Small intestine bacterial overgrowth (SIBO) may be more prevalent among patients with restless legs syndrome (RLS)


Small intestine bacterial overgrowth (SIBO) may be more prevalent among patients with restless legs syndrome (RLS), according to preliminary findings from a small, new study.

Results show that SIBO was found in all seven participants who have RLS.

In contrast, the prevalence of SIBO in the general population is estimated to be no more than 15%.

“We’ve observed extremely high rates of small intestinal bacterial overgrowth in the RLS group,” said lead author Daniel Jin Blum, Ph.D., D.B.S.M., an adjunct clinical instructor at Stanford Center for Sleep Sciences and Medicine in Redwood City, California.

“Exploring the relationship between RLS and gut microbial health has the potential to open novel avenues for possible detection, prevention and treatment for RLS and other sleep disorders.”

SIBO is a condition in which rare gut-residing bacteria are over-represented in the gut.

Human gut harbor 1014 bacterial cells, which are 10 times higher than the number of cells in the human body.12

 Gastrointestinal (GI) tract is considered as the most heavily colonized organ and more than 70% of microbes reside in colon.13 

The human GI tract is inhabited by a vast number of microbial population including bacteria, fungi, and viruses.14 

Bacteria contribute to the largest population of gut microbiota, consisting of 500 (using culture approaches) to 1,000 (by 16S rRNA gene sequencing) different bacterial species.15 The number of bacteria increases from stomach (101 to 103 bacteria/g) to the colon (1011 to 1012 bacteria/g).13 

The small intestine comprises mainly of Gram positive and aerobic bacteria and the large intestine contains predominantly Gram negative and anaerobic bacteria.16 

Majority of bacteria residing in the colon are strictly anaerobes (95% of total) followed by facultative anaerobes and aerobes.15

More than 50 bacterial phyla have been identified in human gut.17 Major phyla residing in the gut are Bacteroidetes and Firmicutes, whilst Proteobacteria, Verrucomicrobia, Actino-bacteria, Fusobacteria, and Cyanobacteria are present in minor proportion.13,18

Normal gut flora may provide several beneficial effects to the host.

These include fermentation of un-digested dietary residue and endogenous mucus producing short chain fatty acids, which are nutrients to the colonic epithelial cells and conservation of energy, absorption of NaCl and water, particularly from the right colon, synthesis of vitamin K, control of epithelial cell proliferation, protection against pathogens by a barrier effect and training of the immune system.1921 

One study showed that small intestine of germ free animal has thin and irregular villi, reduced crypt size, increased number of Peyer’s patches, and infiltration of leukocytes in lamina propria.22,23 

Alteration in the normal flora leads to disturbance in the intestinal homeostasis.2 

There are several intrinsic and extrinsic factors that prevent overgrowth of bacteria in the small intestine.

Intrinsic factors include: (1) secretion of gastric juice and bile, which have antibacterial effect; (2) peristaltic movement preventing adherence of bacteria into the intestinal mucosa; (3) normal gut defense including humoral and cellular mechanisms; (4) mucin production by intestinal mucosal epithelial cell inhibiting pathogenic bacteria; (5) gut antibacterial peptides such as defensins; and (6) ileocecal valve preventing retrograde translocation of bacteria from colon to the small intestine.2426 

Extrinsic factors include diet and drugs modulating gut flora, such as pre and probiotics, gastric acid suppressants such as proton pump inhibitors (PPIs), H2 blockers, and antibiotics and drugs altering motility (prokinetics, anticholinergics, and opioids).4,22,2730 If, there is failure of any of the above-mentioned protective mechanisms, it may lead to development of SIBO (Fig. 1).

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Fig. 1
Schematic diagram showing the frequency of small intestinal bacterial overgrowth (SIBO) using quantitative jejunal aspirate culture, glucose and lactulose hydrogen breath tests (GHBT and LHBT, respectively) among patients with irritable bowel syndrome (IBS), gut defense mechanisms that prevent the development of SIBO, factors associated with SIBO among patients with IBS, and mechanisms of IBS symptom development. As shown in the figure, the frequency of SIBO in IBS patients using LHBT (early-peak criteria) is higher than that by using upper gut aspirate culture and GHBT (LHBT [45%]; upper gut aspirate culture [23%] and GHBT [26%]). Moreover, SIBO is more frequent in healthy controls using LHBT due to false positive test results (LHBT [21%], upper gut aspirate culture [1%] and GHBT [5%]).
GI, gastrointestinal; IBS-D, irritable bowel syndrome, diarrhea-predominan; PPI, proton pump inhibitor; CHO, carbohydrate.

Though quantitative culture of the upper gut aspirate has traditionally been used as the gold standard for the diagnosis SIBO, its limitations include difficulty and invasiveness, cost, contamination by oropharyngeal flora, and inability to culture as high as 70% bacteria colonizing the gut.2,13,30,31 

Moreover, distribution of bacterial overgrowth may be patchy and upper gut aspirate may not be able to detect bacterial overgrowth in distal gut.30,32 

The anaerobic bacteria may not grow if air is used during endoscopy; hence, either nitrogen or carbon dioxide is better for this purpose.

In one of our earlier studies in which we used air during endoscopy, of 34 of 50 patients with malabsorption syndrome in whom bacteria were cultured in jejunal aspirate, only one grew anaerobic bacteria.33 Hence, search for other less invasive and patient-friendly methods for diagnosis of SIBO continues.

In an attempt to overcome some of the limitations of the traditional culture-based method for diagnosis of SIBO, a novel technology, called culturomics, has been developed recently.15

Culturomics confer a new platform for identification of large number of bacterial colonies as well as noncultivable species in a short time duration using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF).15,34 

In a recent study, using 212 different culture conditions, 340 different bacterial, 5 fungal species and one virus were identified, including 31 new species using culturomics (MALDI-TOF) technique.34,35 

Thus, culturomic approaches are feasible, rapid, cost-effective and reproducible for the study of gut microbiota.15,34 

However, studies on SIBO using culturomics method are lacking. Moreover, use of effective culture conditions and sequencing methods may make it rarely usable for routine clinical application.

Breath tests are popular, noninvasive and patient-friendly methods used increasingly for diagnosis of SIBO.36 

Diagnostic role of hydrogen breath tests depends on the type of the substrates used; for example, lactose and fructose hydrogen breath tests are useful for carbohydrate malabsorption; on the other hand, glucose and lactulose hydrogen breath tests (GHBT and LHBT) are useful for diagnosis of SIBO, the former being more specific.

Therefore, choice of the substrate while performing hydrogen breath test is important as only specific substrate diagnoses SIBO and others test for carbohydrate malabsorption.36

 Hydrogen and methane gases are produced by the gut flora from the ingested substrates, particularly the colonic flora in patients with carbohydrate malabsorption and from small bowel bacteria in patients with SIBO.7,24,37 

Eighty percent of the gases like hydrogen and methane are eliminated with the flatus and the remaining 20% are absorbed and exhaled by lung, which can be measured in breath.22,38 

In GHBT, rise in hydrogen by 12 parts per million (ppm) above basal following administration of 50 to 100 g glucose due to bacterial fermentation of the substrate in small intestine is diagnostic of SIBO.36 

A recent study showed that measuring methane does not increase the yield of hydrogen breath test to diagnose SIBO.39 

In presence of SIBO, two peaks may be seen during LHBT: the first one due to bacterial fermentation of lactulose in small bowel and the second one after lactulose reaches colon.36 

Since number of bacteria in colon is higher than that in the small bowel even in patients with SIBO, a rise in breath hydrogen more than 20 ppm above basal is expected from colonic fermentation of the lactulose.40 

Though GHBT is highly specific (78% to 97%),41,42 it is quite insensitive (15.7% to 62%).42,43 

In contrast, conventional double-peak criteria on LHBT lack sensitivity (31% to 68%) and the recently proposed early-peak criterion (rise in breath hydrogen within 90 minutes by 20 ppm above basal following lactulose ingestion) often gives false positive result with specificity of 65% to 97.9%.39,44 

This is the reason for overestimation of frequency SIBO (as high as 78%) in the initial studies from United States.40 

In fact, the early-peak criterion on LHBT, which was used in the initial studies on SIBO in patients with IBS, presumed that normal mouth to cecum transit time is more than 90 minutes in spite of the observation that it may be shorter.36,40 

A study that combined radio-nuclide gut transit and LHBT revealed that in most patients in whom a peak in hydrogen was seen on LHBT, radio-nuclide already arrived in cecum.45 

Other methods for diagnosis of SIBO include CO2 breath tests (14C or 13C D-xylose, 13C glucose and 13C cholylglycine hydrolase).7,22,46,47

Though hydrogen breath tests are quite popular for the diagnosis of SIBO, these are not free from limitations.

In patients with distal SIBO, GHBT may be falsely negative as glucose gets completely absorbed in the proximal small bowel and hence, may not reach the site of SIBO.5,31,36 

In patients with fast gut transit, early peak criteria proposed by Pimentel et al.40often give false positive results.36 

Fast gut transit is not uncommon, particularly in Asia. In a study from our center, median orocecal transit time in healthy subjects was 65 minutes (range, 40 to 110 minutes).48 

A Taiwanese study revealed that average orocecal transit time was 85±37 minutes.49 

Hence, it is important to realize that there is need to search for a noninvasive yet sensitive and specific method for diagnosis of SIBO.

RLS is a sensorimotor disorder characterized by a complaint of a strong, nearly irresistible urge to move the limbs that is often accompanied by other uncomfortable sensations.

These symptoms begin or worsen during periods of rest or inactivity such as lying down or sitting, are partially or totally relieved by movement such as walking or stretching, and occur exclusively or predominantly in the evening or at night.

Low iron in the brain is a key risk factor for RLS.

According to the authors, this brain iron deficiency may be secondary to dietary iron deficiency or, potentially, gut inflammation.

Study participants completed questionnaires concerning sleep and SIBO symptoms and took home a fecal collection kit and a SIBO breath test kit.

Fecal samples were examined by the University of Minnesota Genomics Center, and SIBO breath samples were evaluated by Aerodiagnostics for hydrogen and methane abnormalities.

Additional study participants continue to be recruited at the Stanford Sleep Center. Further analyses will examine fecal microbial composition, subtypes of RLS iron deficiency, and comparisons with insomnia.

More information: Daniel J Blum et al, 0009 Restless Leg Syndrome: Does It Start With A Gut Feeling?, Sleep (2019). DOI: 10.1093/sleep/zsz067.008.

Journal information: Sleep
Provided by American Academy of Sleep Medicine


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