
Any dysbalance of this complex intestinal microbiome, of Rome, Largo A. Gemelli 8, 00168 Rome, Italy; Anthony P
both qualitative and quantitative, might have serious Moran, BSc, PhD, DSc, FRSC, MRIA, Professor, Department of
health consequence for a macro-organism, including Microbiology, National University of Ireland Galway, University
small intestinal bacterial overgrowth syndrome (SIBO). Road, Galway, Ireland
WJG|www.wjgnet.com 2978 June 28, 2010|Volume 16|Issue 24|

Bures J et al . Small intestinal bacterial overgrowth syndrome
Bures J, Cyrany J, Kohoutova D, Förstl M, Rejchrt S, Kvetina J, prevalence differ substantially. For instance, the prevalence
Vorisek V, Kopacova M. Small intestinal bacterial overgrowth syn- of SIBO in patients fulfilling diagnostic criteria for irri-
drome. World J Gastroenterol 2010; 16(24): 2978-2990 Available table bowel syndrome was 30%-85%[9-11,16,18,19]. The preva-
from: URL: http://www.wjgnet.com/1007-9327/full/v16/i24/2978. lence of SIBO in coeliac disease non-responding to a
htm DOI: http://dx.doi.org/10.3748/wjg.v16.i24.2978 gluten-free diet was up to 50%[20]. In liver cirrhosis, SIBO
was diagnosed in more than 50% of cases[21,22]. In a small
group of elderly people (70 to 94 years old) with lactose
malabsorption, SIBO was documented in 90%[23]. An in-
teresting study was performed on asymptomatic morbidly
INTRODUCTION obese subjects and SIBO was found in 17% (compared to
Human intestinal microbiota create a complex polymi- 2.5% in non-obese persons)[15].
crobial ecology. This is characterised by its high popula-
tion density, wide diversity and complexity of interaction.
The duodenum and proximal jejunum normally contain aetiology
small numbers of bacteria, usually lactobacilli and en- There are several endogenous defence mechanisms for
terococci, gram-positive aerobes or facultative anaerobes preventing bacterial overgrowth: gastric acid secretion, in-
(< 104 organisms per mL). Coliforms may be transiently testinal motility, intact ileo-caecal valve, immunoglobulins
present (< 103 bacteria per mL) and anaerobic Bacteroides within intestinal secretion and bacteriostatic properties of
are not found in the jejunum in healthy people. Up to pancreatic and biliary secretion[24].
one third of jejunal aspirates might be sterile in healthy The aetiology of SIBO is usually complex, associated
volunteers. The distal ileum is a transition zone between with disorders of protective antibacterial mechanisms
sparse populations of aerobic bacteria of the proximal (e.g. achlorhydria, pancreatic exocrine insufficiency, immu
small intestine and very dense populations of anaerobic nodeficiency syndromes), anatomical abnormalities (e.g.
micro-organisms in the large bowel[1-3]. The epithelial small intestinal obstruction, diverticula, fistulae, surgical
surface of the small intestine in a healthy human is not blind loop, previous ileo-caecal resections) and/or motil-
colonised. Occasional groups of bacteria can be found ity disorders (e.g. scleroderma, autonomic neuropathy in
in low concentrations within the lumen. Bacteria do not diabetes mellitus, post-radiation enteropathy, small intesti-
form clusters and spatial structures, and the luminal con- nal pseudo-obstruction). In some patients more than one
tents are separated from the mucosa by a mucus layer[4]. factor may be involved. “Aetiological” and “predisposing”
Any dysbalance of this complex intestinal microbi- factors cannot be separated in some patients. SIBO may
ome, both qualitative and quantitative, might have serious occur in elderly people without any evident underlying
health consequences for a macro-organism, including small intestinal pathology.
small intestinal bacterial overgrowth syndrome (SIBO). In some cases, a vicious circle arises: an underlying
disease is complicated by SIBO and then SIBO directly
(as a morphological impact) or vicariously (by malab-
definition sorption or nutrient deficiency) causes further deteriora-
SIBO is a very heterogeneous syndrome characterised by tion of the underlying disease.
an increased number and/or abnormal type of bacteria Out of all diseases and disorders associated with SIBO
in the small bowel. Most authors consider diagnostic of (listed below in detail), 90% of cases comprise small intes-
SIBO to be the finding of ≥ 105 bacteria [i.e. colony- tinal motility disorders (of various aetiology) and chronic
forming units (CFU)] per mL of proximal jejunal aspira- pancreatitis[2].
tion. The normal value is ≤ 104 CFU/mL[3, 5-7].
Achlorhydria
Achlorhydria (due to chronic atrophic gastritis) and long-
prevalence term administration of proton pump inhibitors may cause
The overall prevalence of SIBO in the general public bacterial overgrowth in the stomach and duodenum. Pro-
is unknown. In general, SIBO is substantially underdi- ton pump inhibitors not only increase duodenal bacterial
agnosed. There are several reasons for this fact. Some colonisation but also accelerate intestinal transit[24].
patients may not seek healthcare or SIBO may not be
properly diagnosed by medical investigations. SIBO Exocrine pancreatic insufficiency
might be asymptomatic or with non-specific symptoms Chronic pancreatitis is complicated by SIBO in 30%-40%
only, and last but not least, all symptoms might be in- of cases[7,25]. Multiple factors can be involved: exocrine
correctly ascribed to the underlying disease (leading to pancreatic insufficiency (with absence of anti-bacterial ef-
SIBO). Of course, diagnostic yield also depends on the fect of proteolytic enzymes), abnormal chyme in the small
methods used for investigation. According to different intestinal lumen, motility disorders, administration of
studies with the investigation of small sets of clinically painkillers and ongoing alcohol consumption in some of
healthy people as a control, findings consistent with patients. Cystic fibrosis is also associated with increased
SIBO were found in 2.5% to 22%[8-17]. risk of SIBO. Fridge et al[26] diagnosed SIBO in 14/25 (56%)
In particular diseases and disorders, literature data on patients with cystic fibrosis. SIBO may be a causative fac-

tor of diarrhoea in advanced pancreatic cancer[27] apart afferent hypersensitivity, psycho-social dysfunction) in
from pancreatic exocrine insufficiency, chemotherapy or which motility disorders enable “secondary” bacterial
previous surgery. overgrowth[40,43]. A third group of authors recommend
strict distinction between irritable bowel syndrome (the
Immunodeficiency syndromes hydrogen breath test with lactulose must be negative)
Various immunodeficiency syndromes, such as IgA defi and SIBO (in such a case, it is not irritable bowel despite
ciency, common variable immunodeficiency, AIDS and the diagnostic criteria having been met) in patients with
others, are complicated by miscellaneous infection com identical symptoms[44]. The last authors stated an opin-
plications, including SIBO[28,29]. ion that SIBO does not play any significant role in the
pathogenesis of irritable bowel[45].
Small intestinal obstruction and stagnation Pimentel et al[12] found abnormal lactulose breath test
All anatomical pathology associated with small intesti- results in 93/111 (84%) patients with irritable bowel syn-
nal obstruction and stagnation could be associated with drome. Successful treatment of SIBO using neomycin
SIBO, e.g. strictures, adhesions, tumours of the small (in 35% of patients) was associated with relief of subjec-
tive symptoms. There was another interesting finding in
bowel. Large and/or multiple duodenal and jejunal di-
this study: a subgroup of persons with a methanogenic
verticula are often complicated by SIBO. Sequelae of
phenotype was associated with constipation in 100%
previous abdominal surgery (afferent loop syndrome
(constipation-predominant irritable bowel syndrome)[12].
after Billroth-Ⅱ gastric resection, Roux-en-Y stasis syn-
Another study found that methanogenic status was never
drome, bariatric bypass surgery) may also lead to SIBO
associated in irritable bowel syndrome with diarrhoea and
(with metabolic and nutritional disarrangement)[7,30-32]. Crohn’s disease or ulcerative colitis with diarrhoea[13]. The
Small intestinal pseudo-obstruction and some neurologi- association of methanogenic phenotype and constipation
cal diseases (e.g. myotonic dystrophy, Parkinson disease, was also revealed by other authors[8].
Chagasic enteropathy) can be complicated by SIBO that
is responsible for malabsorption and weight loss[33-36]. Spi-
Coeliac disease
nucci et al[37] described an interesting case of endogenous A wide range of 9% to 55% of patients have been dia
ethanol production in a patient with chronic intestinal gnosed with SIBO as a complication of coeliac dis-
pseudo-obstruction and SIBO. ease[20,46-48]. The prevalence of SIBO is high, especially in
Tursi et al[38] investigated bacterial overgrowth in the
patients who do not respond to a gluten-free diet and/or
small bowel in patients with acute diverticulitis of the
have lactose intolerance[20,46,47].
colon. Small intestinal overgrowth was found in 53/90
(59%) subjects. The authors assumed that the primary
mechanism is a slow large bowel transit with stasis of Crohn’s disease
faeces in the colon. This results in dysmicrobia in the SIBO is frequently found in Crohn’s disease (in about
large bowel with metabolic changes and induction of 25%). Loss of the ileo-caecal valve (due to previous ileo-
inflammation. Subsequent reverse peristalsis facilitates caecal resection) and/or large entero-enteric and entero-
colonisation of the small intestine by bacteria coming colic fistulae are important predisposing factors[49-55]. Cas-
from the large bowel. SIBO deteriorates symptoms of tiglione et al[56] found bacterial overgrowth more frequently
acute colonic diverticulitis, protracts the course of the in those who underwent surgery (30%) compared to non-
disease and thus could be an independent risk factor for operated patients (18%). Furthermore, SIBO may mimic
future relapses of acute diverticulitis of the large bowel. an acute flare of Crohn’s disease (including increased
Rifaximin was effective in the treatment of both acute bowel movements and lower body weight)[57]. Smokers
colonic diverticulitis and SIBO in these patients[38]. may exhibit increased H2 production which could lead to
false positive test results. However, in the study by Klaus
Irritable bowel syndrome et al[57] there was no difference in the proportion of smok-
The aetio-pathogenesis of irritable bowel syndrome has ers and their respective daily consumption of cigarettes
not yet been satisfactorily clarified. Symptoms of SIBO between patients with Crohn’s disease with and without
and irritable bowel syndrome overlap to a large degree. SIBO.
As mentioned earlier, SIBO is frequently found in per-
sons fulfilling criteria of irritable bowel syndrome (30%- Short bowel syndrome
85%)[9-11,16,18,19]. According to authors of the bacterial hy- The problem of short bowel syndrome is not limited only
pothesis, SIBO is the primary event and irritable bowel to the reduced absorptive surface area. The loss of the ileo-
is secondary to SIBO. In some patients, the onset of ir- caecal valve and the loss of the ileal break from resection
ritable bowel is preceded by infective gastroenteritis (so- of the distal small bowel would accelerate the transit of
called post-dysenteric bowel disturbance)[39]. Analysis of chyme throughout the entire gastrointestinal tract. Undi-
the microbial genome found different faecal microbiota in gested food becomes a substrate for bacterial fermenta-
healthy people and patients with irritable bowel (e.g. phy- tion. Large intestinal bacterial flora colonise proximally
lotypes Coprococcus, Collinsella, Coprobacillus)[40-42]. Believ- into the small intestine to result in SIBO. Because digestion
ers in an opposite hypothesis stated that irritable bowel and absorption cannot be completed without adequate
is a primary factor (with motor disturbance, visceral time, these patients face chronic postprandial diarrhoea.

These problems may be exacerbated by SIBO that further than 80% of patients[71]. Severe small bowel involvement
accelerates transit and worsens digestion, absorption and by scleroderma can present as chronic intestinal pseudo-
malnutrition[58]. obstruction and SIBO. The reported prevalence of SIBO
SIBO is an independent negative factor deteriorating in scleroderma was 43% to 56%[72,73]. In our series, SIBO
adaptation of the small intestine in children after exces- was proved in 4/15 (27%) patients with systemic sclero-
sive bowel resections. SIBO lengthens the dependence of sis by means of glucose hydrogen and methane breath
these patients on total parenteral nutrition and deteriorates tests. Half the cases of SIBO had neither diarrhoea nor
malabsorption and hepatopathy associated with short other signs of malassimilation at the time of examination.
bowel syndrome[59,60]. SIBO may lead to intestinal failure There was a tendency towards a higher dose of systemic
in these patients[61]. glucocorticosteroids in persons with positive hydrogen
and methane breath tests[74].
Non-alcoholic steatohepatitis
Wigg et al[17] found a higher prevalence of SIBO (11/22, Autonomic neuropathy in diabetes mellitus
50%) in non-alcoholic steatohepatitis (NASH) compared Gastrointestinal symptoms are present in 50%-70% of pa-
to healthy control subjects (5/23, 22%). Higher values tients with diabetes mellitus. Delayed gastric emptying (or
for the xylose-lactulose test in patients with NASH cor- even diabetic gastroparesis) and intestinal motility disorders
related with higher serum levels of tumor necrosis factor-α are the most important findings (with an unfavourable im-
(TNF-α). However, they were not associated with increased pact on glycaemic control). Impaired intestinal motility is
intestinal permeability or increased serum endotoxin[17]. In often followed by SIBO[75-77]. In diabetes mellitus, first and
another study of NASH[62], SIBO was diagnosed in half foremost all results must be interpreted according to the di-
of the patients (6/12) but only in one subject (1/11, 9%) agnostic method that was used. Cuoco et al[78] performed the
in the healthy control group. Treatment with ciprofloxacin lactulose hydrogen breath test and found that 21/74 (28%)
suppressed bacterial overgrowth, increased serum insulin of subjects were affected by SIBO and delayed oro-caecal
and decreased endogenous ethanol production but did not transit time. After treatment with rifaximin, three patients
influence serum acetylated ghrelin (half values compared to still showed SIBO, five persistent delayed transit time with-
controls). Changes in fasting insulin and ethanol following out SIBO and 13 persons (62%) experienced a significant
ciprofloxacin suggest that these parameters may be influ- improvement in their oro-caecal time (without SIBO)[78].
enced by small intestinal bacterial activity[62]. In an experi- Reddymasu et al[79] used hydrogen and methane breath tests
mental model of NASH in rats, there was a slower transit after glucose challenge. Thirty out of fifty (60%) patients
time and higher quantity of coliform bacteria (Escherichia had a positive breath test result for SIBO on the basis of
coli). Treatment with gentamicin (cidomycin) accelerated hydrogen (63%), methane (27%) or both criteria (10%).
the transit time, decreased TNF-α levels and alleviated se- SIBO was more likely in diabetic patients with gastroparetic
verity of liver involvement in experimental animals. Thus symptoms of longer duration[79].
SIBO might play an important role in the pathogenesis of In about one third of patients with diabetes, SIBO was
NASH[63]. associated with cardiovascular autonomic neuropathy[77].
SIBO in diabetes may rarely manifest itself as protein-
Liver cirrhosis losing enteropathy[80].
Portal hypertension in liver cirrhosis substantially changes
the intraluminal milieu of the gut. Liver cirrhosis is an Radiation enteropathy
independent risk factor for SIBO. Small intestinal motility SIBO and lactose intolerance may occur during and/or
disorder, especially slow transit in advanced liver disease after pelvic (or abdominal) radiotherapy[81-83].
(Child-Pugh C) may partake in SIBO[64,65]. SIBO was di-
agnosed in 50%-60% of patients with liver cirrhosis[66,67]. Fibromyalgia
SIBO is a risk factor for the development of spontaneous Pimentel et al[14] found that 42/42 (100%) patients with
bacterial peritonitis[22,68], however, its role in the patho fibromyalgia had an abnormal lactulose hydrogen breath
genesis has not yet been fully clarified[22]. Prevalence of test. This was a significantly higher rate compared to pa-
SIBO was higher in those patients with liver cirrhosis who tients with irritable bowel syndrome (93/111, 84%) and
had spontaneous bacterial peritonitis (14/20, 70%) com- clinically healthy persons used as a control (3/15, 20%).
pared to those without it (4/20, 20%)[64]. However, this Patients with fibromyalgia also had a higher hydrogenic
finding was not confirmed in other studies[66]. SIBO might profile that correlated with somatic pain[14].
correlate with systemic endotoxaemia[69]. It is necessary to
remind ourselves that glucose hydrogen breath test in liver Other disorders and diseases associated with SIBO
cirrhosis correlates only to a small degree with microbio- Various diseases and disorders have been described to be
logical analysis of jejunal aspirates (sensitivity 27%-52%, associated with or complicated by SIBO, such as lympho-
specificity 36%-80%)[70]. proliferative diseases (lymphoma, chronic lymphocytic
leukaemia), benign lymphoid hyperplasia of the ileum,
Scleroderma metabolic bone disease, acromegaly, hypothyreosis, alco-
Scleroderma (systemic sclerosis) is a chronic connective holism and rosacea[7,84-87]. The prevalence of SIBO rises
tissue disease that affects the gastrointestinal tract in more with age (about 50% in persons > 75 years old)[88].

microbiology, pathogenesis, et al[92] investigated samples of jejunal juice in 63 patients

with diarrhoea and/or malabsorption. The diagnostic
pathophysiology and pathology criteria of SIBO were fulfilled in 55 persons (87%). The
The total bacterial count in the proximal jejunum is < 104 authors identified 141 micro-aerophilic strains (Streptococcus
bacteria per mL of jejunal content in healthy people. In 60%, Escherichia coli 36%, Staphylococcus 13%, Klebsiella 11%
the ileum, enteric bacterial populations increase in amount and others) and 117 anaerobes (Bacteroides 39%, Lactobacillus
(including coliforms) up to 109 CFU/mL in the terminal 25%, Clostridium 20% and others)[92].
ileum. There are several beneficial effects of normal small SIBO may be accompanied by both maldigestion and
intestinal bacteria to the host. They can be extrapolated malabsorption. Bacteria in SIBO might significantly in-
from experimental studies in germ-free animals. The small terfere with enzymatic, absorptive and metabolic actions
intestinal villi of these animals are thin and unusually of a macro-organism. Due to injury of the brush-border
regular, with relatively shortened crypts. The enterocytes of enterocytes, the activity of disaccharideses may be de-
are cuboidal rather than columnar. In addition, the num- creased. If bacteria simultaneously metabolise fructose,
ber and size of Peyer’s patches, the degree of leukocyte lactose and sorbitol, malabsorption of saccharides may
infiltration in the lamina propria, and the rate of mucosal occur. Injured small intestinal mucosa can have undesir-
regeneration are reduced. The introduction of micro- able consequences in increased intestinal permeability
organisms rapidly restores the normal morphologic ap- and/or protein-losing enteropathy. Deficiency of vitamin
pearance and physiologic function of the small bowel B12 results from the consumption of this vitamin by an-
mucosa[7]. aerobic micro-organisms. Bacteria may also utilise intralu-
Normal autochthonous bacterial flora of the gastroin- minal protein in the small bowel, this may lead to protein
testinal tract is an important factor for preservation of its deficiency for the macro-organism and excessive produc-
integrity and normal functioning in humans. They partici- tion of ammonia by bacteria. Deconjugation of bile acids
pate in the protection of macro-organisms against patho- by bacteria results in malabsorption of fat and liposoluble
genic micro-organisms, stimulate the human immune vitamins. Extensively formed lithocholic acid is poorly ab-
system and influence the metabolic and trophic function sorbable and acts enterotoxically[5,7,93-95].
of the intestinal mucosa. Enteric bacteria produce some Bacteria produce various toxic agents that may have
nutrients (e.g. short-chain fatty acids) and vitamins such surprising systemic effects. These agents are ammonia,
as folates and vitamin K. Last but not least, they impact D-lactate, endogenous bacterial peptidoglycans and oth-
the sensor and motor function of the gut. On the other ers. SIBO is regularly associated with increased serum en-
hand, intestinal bacteria are influenced by many factors, dotoxin and bacterial compounds stimulating production
first of all by the amount and composition of food, but of (pro)inflammatory cytokines[7,96]. SIBO might be asso-
also by environmental (and geographic) effects, drugs, ciated with endogenous production of ethanol (probably
alcohol and probably by several other factors (lifestyle, synthesised by Candida albicans and Saccharomyces cerevisiae).
psychosomatic stress, etc.)[5,89]. The prevalence of bacteria Serum ethanol disappears after successful treatment of
in different parts of the GI tract appears to be dependent SIBO[37].
on several factors, such as pH, peristalsis, redox potential, Small intestinal bacterial overgrowth has a negative
bacterial adhesion, bacterial co-operation and antagonism, impact not only on the function but also on the morpho-
mucin secretion, diet and nutrient availability[90]. logical structure of the small bowel. Microscopic inflam-
There are several host defence mechanisms to pre- matory changes (especially in the lamina propria) and vil-
vent excessive colonisation of the small bowel by bacte- lous atrophy are found regularly. In such a case, the villous
ria: antegrade peristalsis prevents attachment of ingested atrophy in SIBO must be distinguished from that of co-
micro-organisms; gastric acid and bile destroy many eliac disease. Macroscopic changes may also be visible in
micro-organisms before they leave the stomach; diges- some patients. Hoog et al[97] found small intestinal mucosal
tion by proteolytic enzymes helps destroy bacteria in the breaks (erosions or ulcers) in 16/18 patients with chronic
small intestine; the intestinal mucus layer traps bacteria; myopathic or neuropathic motility disorders of the small
an intact ileo-caecal valve inhibits retrograde transloca- bowel by means of wireless capsule endoscopy.
tion of bacteria from the colon to the small bowel; the In some patients with short bowel syndrome, bacte-
immune system plays a role as evidenced by the high rial overgrowth can, to some extent, paradoxically exert
prevalence of bacterial overgrowth in patients who have a favourable effect on the macro-organism. Bacteria may
immunodeficiency; the largest fraction of immunoglob- partly metabolise saccharides and thus form some fur-
ulins secreted in the human body is the secretory IgA ther energy substrates more easily utilisable by a diseased
originating in the gastrointestinal tract, which aids in pre- human.
venting bacterial proliferation[7,91]. SIBO may develop if
some of the natural defensive mechanisms of a macro-
organism (listed above) are disrupted. CLINICAL FEATURES
In most patients, SIBO is not caused by a single bac- Clinical symptoms are expressed more or less according
terial strain. In general, there is an extension of colonic to the severity of involvement and they are modified by a
bacteria into the small bowel. Less frequently, the “normal” primary underlying disease. SIBO may be clinically asymp-
amount of small intestinal bacteria increases. Bouhnik tomatic or can resemble irritable bowel syndrome with

non-specific symptoms (bloating, flatulence, abdominal bial investigation of jejunal aspirates. Such a sample can be
discomfort, diarrhoea, abdominal pain). In more severe obtained by a special sonde or by means of enteroscopy.
cases, there are signs of malabsorption (weight loss, ste- Nowadays, there are commercially available special aspira-
atorrhoea, malnutrition), liver lesion, skin manifestation tion catheters (with a spiral pattern of holes at the distal
(rosacea), arthralgias and deficiency syndromes (anaemia, tip) for contaminate-free collection of fluids. Microbial
tetany in hypocalcaemia induced by vitamin D deficiency, investigation places high demands on the quality of labo-
metabolic bone disease, polyneuropathy due to vitamin ratory work (determination of quantitative proportion of
B12 deficiency, impaired barrier function of the gut, etc.). anaerobes) and has several difficulties (low reproducibility
Anaemia is usually macrocytic (megaloblastic) due to and identifying cultivation-resistant bacteria). Distribution
vitamin B12 deficiency. It could also be microcytic iron de- of bacterial overgrowth might be irregular and that is why
ficiency (due to occult gastrointestinal blood loss) or nor- a single investigation might not detect it. Bacterial over-
mocytic (as anaemia of chronic disease)[3,5-7]. Serum folate growth may be restricted to a particular, difficult-to-access
and vitamin K levels are usually normal. Serum vitamin K area for aspiration (e.g. a blind loop)[7].
can even be increased owing to its bacterial overproduc- Hydrogen and methane breath tests are currently the
tion. Moreover, there are some concerns as to whether most important diagnostic methods. The principles and
endogenous intestinal production of vitamin K by bacte- methods of hydrogen and methane breath tests were de-
ria might interfere with warfarin treatment in SIBO[98-100]. scribed in detail elsewhere[102-105]. In humans, hydrogen and
In the case of oedema of lower extremities, the aetiology methane are exclusively produced by intestinal bacteria,
is usually more complex (anaemia, malnutrition, hypopro- namely in the large bowel in healthy people and also in the
teinaemia, vitamin B12 deficiency). small intestine in the case of SIBO. About 80% of hydro-
D-lactic acidosis is a severe complication of patients gen and methane is expelled by flatus, 20% is exhaled by
with short bowel syndrome (with intact large bowel). It is lungs and can be measured in breath[106]. Hydrogen and
caused by an excessive overgrowth of lactobacilli. Non- methane breath tests to diagnose SIBO are performed
absorbed saccharides pass from the small intestine to the after peroral glucose or lactulose challenge. Most authors
large bowel and they are fermented down to the D-isomer (including our Department) use gas chromatography for
of lactic acid. There is no human pathway to metabolise breath analysis. A parallel measurement of CO2 and cor-
D-lactic acid. D-lactic acid is absorbed from the large rection of hydrogen values to CO2 concentration make
bowel; its serum concentration is regularly increased in the measurement more precise[7,74,103,104]. Low humidity (<
these patients. Nevertheless, most patients remain asymp- 25%) must be maintained in the laboratory atmosphere to
tomatic. In clinically expressed cases, leading symptoms obtain consistent measurements. There is an early increase
comprise characteristic neurologic abnormalities including in breath hydrogen and/or methane (single early peak) af-
confusion, cerebellar ataxia, slurred speech, and loss of ter glucose administration due to bacterial glucose fermen-
memory. Patients exhibit some degree of altered mental tation in the small bowel. There are two peaks in the lactu-
status. They may complain of or appear to be drunk in the lose breath test, the first one owing to bacterial activity in
absence of ethanol intake. In the treatment, it is necessary the small intestine, the second one after lactulose reaches
to compensate metabolic acidosis and administer peroral the colon. Unfortunately, hydrogen and methane breath
antibiotics (metronidazole, rifaximin). To prevent this seri- tests have not yet been standardised, particular protocols
ous complication, it is important to reduce peroral intake differ in dose (and concentration) of the test substrate,
of simple sugars, polysaccharides given in smaller amounts duration of tests, time intervals of breath sampling and
together with a higher intake of fat[101]. basic and peak cut-off values. According to most authors,
basal cut-off values of hydrogen and/or methane in posi-
tive breath tests are ≥ 20 parts per million (ppm), 10-
diagnostics 20 ppm is a grey zone. After a glucose challenge, an in-
It is mandatory to consider SIBO in all cases of complex crease ≥ 12 ppm at 120 min is a positive result for bacte-
non-specific dyspeptic complaints (bloating, abdominal rial overgrowth. A lactulose breath test is assessed as posi-
discomfort, diarrhoea, abdominal pain), in motility disor- tive if there is a biphasic course or an early plateau pattern
ders, anatomical abnormalities of the small bowel and in with a hydrogen increase of ≥ 12 ppm is found (possibly
all malassimilation syndromes (malabsorption, maldiges- with an increase in methane at the second peak)[104,107-110].
tion)[3,5-7]. The hydrogen breath test is considered to be more ac-
Physical investigation usually provides non-specific curate for the diagnosis of SIBO compared to the meth-
findings and could be modified by a primary underly- ane breath test according to most authors[111-114]. There is
ing disease. The abdomen may be distended and a small a sensitivity of 62.5% and specificity of 82% (diagnostic
intestinal succussion splash might be identified. Physical accuracy of 72%) after glucose and 52% and 86% (diag-
investigation can further reveal latent tetany, polyneuro nostic accuracy of 55%) after lactulose administration[109].
pathy and skin manifestation (rosacea). Hydrogen alone, methane alone or both gases simultane-
Laboratory tests usually find anaemia, low serum vita ously might be found in breath samples. That is why it is
min B12 levels and laboratory signs of malnutrition (lym important to always determine both gases in the breath
phopenia, low serum prealbumin and transferrin). samples. There are several advantages of hydrogen and
The gold standard for diagnosing SIBO is still micro- methane breath tests. They are non-invasive, non-toxic,

relatively easily available and performed at a low cost. humans[134]. According to some authors, a methanogenic
However, hydrogen and methane breath tests have phenotype is associated with constipation[8,12]. Methane
some drawbacks with possible false results and difficulties production has been related to more severe colonic impa
in their interpretation. Very rapid absorption of glucose ction in children with encopresis[135]. Higher production
in the proximal jejunum can be responsible for a false of methane has been detected in colorectal adenomas and
negative result. In the case of bacterial overgrowth in the cancer[136]. However, there is a general agreement that cons
terminal ileum, it might be difficult to distinguish a patho- tipation itself is not a risk factor for the development of
logical ileal peak from a “normal peak” after the caecum is colorectal cancer.
reached. In short bowel syndrome (with intact large bow- Hydrogen and methane breath tests can be combined
el), the test substrate may reach the colon very quickly and with a simultaneous D-xylose breath test[107,110]. This com
cause a false positive result. In the case of a low density of bination increases the sensitivity of non-invasive diagnostics
anaerobes, breath can be false negative[109,113,115-117]. If there of SIBO[107,114]. The cholyl-1-13C-glycine hydrolase breath
is only one peak of hydrogen recorded in the lactulose test is another possible alternative for the diagnosis of
breath test and the second peak is absent for hydrogen SIBO. The principle of this test is based on the fact that
and methane, this could be assessed as a combination of bacterial overgrowth will cause more rapid deconjugation
SIBO and fermentative colopathy[108]. Results of hydrogen of cholyl-1-13C-glycine[137]. The reported sensitivity for this
and methane breath tests are usually difficult to interpret test was 70%[138]. The lack of sensitivity was attributed to
in the case of advanced lung disease. In the case of a high bacterial overgrowth with species lacking cholylglycine
concentration of hydrogen and low concentration of hydrolase[137]. On the other hand, patients with bile acids
methane, analytical precision for methane determination malabsorption in the ileum might have a false positive re-
is less accurate[104]. sult in this breath test after rapid deconjugation of cholyl-
All hydrogen and methane are produced by so call glycine in the proximal colon[139]. Berthold et al[140] recently
ed “hydrogenic and methanogenic” bacteria in hum proposed a lactose-13C-ureide breath test for the diagnosis
ans[103,104,106,118]. However, most authors usually do not of small bowel bacterial overgrowth. This test should
specify which particular bacteria constitute these produ have 100% specificity (and thus predict positive culture in
cers. Nitrogen, oxygen, carbon dioxide, hydrogen and SIBO) but lower sensitivity (66%)[140].
methane account for more that 99% of expelled intestinal There are several other tests to diagnose SIBO, for
gas. Hydrogen is produced by bacterial fermentation of instance evaluation of short-chain fatty acids in jejunal as-
saccharides in the intestinal lumen. Concurrently, hyd piration[141], serum non-conjugated bile acids, urinary out-
rogen is consumed by other intestinal bacteria to synth put of p-aminobenzoic acid (after peroral administration
esise methane, acetate and hydrogen sulphide. Methane is of colil-PABA) or urinary indican[6]. However, none of
synthesised solely by bacteria in the intestine (four mmols these tests has yet acquitted itself well in routine clinical
of hydrogen and one mmol of carbon dioxide create one practice.
mmol of methane and water). This reaction reduces the If it is impossible to perform any diagnostic test for
volume of gas that would otherwise be present in the co- SIBO (if no test is available for a particular department)
lon[119-124]. The question of intestinal methane producers on a patient with legitimate suspicion of SIBO, it is pos-
has not been definitely solved yet. Methanobrevibacter smithii, sible to consider the exceptional use of an empiric thera-
Methanosphaera stadtmanae and other Methanobacteriales are peutic test with rifaximin (for 7-10 d). Quick disappearance
able to synthesise methane and some authors consider of symptoms supports a possible diagnosis of SIBO, how
Methanobrevibacter to be the major producer of methane ever, this is not definite outright proof of SIBO. On the
in the gut of humans[125,126]. It was assumed (based on other hand, demonstration of SIBO is not 100% proof of
16S ribosomal DNA studies) that Methanobrevibacter smithii causal association between bacterial overgrowth and clini-
could make up about one in ten of all the prokaryotes cal symptoms (or laboratory abnormal results).
in the human gut[127]. However, there is no final proof In some patients with SIBO, secondary inflammatory
available that Archea (Methanobrevibacter and others) would changes might be found not only in the small bowel but
be the prevailing microorganisms in the methanogenic also in the colon as a response to absorbed bacterial anti-
phenotype of the human gut. We hypothesised that com- gens. This inflammatory involvement can cause separate
mon coliform bacteria could also synthesise methane[128], symptoms[7]. Successful treatment with 5-aminosalicylates
however, this assumption was not proved by our further and glucocorticosteroids supports this theory[142].
studies[129,130]. McKay et al[131] found that several anaerobes
(Bacteroides, Clostridium and others) produced hydrogen but
rarely methane. Hydrogen is also produced by Enterobacte- DIFFERENTIAL DIAGNOSIS
riaceae[128,132]. Diagnosis and differential diagnosis of SIBO is difficult
In adult Caucasians, only 30%-50% of persons pro- if this possibility is not considered. It is necessary to dis-
duce methane while hydrogen is produced by 90%-98% of tinguish functional disorders (of no organic cause) and
people[104]. Most subjects with lactose intolerance who do chronic gastrointestinal infections (e.g. giardiasis).
not produce hydrogen would form methane after lactulose The relationship between SIBO and irritable bowel
administration instead of hydrogen[133]. Bile in the intestinal syndrome was discussed above. Esposito et al[44] proposed
lumen is an important suppressor of methanogenesis in use of the lactulose breath test to distinguish SIBO and

irritable bowel syndrome. Parodi et al[143] recommend et al[145] administered a placebo, norfloxacin (800 mg/d),
differentiating patients fulfilling the diagnostic criteria amoxicillin clavulanate (1500 mg/d) and Saccharomyces
of irritable bowel syndrome (IBS-like symptoms) from boulardii (1500 mg/d) successively in 7-d intervals in 10
functional bloating. If SIBO is proved, the first group will patients. Norfloxacin and amoxicillin clavulanate signifi-
profit from antibiotic treatment while the second group cantly decreased the frequency of diarrhoea compared to
will not[143]. the placebo (in 9/10 and 6/10 patients, respectively), but
It is always necessary to consider SIBO in the case of the hydrogen breath test was normalised in only 3 and 5
unexplained deterioration of the clinical status of patients subjects[145]. In Crohn’s disease, Castiglione et al[56] achieved
with Crohn’s disease, chronic pancreatitis or scleroderma. normalisation of the hydrogen breath test in 13/15 (87%)
SIBO must be taken into account in coeliac disease non- persons treated with metronidazole (750 mg/d) and in
responding to adequate gluten-free diet. SIBO is a crucial 14/14 (100%) treated with ciprofloxacin (1000 mg/d)[56].
point in the differential diagnosis of short bowel syn- Di Stefano et al[146] divided 21 patients with a blind loop
drome and all other malassimilation syndromes (both with syndrome into three different treatment groups: (1) ri-
maldigestion and malabsorption). faximin followed by metronidazole, or (2) two courses
On the other hand, some other intestinal disorders of metronidazole, or (3) two courses of rifaximin. Both
might mimic SIBO and must be considered in the diffe antibiotics were effective; metronidazole markedly reduced
rential diagnosis. Flatulence, abdominal bloating and dis- both hydrogen breath tests and patients’ symptoms[146].
tension, and malabsorption of mono- or disaccharides (like However, rifaximin was more effective than metronida-
fructose or lactose) must be taken into account. Pneuma- zole in another study (63% vs 44%)[147]. A drawback in all
tosis cystoides intestinalis is usually asymptomatic but it of these studies was not only the small set of patients but
may be associated with abdominal pain, bloating and/or also the absence of long-term follow-up. Pimentel et al[12]
diarrhoea[106]. administered neomycin or a placebo to 111 patients with
irritable bowel syndrome (84% abnormal lactulose breath
test). Neomycin improved both symptoms and the breath
PRINCIPLES OF TREATMENT test in 35% of persons compared with 11% in the placebo
Therapy for SIBO must be complex (addressing all causes, group[12]. Some other peroral antibiotics, such as cepha-
symptoms and complications) and fully individualised. It lexin, trimethoprim-sulfamethoxazole, levofloxacin and
should include treatment of the underlying disease, nutri- gentamicin were used for the therapy of SIBO[7].
tional support and cyclical gastro-intestinal selective anti- The greatest experience for treatment of SIBO was
biotics. acquired with rifaximin[43,148-154]. Rifaximin is a semi-syn-
The most important thing is always treatment of thetic rifamycin-based non-systemic antibiotic, with a low
the basic underlying disease if possible. Nutritional sup- gastrointestinal absorption and good bactericidal activity.
port is mandatory in SIBO associated with malnutrition, The antibacterial action covers Gram-positive and Gram-
weight loss and nutrient deficiency. We usually use indi- negative organisms, both aerobes and anaerobes [155].
vidualised diet, enteral nutrition by fine-bore naso-jejunal According to different studies, rifaximin improves symp-
tube or nutritional support by sipping of polymeric toms in 33%-92% and eradicates small intestinal bacterial
formulas. In several patients, it is necessary to exclude overgrowth in up to 80% of patients[151,152]. Most authors
lactose from the diet, to reduce other simple sugars, to recommend administering rifaximin for 7-10 d as one
increase coverage of energy needs by fat and to adminis- treatment course or as a cyclic therapy. Higher doses
ter MCT oils (medium-chain triacylglyceroles). (1200 or 1600 mg/d) are more effective than standard
Antibiotic treatment should selectively target those doses (600 or 800 mg/d)[148,154]. Rifaximin is probably the
bacterial strains that cause SIBO. The choice of antibiot- only antibiotic that is capable of achieving a long-term
ics should be based on sensitivity testing to particular an- favourable clinical effect in patients with irritable bowel
tibiotics. However, this requirement is difficult to achieve and SIBO[43].
in clinical practice as various bacteria are usually found Prebiotics and probiotics exert various beneficial ef-
simultaneously, each with different sensitivity to antibiot- fects in the macro-organism, they strengthen the barrier
ics. There is no common agreement concerning choice, function of the gut, inhibit several pathogens, modify the
dosing and duration of antibiotic therapy. In general, inflammatory response of the bowel, and they also reduce
long-term treatment with broad-spectrum antibiotics is visceral hypersensitivity[156-159]. They seem to be more ef-
not the optimal solution as such a therapy is associated fective in influencing the clinical symptoms of irritable
with several problems (intolerance by the patient, dysmi- bowel syndrome compared to a placebo[159,160]. Studies
crobia, diarrhoea, Clostridium difficile expansion, possible dealing with the therapeutic use of prebiotics or probiot-
increased resistance to antibiotics, financial cost, etc.). ics in SIBO (except irritable bowel syndrome) are lim-
Tetracycline was considered the treatment of choice ited[161-163], and it is not therefore possible to recommend
for a long time. Di Stefano et al[144] administered tetracycline them for general clinical use[157,158]. Lactobacilli-based probi-
to patients with SIBO for 7 d (1000 mg/d) and achieved otics are contraindicated in patients with a risk of D-lactic
normalisation of the hydrogen breath test together with re- acidosis. Very little data are available from experimental
lief of symptoms in only 3/11 (27%) subjects[144]. Various studies. Short-term administration of the hydrogenic pro-
antibiotics were tried in other small clinical studies. Attar biotic Escherichia coli 1917 Nissle (3.5 × 1010 bacteria per

day for 14 d) did not influence methanogenic phenotype and cyclical gastrointestinal selective antibiotics. Prognosis
of experimental non steroidal anti-inflammatory drug- is usually serious, determined mostly by the underlying dis-
enteropathy in pigs[129]. ease that led to SIBO.
Prokinetics seem to be a logical therapeutic step in
SIBO due to motility disorders. Several studies tried me
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com/1007-9327office World J Gastroenterol 2010 June 28; 16(24): 2978-2990

Marcela Kopacova, Associate Professor, MD, PhD, Series Editor

Small intestinal bacterial overgrowth syndrome

© 2010 Baishideng. All rights reserved.

Abstract Key words: Bacterial overgrowth; Breath test; Hydrogen;

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microbiology, pathogenesis, et al[92] investigated samples of jejunal juice in 63 patients

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bowel bacterial overgrowth in patients with Crohn's disease. 163: 417-421

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