Iycee Charles de Gaulle Summary Introduction: (SBBO). SBBO, is a condition that

Introduction: (SBBO). SBBO, is a condition that


A healthy and well-balanced gut flora
is an important factor to a host, providing many beneficial effects such as
fermentation of dietary by-products that were un-digested, vitamin K synthesis,
providing a barrier from invading pathogens, and to keep the immune system on standby.
However, disruption of the normal flora will result in intestinal
dyshomeostasis. There are several factors that
controls and prevents the excessive growth of bacteria in the small bowel, such
as: 1) bile and gastric juice secretion, which offers antibacterial effects; 2)
motility of the bowel via peristaltic movements, which prevents bacterial
adherence to the mucosa of the bowel; 3) inhibition of pathogenic bacteria by
production of mucin from epithelial cells of the bowel mucosa; 4) gut defensins
that serve as antibacterial and antifungal peptides; 5) prevention of bacterial
translocation to the small bowel from the colon via the ileocecal valve; and 6) normal cell mediated and humoral immune system
of the gut. Disruption or failure to maintain to any of the processes
mentioned above, may result in small bowel bacterial overgrowth (SBBO).

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SBBO, is a condition that is commonly
associated with various other diseases such as, irritable
bowel syndrome (IBS), Parkinson’s Disease (PD), malabsorption, B12 deficiency,
diarrhoea, and even restless leg syndrome (RLS). Currently, whether SBBO causes
these diseases or rather is the symptom of these diseases is still poorly
understood and controversial. Identifying the possible relationship of SBBO in pathophysiology of symptoms with patients with these
diseases may give a better understanding of why they occur and may lead to
novel treatments for such patients.

is widely accepted as the growth of bacteria ? 105 CFU/ml of the
upper gut aspirate culture  although some argue of the threshold being ?
103 CFU/ml. Direct
culture of the upper gut aspirate is often considered the gold standard in SBBO
diagnosis, but it is a difficult and is an
invasive test to perform, thus various other non-invasive methods such as
glucose and lactulose hydrogen breath tests (GHBT and LHBT) are popular
and widely used to diagnose SBBO.

Breath Test:

The hydrogen
breath test follows the physiological
principle of carbohydrate fermentation by the bacteria in the small bowel,
using lactulose or glucose. This results in production of hydrogen gas that can
be measured using a gas chromatograph (Figure
1) via exhalation over a period of time. Subjects are told to fast at least 12
hours before the test and to avoid consumption of slowly absorbed carbohydrate
during the previous 24 hours to avoid delayed excretion of hydrogen in the
breath sample; on the day of the test, smoking is not allowed 30 min before the
test, and during any of the breaks in the middle till the test is completed,
together with a halt in any strenuous activity; 
application of mouth wash and brushing of teeth is also advised before
the test.

opposed to GHBT typically produces an early peak within 90 mins of carbohydrate
ingestion showing small bowel fermentation (indication of SBBO) or sometimes, a
second peak showing colon fermentation (Figure 1, B2 and B3). Being said, there
are many limitations in these test; patients with rapid intestinal transit may
share similar hydrogen gas production patterns, making it difficult to conclude
SBBO. In patients with rapid intestinal transit an early peak may often give a
false positive result; in a study conducted on healthy Taiwanese nationals the
average time taken for oro-cecal transit was about
85 min, while in another study on Indian nationals, the average time taken for oro-cecal transit was about 65 min. Even with the
double peak of the LHBT, it only has a sensitivity of 31% comparing to the
sensitivity of GHBT at 44% against the upper gut
aspirate culture as a reference, to diagnose SBBO. Hence GHBT should be
considered the best option of a non-invasive means in the diagnosis of SBBO. It should also be noted that in the
presence of Methanogenic gut flora such as Methanobrevibacter
stadmanae and Methanobrevibacter smithii, which
can be seen in 15% of people; production of methane instead of hydrogen
is observed; as such, in these cases GHBT and LHBT may result in a false
negative reading and cannot be used alone to diagnose SBBO accurately. Methane gas
levels should be recorded along with hydrogen levels in all breath samples to
give an accurate diagnosis.


Small Bowel Bacteria Overgrowth and
Irritable Bowel Syndrome:

IBS is a functional
gastrointestinal disorder which is
defined under the Rome IV criteria as the
recurrent abdominal pain of at 1 day per week in the last 3 months, associated
with 2 or more of the following: 1) related to defecation, 2) associated with
the change in frequency of stool and 3) associated with change of stool
appearance. IBS is characterised by the clinical manifestations of abdominal
distention and pain, diarrhoea, change in bowel habits and abnormal intestinal
motility. It is uncertain what exactly causes IBS but there are several
hypotheses that suggest visceral hypersensitivity of the gut, altered gut
motility, and abnormal nervous interaction of the gut and brain being its
predominant pathophysiology
(Crowell et al., 2005).  Symptoms
of IBS are usually similar to those of SBBO, such as bloating and diarrhoea,
resulting in wrongfully diagnosing SBBO as IBS. Whether or not SBBO is a cause
or symptom of IBS is still not known, due to IBS having more clinical
diagnosis criteria then of SBBO . Different
results may occur from different criteria. Several studies have been
done using different diagnostic
methods such as upper gut aspirate culture, GHBT and LHBT to evaluate the frequency of SBBO in patients
diagnosed with IBS. The summary of these studies can be seen in Table 1. From
the results seen in Table 1, a wide range of 4% – 78% of IBS
patients had SBBO, compared to the 1% – 40% of the control who had SBBO. Most
of the results seen in Table 1 revealed that SBBO was indeed more prevalent in
IBS patients than the controls, suggesting the association of IBS and SBBO to
be definite.

IBS is considered to be heterogeneous with 3 sub
types, consisting of diarrhoea (IBS-D), constipation (IBS-C) or an alternating
mix of both (IBS-M). Patients with IBS showing predominant symptoms of
diarrhoea are more often to be implicated with SBBO than of the other
subtypes.  A study conducted in India on
2011 stated that out of 59 IBS patients (27 IBS-D, 11 IBS-C and 21 IBS-M) and
37 healthy controls, SBBO was frequently seen in patients with IBS (14 out of
59 – 23.7%) than of the healthy control (1 out of 37 – 2.7%) using GHBT. IBS-D
patients was seen to have more occurrence of SBBO then of the other 2 sub
types, 37% vs 12.5% respectively, IBS-C being the lowest. Similar results were also
found in other studies as well. This would have indicated that SBBO is more
prominently seen in IBS-D compared to other IBS sub types and studies with a
larger sample size of IBS-D patients are, more likely to provide a higher
frequency of SBBO. The possible reasons of diarrhoea in SBBO positive IBS
patients may be due to the damage of the small intestine’s inner lining by the
effects of enterotoxins from bacterial by-products after fermentation, which
subsequently triggers immune activation resulting in inflammation and increased
permeability of the small intestine ultimately causing diarrhoea due to
increased osmotic load. Increased number of bacteria may also cause bile salts
de-conjugation that is commonly found in the small bowel for fat
emulsification. The de-conjugated bile salts then trigger the secretion of
water from the colon resulting in diarrhoea. Pro-inflammatory cytokines may
then also be released due to the inflammation of the mucosal layer by bile
acids. IBS patients with no signs of SBBO may also result in diarrhoea as a
direct impact from increased gut motility, giving the intestines lesser time to
absorb water from the undigested food.

Patients with symptoms of bloating were also found to
have SBBO more often than those without. Although
not fully understood, one of the possible reason pain or discomfort occurring
from visceral sensation, may be due to bloating which results from accumulation
of hydrogen gas in the gut, following ingestion of fermentable substrates such
as carbohydrates or glucose, compared to healthy controls. One of the reasons for these observations seen in
IBS may be a result from having SBBO, due to fermenting bacteria
colonizing the small bowel.

Formation of short
chain fatty acids such as butyric
acid, acetic acid and propionic acid may result as by-products of carbohydrate fermentation. These short chain fatty acids though useful in the colon for energy conservation,
providing nutrients to colonocytes and absorption of electrolytes; they
increase motility of the colon due to acidification, hinder absorption of
nutrients, and reduces motility of the small bowel which in turn causes a
higher chance of promoting SBBO. Endotoxins such as lipopolysaccharides
also hinder gut motility due to overgrowth of Gram
negative bacteria and may worsen the condition.

Sensory-motor functions
are also affected by chemotactic peptides of bacteria, such as
formyl-methionyl-leucyl-phenylalanine, which causes the stimulation of afferent
nerves and the enteric nervous system resulting in abnormal brain-gut

Therefore, changes in
gut flora in cases such as SBBO may affect, visceral hypersensitivity, gut motility and abnormal nervous interaction
of the gut and brain. These may be the reason why SBBO might be predisposed to
IBS like symptoms

Small Bowel Bacteria Overgrowth in Diarrhoea,
Malabsorption & B12Deficiency:

SBBO is a well-known
cause of malabsorption and diarrhoea; bacteria compete with the enterocytes in
the small bowel for nutrition and in addition to excessive bacteria found
‘stealing’ and metabolising luminal nutrients before intestinal absorption can
occur they can deconjugate bile acids and
damage small bowel enterocytes. In normal conditions, conjugated bile acids are
water soluble and form mixed micelles together with ingested lipids in the
small bowel for fat absorption. Conjugated bile acids are normally not
reabsorbed until the ileum, but when bacteria deconjugates bile acids, these
acids are reabsorbed in the
jejunum before reaching the ileum. This short-cut of reabsorption of bile
acids impairs the formation of the micelle complexes which results in fat
malabsorption and causes steatorrhoea. As a direct cause of fat malabsorption, fat soluble vitamins such as
A, D, E and K may also be mal-absorbed. In addition to causing fat malabsorption, these deconjugated
free bile acids and enterotoxins from bacterial overgrowth may be harmful to
the small bowel enterocytes, as structural and functional lesions have been
identified with the help of electron & light microscopy and reduced
enzymatic activity of the mucosa respectively, resulting in increased
permeability and colonic secretions causing watery diarrhoea.  A study in 1996 of 53 children with either chronic diarrhoea,
abdominal pain or both were tested for SBBO, 18 (34%) of them were tested
positive and 35 (66%) were tested negative on a GHBT; a group of 15 children with
no gastrointestinal symptoms were used as negative controls and a group of 6
children with documented SBBO were used as positive control. GHBT test results
were comparable with the 18 children tested positive to the positive control
and as well as the 35 children tested negative to the negative control. 15
(83%) out of the 18 children tested positive on the GHBT showed symptoms of
chronic diarrhoea. All symptoms ceased within 1 week of SBBO antibiotic therapy
and GHBT was negative. Another study in 2004, done with 87 patients with chronic
diarrhoea, resulted in 48% positive for SBBO, 13% for IBS, 11% unknown and 28%
for others; subsequently breath test and duodenal culture were carried out on
18 patients with chronic diarrhoea and 15 patients as control; 33% and 50% of
the patients were tested positive SBBO by duodenal culture and 14C-D-xylose
breath/lactulose test respectively and 67% were tested positive for a
combination of both test, while in the control group 0% and 13% of the patients
were tested positive SBBO by duodenal culture and 14C-D-xylose
breath/lactulose test respectively and 13% were tested positive for a
combination of both test. Similar results showing diarrhoea was mostly related
to SBBO was also found in another study.

Damage to the brush border, impairs disaccharidase
function of the enterocytes and along with increased carbohydrate fermentation
by bacteria, carbohydrate malabsorption is seen;
short chain fatty acids that is a by-product of carbohydrate fermentation may also increase
osmolarity causing an influx of intestinal fluid that results in diarrhoea. Although
protein malabsorption is seen in SBBO, severe cases are rare. Bacteria competes
for protein as much as they do for carbohydrates, but do not contribute
significantly to the malabsorption, the damage to mucosa of the small bowel
results in the decreased peptide and amino acid intake. A 2003, study on
50 patients with malabsorption syndrome and 12 patients with IBS as controls,
resulted in SBBO being more common in patients with malabsorption syndrome (21 out of 50 – 42%) then in the control (0 out of 12
– 0%). Another recent study done in 2016 with 26 diabetic patients positive for
SBBO and 175 healthy controls, resulted in a mean of 0.71 ± 0.26 for SBBO positive patients (p<0.001) and a mean of 1.78 ± 0.21 in the control for a Urine d-xylose test (g/5 g d-xylose/5 hours); and 76.9% (20 out of 26) of the SBBO positive patients (p<0.001) were lactose intolerant compared to 39.4 % (69 out of 175) of the control (Rana et al., 2016).  The small bowel usually easily absorbs d-xylose, but when there is an issue with intestinal absorption, levels of d-xylose would be low in the urine, due to malabsorption. Patients who are lactose intolerant (lactose malabsorption), usually have a reduced expression of the lactase enzyme due to either damaged enterocytes or failure to incorporate dairy product in their diets. Another study in 2006, showed patients who had malabsorption syndrome and SBBO had higher concentrations of chain fatty acids and unconjugated bile acids then those without SBBO, indicating that SBBO can in fact worsen carbohydrate and fat malabsorption Small Bowel Bacteria Overgrowth in B12 Deficiency: Vitamin B12 (Cobalamin) deficiency can result from over utilization of the vitamin by bacteria in SBBO. The human body does not synthesize vitamin B12 but is made by microorganisms and can be obtained from consuming meat, eggs or dairy products; vitamin B12 cannot be obtain from vegetable and fruits. Symptoms and signs of B12 deficiency may include megaloblastic anaemia, neural deficits of the central and peripheral nervous systems, including loss of sense in position, cognitive changes, pyramidal tract hinderance and peripheral neuropathy. The process of vitamin B12 digestion is shown in (Figure 2). When meat, eggs, or dairy products are ingested, vitamin B12 is liberated from the dietary protein complex by gastric acids and pepsinogens; R-proteins (Transcobalamin 1) found in salivary juices then immediately forms a complex with the released vitamin B12 to protect it from degradation in the stomach and transports it to the duodenum. The vitamin B12-R-protein complex is then degraded by proteases releasing vitamin B12 to be bounded with intrinsic factor. The complex then travels down to the ileum and then binds on to vitamin B12-intrinsic factor receptor, and vitamin B12 is absorbed into the blood stream. But is not the case in SBBO; bacterial overgrowth may result in an increased competition for digested vitamin B12. Although gram negative aerobic bacteria can utilize free vitamin B12, binding to intrinsic factor would hinder its ability to do so, while intrinsic factor bounded to vitamin B12 has no effect on 'inhibiting' gram negative anaerobic bacteria from utilizing it, in particularly some Bacteroides and Clostridia. Vitamin B12-intrinsic factor complex is partially cleaved by bacteria to inactive analogues, which affects the binding and absorption of Vitamin B12 in the ileum ultimately resulting in Vitamin B12 deficiency. Gram negative anaerobic bacteria being the major cause of vitamin B12 deficiency, was concluded when penicillin and kanamycin given, greatly reduced both gram positive and gram negative aerobic bacterial growth but failed to improve vitamin B12 absorption, while metronidazole, which greatly reduced anaerobic bacterial growth, resolved vitamin B12 malabsorption. While SBBO might theoretically be a possible reason for vitamin B12 deficiency, no major findings or direct evidences has published recently to prove its cause. Parkinson's Disease: Parkinson's disease (PD) is one of the most common neurodegenerative disease that is considered to be no.2 in the world resulting from loss of dopamine neurons in the midbrain, specifically in the substantia nigra pars compacta.Clinical symptoms of PD is characterised by either the "common" motor disturbances such as  resting tremors, slowing of movements, muscular rigidity and postural instability, or non-motor disturbances such as Gastrointestinal (GI) dysfunctions, including abdominal bloating, constipation, pain and weight loss. These GI dysfunctions are thought to be results of delayed gastric emptying, defecatory dysfunction and impaired gut motility in PD patients. GI dysfunctions, particularly in the small bowels are known to result in the prevalence of SBBO. It was shown in a 2011 study that the prevalence of SBBO was significantly increased in patients with PD (26 out of 48 – 54.17%) then in the control (3 out of 36 – 8.33%) and that during PD medication "ON" periods, PD patients positive for SBBO had a significantly higher level on the Hoehn and Yahr Stage (H&Y Stage) and Unified PD Rating Scale (UPDRS) then of the SBBO negative patients (3.4 ± 0.8 and 26.1 ± 12.7 vs 2.4 ± 0.9 and 13.4 ± 7.9 respectively). This would suggest that patients with a higher progression of PD are more likely to have SBBO then those of the lower level, as both the H&Y Stage and UPDRS are methods to evaluate the progression of PD in patients. Another study that was investigating the contribution of SBBO in the motor fluctuations had a similar significant prevalence of SBBO in PD patients (18 out of 33 – 54.5%) than to the controls (6 out of 30 – 20%) and also found that SBBO positive PD patients had a significantly higher level of unpredictable fluctuations compared to SBBO negative PD patients (87.5% vs 8.3% respectively; which was confirmed when SBBO eradication improved motor fluctuations. Results from a recent study on Chinese patients in 2016, showed out of 182 PD patients, 55 (30.2%) of them were SBBO positive while in the control group of 200 healthy subjects, 19 (9.5%) of them were SBBO positive, again stating the significance of SBBO prevalence in PD patients, and also presented that SBBO positive PD Patients had a significantly higher level of motor fluctuations as compared to SBBO negative PD patients (70.9% vs 45.7% respectively). In a 2014 study, though association of SBBO on motor fluctuations was not confirmed, they concluded that 26 out of 103 (25.3%) PD patients had SBBO and had significantly worse motor functions during medication "ON" state on a series of timed motor test using UPDRS as compared to PD patients without SBBO ; although they had a lower prevalence of SBBO compared to the other studies , it was claimed to might have been due to their specific exclusion criteria of anti-acid medication that causes hypochlorhydria which  results in the over growth of bacteria in the small bowel. The causative link between the severity of PD and SBBO is hard to ascertain based on Table 2, as 1) prevalence of SBBO in PD patients with longer disease duration was seen in studies of Gabrielli et al., (2011) and Niu et al., (2016), while prevalence of SBBO in PD patients with shorter disease duration was seen in studies of Tan et al., (2014) and Fasano et al., (2013); and 2) although done with either "ON" or "OFF" states higher UPDRS staging of SBBO positive PD patients was seen in Gabrielli et al., (2011) , Niu et al., (2016) and Tan et al., (2014) compared to SBBO negative PD patients, while lower UPDRS staging of SBBO positive PD patients was seen in Fasano et al., (2013) compared to SBBO negative PD patients. It is still an important feature to note that in all 4 studies, SBBO was more prevalent on PD patients comparing to healthy controls and that the H&Y Staging for all SBBO positive PD patients was higher than of the SBBO negative PD patients except to regards of Fasano et al., (2013), where both SBBO positive and negative PD patients had equal stages (Table 2). PD Patients that were SBBO positive showing a significantly higher motor fluctuation and significantly worse motor functions might have been due to the inability of the small bowel to absorb levodopa or any other dopaminergic drugs as a result of small bowel inflammation and injury to the enterocytes or a partial metabolism by the bacteria itself. Iron malabsorption may also exacerbate PD as iron is needed for the synthesis of dopamine. There is also evidence suggesting that neurodegenerative process in PD patients could be exacerbated via activation of microglial cells due to the GI inflammation, and that SBBO induced intestinal permeability could result in the creation of a proinflammatory environment due to the translocation of bacteria across the intestinal epithelium which was shown by an intense staining of the intestinal mucosa of PD patients that were newly diagnosed ; the aggregation of alpha-synuclein in the enteric neurons correlated with these changes. Eradication of SBBO in PD patients corrected fluctuation, but due to the persistence of the underlying main issue of abnormal GI motility due to DP, relapse of SBBO was common Fasano et al., (2013). But eradication of SBBO may not completely come as an advantage, exposure of SBBO may stimulate gut motility due to toxins and metabolites of the bacteria, which may benefit patients with constipation. It is not fully known how SBBO interacts with PD but interrupted absorbance of dopaminergic drugs in the small bowel is clear.