Introduction: (SBBO). SBBO, is a condition that
Introduction:A healthy and well-balanced gut florais an important factor to a host, providing many beneficial effects such asfermentation 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 intestinaldyshomeostasis. There are several factors thatcontrols and prevents the excessive growth of bacteria in the small bowel, suchas: 1) bile and gastric juice secretion, which offers antibacterial effects; 2)motility of the bowel via peristaltic movements, which prevents bacterialadherence to the mucosa of the bowel; 3) inhibition of pathogenic bacteria byproduction of mucin from epithelial cells of the bowel mucosa; 4) gut defensinsthat serve as antibacterial and antifungal peptides; 5) prevention of bacterialtranslocation to the small bowel from the colon via the ileocecal valve; and 6) normal cell mediated and humoral immune systemof the gut. Disruption or failure to maintain to any of the processesmentioned above, may result in small bowel bacterial overgrowth (SBBO).
SBBO, is a condition that is commonlyassociated with various other diseases such as, irritablebowel syndrome (IBS), Parkinson’s Disease (PD), malabsorption, B12 deficiency,diarrhoea, and even restless leg syndrome (RLS). Currently, whether SBBO causesthese diseases or rather is the symptom of these diseases is still poorlyunderstood and controversial. Identifying the possible relationship of SBBO in pathophysiology of symptoms with patients with thesediseases may give a better understanding of why they occur and may lead tonovel treatments for such patients.SBBOis widely accepted as the growth of bacteria ? 105 CFU/ml of theupper gut aspirate culture although some argue of the threshold being ?103 CFU/ml. Directculture of the upper gut aspirate is often considered the gold standard in SBBOdiagnosis, but it is a difficult and is aninvasive test to perform, thus various other non-invasive methods such asglucose and lactulose hydrogen breath tests (GHBT and LHBT) are popularand widely used to diagnose SBBO.
HydrogenBreath Test:The hydrogenbreath test follows the physiologicalprinciple of carbohydrate fermentation by the bacteria in the small bowel,using lactulose or glucose. This results in production of hydrogen gas that canbe measured using a gas chromatograph (Figure1) via exhalation over a period of time. Subjects are told to fast at least 12hours before the test and to avoid consumption of slowly absorbed carbohydrateduring the previous 24 hours to avoid delayed excretion of hydrogen in thebreath sample; on the day of the test, smoking is not allowed 30 min before thetest, 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 beforethe test. LHBT asopposed to GHBT typically produces an early peak within 90 mins of carbohydrateingestion showing small bowel fermentation (indication of SBBO) or sometimes, asecond peak showing colon fermentation (Figure 1, B2 and B3). Being said, thereare many limitations in these test; patients with rapid intestinal transit mayshare similar hydrogen gas production patterns, making it difficult to concludeSBBO. In patients with rapid intestinal transit an early peak may often give afalse positive result; in a study conducted on healthy Taiwanese nationals theaverage time taken for oro-cecal transit was about85 min, while in another study on Indian nationals, the average time taken for oro-cecal transit was about 65 min. Even with thedouble peak of the LHBT, it only has a sensitivity of 31% comparing to thesensitivity of GHBT at 44% against the upper gutaspirate culture as a reference, to diagnose SBBO. Hence GHBT should beconsidered the best option of a non-invasive means in the diagnosis of SBBO.
It should also be noted that in thepresence of Methanogenic gut flora such as Methanobrevibacterstadmanae and Methanobrevibacter smithii, whichcan be seen in 15% of people; production of methane instead of hydrogenis observed; as such, in these cases GHBT and LHBT may result in a falsenegative reading and cannot be used alone to diagnose SBBO accurately. Methane gaslevels should be recorded along with hydrogen levels in all breath samples togive an accurate diagnosis. Small Bowel Bacteria Overgrowth andIrritable Bowel Syndrome:IBS is a functionalgastrointestinal disorder which isdefined under the Rome IV criteria as therecurrent abdominal pain of at 1 day per week in the last 3 months, associatedwith 2 or more of the following: 1) related to defecation, 2) associated withthe change in frequency of stool and 3) associated with change of stoolappearance.
IBS is characterised by the clinical manifestations of abdominaldistention and pain, diarrhoea, change in bowel habits and abnormal intestinalmotility. It is uncertain what exactly causes IBS but there are severalhypotheses that suggest visceral hypersensitivity of the gut, altered gutmotility, and abnormal nervous interaction of the gut and brain being itspredominant pathophysiology(Crowell et al., 2005). Symptomsof 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 causeor symptom of IBS is still not known, due to IBS having more clinicaldiagnosis criteria then of SBBO . Differentresults may occur from different criteria. Several studies have beendone using different diagnosticmethods such as upper gut aspirate culture, GHBT and LHBT to evaluate the frequency of SBBO in patientsdiagnosed with IBS. The summary of these studies can be seen in Table 1. Fromthe results seen in Table 1, a wide range of 4% – 78% of IBSpatients had SBBO, compared to the 1% – 40% of the control who had SBBO. Mostof the results seen in Table 1 revealed that SBBO was indeed more prevalent inIBS patients than the controls, suggesting the association of IBS and SBBO tobe definite. IBS is considered to be heterogeneous with 3 subtypes, consisting of diarrhoea (IBS-D), constipation (IBS-C) or an alternatingmix of both (IBS-M).
Patients with IBS showing predominant symptoms ofdiarrhoea are more often to be implicated with SBBO than of the othersubtypes. A study conducted in India on2011 stated that out of 59 IBS patients (27 IBS-D, 11 IBS-C and 21 IBS-M) and37 healthy controls, SBBO was frequently seen in patients with IBS (14 out of59 – 23.7%) than of the healthy control (1 out of 37 – 2.
7%) using GHBT. IBS-Dpatients was seen to have more occurrence of SBBO then of the other 2 subtypes, 37% vs 12.5% respectively, IBS-C being the lowest.
Similar results were alsofound in other studies as well. This would have indicated that SBBO is moreprominently seen in IBS-D compared to other IBS sub types and studies with alarger sample size of IBS-D patients are, more likely to provide a higherfrequency of SBBO. The possible reasons of diarrhoea in SBBO positive IBSpatients may be due to the damage of the small intestine’s inner lining by theeffects of enterotoxins from bacterial by-products after fermentation, whichsubsequently triggers immune activation resulting in inflammation and increasedpermeability of the small intestine ultimately causing diarrhoea due toincreased osmotic load. Increased number of bacteria may also cause bile saltsde-conjugation that is commonly found in the small bowel for fatemulsification. The de-conjugated bile salts then trigger the secretion ofwater from the colon resulting in diarrhoea.
Pro-inflammatory cytokines maythen also be released due to the inflammation of the mucosal layer by bileacids. IBS patients with no signs of SBBO may also result in diarrhoea as adirect impact from increased gut motility, giving the intestines lesser time toabsorb water from the undigested food.Patients with symptoms of bloating were also found tohave SBBO more often than those without. Althoughnot fully understood, one of the possible reason pain or discomfort occurringfrom visceral sensation, may be due to bloating which results from accumulationof hydrogen gas in the gut, following ingestion of fermentable substrates suchas carbohydrates or glucose, compared to healthy controls.
One of the reasons for these observations seen inIBS may be a result from having SBBO, due to fermenting bacteriacolonizing the small bowel. Formation of shortchain fatty acids such as butyricacid, 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; theyincrease motility of the colon due to acidification, hinder absorption ofnutrients, and reduces motility of the small bowel which in turn causes ahigher chance of promoting SBBO. Endotoxins such as lipopolysaccharidesalso hinder gut motility due to overgrowth of Gramnegative bacteria and may worsen the condition.
Sensory-motor functionsare also affected by chemotactic peptides of bacteria, such asformyl-methionyl-leucyl-phenylalanine, which causes the stimulation of afferentnerves and the enteric nervous system resulting in abnormal brain-gutinteractions Therefore, changes ingut flora in cases such as SBBO may affect, visceral hypersensitivity, gut motility and abnormal nervous interactionof the gut and brain. These may be the reason why SBBO might be predisposed toIBS like symptomsSmall Bowel Bacteria Overgrowth in Diarrhoea,Malabsorption & B12Deficiency:SBBO is a well-knowncause of malabsorption and diarrhoea; bacteria compete with the enterocytes inthe small bowel for nutrition and in addition to excessive bacteria found’stealing’ and metabolising luminal nutrients before intestinal absorption canoccur they can deconjugate bile acids anddamage small bowel enterocytes. In normal conditions, conjugated bile acids arewater soluble and form mixed micelles together with ingested lipids in thesmall bowel for fat absorption.
Conjugated bile acids are normally notreabsorbed until the ileum, but when bacteria deconjugates bile acids, theseacids are reabsorbed in thejejunum before reaching the ileum. This short-cut of reabsorption of bileacids impairs the formation of the micelle complexes which results in fatmalabsorption and causes steatorrhoea. As a direct cause of fat malabsorption, fat soluble vitamins such asA, D, E and K may also be mal-absorbed. In addition to causing fat malabsorption, these deconjugatedfree bile acids and enterotoxins from bacterial overgrowth may be harmful tothe small bowel enterocytes, as structural and functional lesions have beenidentified with the help of electron & light microscopy and reducedenzymatic activity of the mucosa respectively, resulting in increasedpermeability 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 testedpositive and 35 (66%) were tested negative on a GHBT; a group of 15 children withno gastrointestinal symptoms were used as negative controls and a group of 6children with documented SBBO were used as positive control. GHBT test resultswere comparable with the 18 children tested positive to the positive controland 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 ofchronic diarrhoea.
All symptoms ceased within 1 week of SBBO antibiotic therapyand GHBT was negative. Another study in 2004, done with 87 patients with chronicdiarrhoea, resulted in 48% positive for SBBO, 13% for IBS, 11% unknown and 28%for others; subsequently breath test and duodenal culture were carried out on18 patients with chronic diarrhoea and 15 patients as control; 33% and 50% ofthe patients were tested positive SBBO by duodenal culture and 14C-D-xylosebreath/lactulose test respectively and 67% were tested positive for acombination of both test, while in the control group 0% and 13% of the patientswere tested positive SBBO by duodenal culture and 14C-D-xylosebreath/lactulose test respectively and 13% were tested positive for acombination of both test. Similar results showing diarrhoea was mostly relatedto SBBO was also found in another study. Damage to the brush border, impairs disaccharidasefunction of the enterocytes and along with increased carbohydrate fermentationby bacteria, carbohydrate malabsorption is seen;short chain fatty acids that is a by-product of carbohydrate fermentation may also increaseosmolarity causing an influx of intestinal fluid that results in diarrhoea. Althoughprotein malabsorption is seen in SBBO, severe cases are rare. Bacteria competesfor protein as much as they do for carbohydrates, but do not contributesignificantly to the malabsorption, the damage to mucosa of the small bowelresults in the decreased peptide and amino acid intake. A 2003, study on50 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 forSBBO and 175 healthy controls, resulted in a mean of 0.71 ± 0.26 for SBBO positive patients (p<0.
001) and a meanof 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) ofthe SBBO positive patients (p<0.001) were lactose intolerant compared to39.
4 % (69 out of 175) of the control (Rana et al., 2016). The smallbowel usually easily absorbs d-xylose, but when there is an issuewith intestinal absorption, levels of d-xylose would be low in theurine, due to malabsorption. Patients who are lactose intolerant (lactose malabsorption), usually have a reducedexpression of the lactase enzyme due to either damaged enterocytes or failureto incorporate dairy product in their diets. Another study in 2006, showedpatients who had malabsorption syndrome and SBBO had higherconcentrations of chain fatty acids and unconjugated bile acids then those without SBBO, indicating thatSBBO can in fact worsen carbohydrate and fat malabsorptionSmall Bowel Bacteria Overgrowth in B12Deficiency:Vitamin B12 (Cobalamin) deficiency can result fromover utilization of the vitamin by bacteria in SBBO. The human body does notsynthesize vitamin B12 but is made by microorganisms and can be obtained fromconsuming meat, eggs or dairy products; vitamin B12 cannot be obtain fromvegetable and fruits. Symptoms and signs of B12 deficiency may includemegaloblastic anaemia, neural deficits of the central and peripheral nervoussystems, including loss of sense in position, cognitive changes, pyramidaltract hinderance and peripheral neuropathy. The process of vitamin B12digestion is shown in (Figure 2).
When meat, eggs, or dairy products areingested, vitamin B12 is liberated from the dietary protein complex by gastricacids and pepsinogens; R-proteins (Transcobalamin 1) found in salivary juices thenimmediately forms a complex with the released vitamin B12 to protect it fromdegradation in the stomach and transports it to the duodenum. The vitaminB12-R-protein complex is then degraded by proteases releasing vitamin B12 to bebounded with intrinsic factor. The complex then travels down to the ileum andthen binds on to vitamin B12-intrinsic factor receptor, and vitamin B12 isabsorbed into the blood stream. But is not the case in SBBO; bacterial overgrowth mayresult in an increased competition for digested vitamin B12. Although gramnegative aerobic bacteria can utilize free vitamin B12, binding to intrinsicfactor would hinder its ability to do so, while intrinsic factor bounded tovitamin B12 has no effect on ‘inhibiting’ gram negative anaerobic bacteria fromutilizing it, in particularly some Bacteroidesand Clostridia.
Vitamin B12-intrinsicfactor complex is partially cleaved by bacteria to inactive analogues, whichaffects the binding and absorption of Vitamin B12 in the ileum ultimatelyresulting in Vitamin B12 deficiency. Gram negative anaerobic bacteria being themajor cause of vitamin B12 deficiency, was concluded when penicillin andkanamycin given, greatly reduced both gram positive and gram negative aerobicbacterial growth but failed to improve vitamin B12 absorption, whilemetronidazole, which greatly reduced anaerobic bacterial growth, resolvedvitamin B12 malabsorption. While SBBO might theoretically be a possible reasonfor vitamin B12 deficiency, no major findings or direct evidences has publishedrecently to prove its cause.Parkinson’s Disease:Parkinson’sdisease (PD) is one of the most common neurodegenerative disease that isconsidered to be no.2 in the worldresulting from loss of dopamine neurons in the midbrain, specifically in thesubstantia nigra pars compacta.Clinical symptoms of PD is characterised byeither the “common” motor disturbances such as resting tremors, slowing of movements, muscular rigidity and posturalinstability, 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 delayedgastric emptying, defecatorydysfunction and impaired gut motility in PD patients.
GI dysfunctions, particularly in the small bowels areknown to result in the prevalence of SBBO. It was shown in a 2011 study thatthe 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 thatduring PD medication “ON” periods, PD patients positive for SBBO had asignificantly 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 ahigher progression of PD are more likely to have SBBO then those of the lowerlevel, as both the H&Y Stage and UPDRS are methods to evaluate theprogression of PD in patients. Another study that was investigating thecontribution of SBBO in the motor fluctuations had a similar significantprevalence of SBBO in PD patients (18 out of 33 – 54.5%) than to thecontrols (6 out of 30 – 20%)and also found that SBBO positive PD patients had a significantly higher level of unpredictable fluctuationscompared to SBBO negative PD patients (87.5% vs 8.
3% respectively; which wasconfirmed when SBBO eradication improved motor fluctuations. Results from a recentstudy on Chinese patients in 2016, showed out of 182 PD patients, 55 (30.2%) ofthem 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 SBBOprevalence in PD patients, and also presented that SBBO positive PD Patientshad a significantly higher level of motor fluctuations as compared to SBBOnegative PD patients (70.9% vs 45.7% respectively). In a 2014 study, thoughassociation of SBBO on motor fluctuations was not confirmed, they concludedthat 26 out of 103 (25.
3%) PD patients had SBBO and had significantly worsemotor functions during medication “ON” state on a series of timed motor testusing UPDRS as compared to PD patients without SBBO ; although they had a lowerprevalence of SBBO compared to the other studies , it was claimed to might havebeen due to their specific exclusion criteria of anti-acid medication thatcauses hypochlorhydria which results inthe over growth of bacteria in the small bowel. The causative link between theseverity of PD and SBBO is hard to ascertain based on Table 2, as 1) prevalenceof SBBO in PD patients with longer disease duration was seen in studies of Gabrielliet al., (2011) and Niu et al., (2016), while prevalence of SBBO in PD patientswith shorter disease duration was seen in studies of Tan et al., (2014) and Fasanoet al.
, (2013); and 2) although done with either “ON” or “OFF” states higher UPDRSstaging of SBBO positive PD patients was seen in Gabrielli et al., (2011) , Niuet 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 etal., (2013) compared to SBBO negative PD patients. It is still an importantfeature to note that in all 4 studies, SBBO was more prevalent on PD patientscomparing to healthy controls and that the H&Y Staging for all SBBOpositive PD patients was higher than of the SBBO negative PD patients except toregards of Fasano et al., (2013), where both SBBO positive and negative PDpatients had equal stages (Table 2).
PD Patients that were SBBO positiveshowing a significantly higher motor fluctuation and significantly worse motor functions might have been due to theinability of the small bowel to absorb levodopa or any other dopaminergic drugsas a result of small bowel inflammation and injury to the enterocytes or apartial metabolism by the bacteria itself. Iron malabsorption may alsoexacerbate PD as iron is needed for the synthesis of dopamine. There is alsoevidence suggesting that neurodegenerative process in PD patients could be exacerbatedvia activation of microglial cells due to the GI inflammation, and that SBBOinduced intestinal permeability could result in the creation of aproinflammatory environment due to the translocation of bacteria across theintestinal epithelium which was shown by an intense staining of the intestinalmucosa of PD patients that were newly diagnosed ; the aggregation of alpha-synucleinin the enteric neurons correlated with these changes. Eradication of SBBO in PDpatients corrected fluctuation, but due to the persistence of the underlyingmain issue of abnormal GI motility due to DP, relapse of SBBO was common Fasanoet al., (2013).
But eradication of SBBO may not completely come as anadvantage, exposure of SBBO may stimulate gut motility due to toxins andmetabolites of the bacteria, which may benefit patients with constipation. Itis not fully known how SBBO interacts with PD but interrupted absorbance of dopaminergicdrugs in the small bowel is clear.
