Many patients with bloating, abdominal pain, constipation or diarrhea are diagnosed with irritable bowel syndrome and never get adequate responses to treatment. Others are given no diagnosis at all for their suffering which leads to even less chance of recovery. Our experience is that many of these perplexing patients have commensal microbial overgrowth. This article details the complex issue of small intestine bacterial overgrowth (SIBO).
Small intestine bacterial overgrowth (SIBO) is a condition in which abnormally large numbers of commensal bacteria (or other microorganisms) are present in the small intestine. SIBO is a common cause of IBS – in fact it is involved in over half the cases of IBS1(Peralta S, 2009) and as high as 84% in one study using breath testing as the diagnostic marker 2(Lin HC, 2004.) It accounts for 37% of cases when endoscopic cultures of aerobic bacteria are used for diagnosis 3(Pyleris E, 2012.) Eradication of this overgrowth leads to a 75% reduction in IBS symptoms 4 (Pimentel M, 2003). Either bacterial overgrowth or the overgrowth of methanogenic archaea leads to impairment of digestion and absorption and produces excess quantities of hydrogen, hydrogen sulfide or methane gas. Hydrogen and methane are not produced by human cells but are the metabolic product of fermentation of carbohydrates by intestinal organisms. When commensals (oral, small intestine or large intestine flora) multiply in the small intestine to excessive numbers, IBS is likely. Hydrogen/methane breath testing is the most widely used diagnostic method for this condition. Stool analysis has no value in diagnosing SIBO.
Symptoms of SIBO include:
• Bloating/ abdominal gas
• Flatulence, belching
• Abdominal pain, discomfort or cramps
• Constipation, diarrhea or a mixture of the two
• Heartburn
• Nausea
• Malabsorption – steatorrhea; iron, vitamin D, vitamin K or B12 deficiency with or without anemia; and osteoporosis 5(Anantharaju A, 2003)
• Systemic symptoms - headache, fatigue, joint/muscle pain and certain dermatology conditions
· Other diseases associated with SIBO include hypothyroidism 6 (Lauritano EC, 2007), lactose intolerance 7 (Almeida JA, 2008), gallstones 8(Kaur J, 2014), Crohn disease 9(Klaus J, 2009), systemic sclerosis 10 (Marie I, 2009), celiac disease 11 (Rubio-Tapia A 2009), chronic pancreatitis 12 (Mancilla AC, 2008), diverticulitis 13(Tursi A, 2005), diabetes with autonomic neuropathy 14 (Ojetti V, 2009), fibromyalgia and chronic regional pain syndrome 15(Goebel A, 2008), hepatic encephalopathy 16 (Gupta A, 2010), non-alcoholic steatohepatitis 17 (Shanab AA, 2011), interstitial cystitis 18 (Weinstock LB, 2007), restless leg syndrome 19 (Weinstock ,LB, 2011), acne rosacea 20 (Parodi A, 2008) and erosive esophagitis 21(Kim KM, 2012). Based on clinical experience, we suspect that biliary dyskinesia and lymphocytic colitis may also be associated with SIBO.
In our practices we have found that the following indicators increase the chances that a patient’s IBS is caused by SIBO:
• When a patient develops IBS following a bout of acute gastroenteritis (post-infectious IBS)
• When a patient reports dramatic transient improvement in IBS symptoms after antibiotic treatment
• When a patient reports worsening of IBS symptoms from ingesting probiotic supplements which also contain prebiotics
• When a patient reports that eating more fiber increases constipation and other IBS symptoms
• When a celiac patient reports insufficient improvement in digestive symptoms even when carefully following a gluten-free diet
• When a patient develops constipation type IBS (IBS-C) after taking opiates
• When a patient has a chronic low ferritin level with no other apparent cause
• When abdominal imaging reveals a large gas accumulation obscuring the pancreas
• When small bowel follow through imaging reveals areas of “flocculation” 22(Pimentel M, 2014)
Mechanisms by which overgrowth is prevented
An important protective mechanism against SIBO is proper small intestine motility via the migrating motor complex 23 (Husebye E, 1999) because stasis promotes bacterial growth. Also key in prevention are gastric, pancreatic, and gall bladder secretions, since hydrochloric acid, enzymes, and bile are bactericidal/static 24 (Bures J, 2010.) Conditions that disrupt the glycocalyx and microvillus portions of the brush border may fuel overgrowth. The pathophysiology involved is the loss of disaccharidases in these areas and the resulting carbohydrate malabsorption which provides excess substrate for microbial growth. The role of proper ileocecal valve function in preventing cecoileal reflux of colonic bacteria into the small intestine may also be important 25,26 (Machado WM, 2008, Roland BC, 2014.) Surprisingly, a recent study suggests that surgical removal of the gall bladder reduces the risk as well 27(Gabbard SL, 2014.) Mucosal biofilms may be preventive or may be a risk28,29(Chedid V, 2014 and MacFarlane S, 2008). Heavy drinking, as well as moderate use of alcohol, is significantly associated with increased SIBO risk 30(Gabbard SL, 2014.) The use of proton pump inhibitors encourages overgrowth, especially of the hydrogen producing type 31,32(Pyleris E, 2012; Jacobs C,, 2013.)
Definition
Traditionally, ≥ 100,000 colony-forming units (CFU) per mL of proximal jejunal aspiration has been the definition of SIBO in culturing studies. ≥ 1000 CFU’s is now the suggested definition from more recent studies revealing ≤1000 CFU’s is the normal level in healthy controls 33,34 (Khosini R, 2008; Pimentel M, 2012). The bacteria which are most commonly overgrown are both commensal anaerobes - Bacteroides 39%, Lactobacillus 25%, Clostridium 20% and commensal aerobes - Streptococcus 60%, Escherichia coli 36%, Staphylococcus 13%, Klebsiella 11%35(Bouhnik Y, 1999.) A more recent study found the aerobes to be Escherichia coli 37%, Enterococcus spp 32%, Klebsiella pneumonia 24%, and Proteus mirabilis 6.5% 36(Pyleris E, 2012). Colonic hydrogen production is believed to be anti-inflammatory and antineoplastic 37(Carbonero F, 2012) whereas excessive small intestine hydrogen causes the symptoms and signs of diarrhea type irritable bowel syndrome (IBS-D.) In addition to bacteria, the source of methane generation in SIBO is the archaeon Methanobrevibacter smithii. This organism has been linked to obesity in humans 38(Million M, 2013.) In addition, sulphate reducing bacteria, such as Desulfovibrio species are anaerobes that reduce sulfate to hydrogen sulfide (H2S). In addition to its role in SIBO, H2S is being studied as a possible etiologic factor in ulcerative colitis and colonic carcinogenesis 39(Medani M, 2011.) In normal low levels H2S has GI protective activity 40(Elsheikh W, 2014).
Pathophysiology of SIBO – Autoimmunity
Post-infectious IBS (PI-IBS) has been shown to have an autoimmune etiology in both murine and human studies. Infectious gastroenteritis is the most significant environmental risk factor for IBS 41(Rodriguez LA, 1999). Organisms that trigger PI-IBS include Campylobacter, Salmonella, Shigella, E. coli 42,43(Rodriguez LA, 1999 and Beatty JK, 2014), Viruses 44(Zanini B, 2012) and Giardia 45(Hanevik K, 2009).
Cytolethal distending toxin (CDT) is produced by enteric pathogens that cause PI-IBS. Campylobacter jejuni is the prototypical bacteria that produces CDT 46(Pokkunuri V, 2012.) Other bacteria that produce CDT include Haemophilus ducreyi (chancroid), Aggregatibacter actinomycetemcomitans (periodontitis), Escherichia coli (traveler’s diarrhea), Shigella dysenteriae (dysentery), Salmonella enterica (typhoid fever) and Campylobacter upsaliensis (enterocolitis).
The interstitial cells of Cajal (ICC) are fibroblast-like cells that act as pacemakers for the migrating motor complex (MMC). A key underlying cause of SIBO is thought to be deficiency of the MMC, which moves debris and bacteria down into the large intestine during fasting at night and between meals 47(Pimentel M, 2009). The number of interstitial cells of Cajal (ICCs) are reduced in post Campylobacter jejuni gastroenteritis infected rats that eventually develop SIBO 48(Pokkunuri V, 2012.) Three months after C. jejuni gastroenteritis, 27% of rats had SIBO. These rats had a lower number of interstitial cells of Cajal (ICC) than controls in the jejunum and ileum (0.12 ICC/villus was the threshold for developing SIBO.)
CDT toxin may have a direct effect by damaging DNA in the interstitial cell of Cajal. In addition, CDT when deposited in GI nerve cells leads to production of c-kit and - by molecular mimicry- production of autoantibodies. Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions. Vinculin allows cells to connect and stretch. The antigen-antibody complexes between anti-vinculin antibodies and cytolytic distending toxin simplify this lead to autoimmune destruction of interstitial cells of Cajal. (ACG 2013 “Antivinculin Aby… and UEG Molecular Mimicry and Auto…)
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How SIBO causes the symptoms of IBS
There are two main pathophysiological issues involved in SIBO. First, bacteria are able to ferment carbohydrates and consume other nutrients ingested by the host simply by their inappropriate location in the small intestine. This allows them premature exposure to host nutrition before there is time for absorption. Bacterial fermentation produces hydrogen and/or hydrogen sulfide gas. In addition M. smithii produces methane 49(Kim G, 2012.) M. smithii may be present in the intestinal tracts of up to 95.7% of humans 50(Dridi B, 2009). Microbial gas leads to the IBS symptoms of bloating, pain, altered bowel movements, eructation and flatulence (Figure 1- SIBO Pathophysiology I). The quantity of gas may be extensive, causing severe bloating and distention 51 (Youn YH 2011.) It is estimated that with normal levels of enteric flora, the quantity of lactose in an ounce of milk fuels the production of 50 cc of gas. With microbial overgrowth, gas levels produced from one ounce of milk may approach 5000 cc 52 (Gottschall E, 1994.) Excess gas can then exit the body as flatulence or eructation. A portion is also absorbed into the blood and eventually filters through the pulmonary alveolus to exit on exhalation. The intestines are sensitive to pressure and therefore the pressure of distention can lead to abdominal pain. In addition, visceral hypersensitivity, a feature of IBS, may create a lower threshold for pain/discomfort 53 (Elsenbruch S, 2011) and a hyper responsiveness of muscular contraction in response to the gas, leading to cramps 54 (Pimentel M, 2006.) The gases also affect bowel motility. Hydrogen has a greater association with diarrhea and methane has an almost exclusive association with constipation 55,56 (Pimentel M, 2003; Kunkel D, 2011.) Methane has been shown to slow gastrointestinal motility by 59% (check percentage) in animal studies 57 (Pimentel M, 2006), and the volume of methane overproduction correlates with the severity of constipation 58 (Chatterjee S, 2007.) Therefore when both hydrogen and methane are present, diarrhea, constipation, or a mixture of both can be present based on the relative amounts of these gases 59 (Pimentel, 2003.) It appears that the pressure created by either gas or the decreased gastric motility may lead to gastric distention resulting in gastroesophageal reflux (GERD) 60 (Kim KM, 2012.) The bacterial consumption and uptake of host nutrients, such as B12 and iron, can lead to macrocytic and/or microcytic anemia or chronic low ferritin levels in addition to general malabsorption and malnutrition in more severe cases 61,62 (Singh V, 2004; Leung Ki EL, 2010.) The increased motility of diarrhea may also induce malabsorption. Finally, continuous fermentation of host nutrition by repeated exposure to daily meals, perpetuates bacterial overgrowth and IBS symptoms, creating a vicious cycle
The second mechanism is microbial damage to the digestive and absorptive function of the small intestine. Unlike the colon, the small intestine is not designed for heavy bacterial colonization. Commensal organisms may synthesize glycosidase leading to damage of glycocalyx or disaccharidases. Key factors include bacterial deconjugation of bile which induces fat malabsorption, steatorrhea and fat soluble vitamin deficiencies 63 (DiBaise JK, 2008), bacterial digestion of disaccharidase enzymes which furthers carbohydrate malabsorption, fermentation, and gas 64 (Prizont R, 1981), and increased intestinal permeability (leaky gut) which often leads to systemic symptoms 65,66 (Lauritano EC, 2010; Resnick C, 2010.)
Diagnosis of SIBO
As mentioned above, hydrogen/methane breath testing is the most common method of assessing SIBO. Instrumentation is available from Quintron Instrument Company in Milwaukie, Wisconsin. They build and distribute the Breathtracker, which is used to measure these gases following a 24-48 hour prep diet and an overnight fast. After collection of the fasting baseline specimen, a solution of lactulose -an unabsorbable synthetic sugar- is ingested as the substrate for bacterial fermentation. Lactulose is non-absorbable because only bacteria, not humans, produce the enzymes to digest it. Lactulose is a disaccharide solution of galactose and fructose in a base which also contains a minute quantity of lactose and epilactose (add package reference). Transit time for lactulose through the stomach and small bowel is approximately 120 minutes. Glucose may also be used as a test substance, but because of its rapid absorption in the proximal small intestine, it may fail to identify more distal SIBO 67 (Pimentel M, 2012). Serial breath specimens are taken every 20 minutes during this time and for a third hour as well. Breath may be sampled and immediately analyzed at a lab or these samples may be acquired at home using a series of tubes and a transfer device for later analysis. Home breath samples are exhaled into special vials similar to a vacutainer tube which stores the labeled sample until it can be delivered to the lab. Not all labs have the equipment to test for methane and the methodology for hydrogen sulfide is currently being perfected and is therefore not yet available. Testing for methane in addition to hydrogen is important because treatment varies based on the type of gas. The key symptoms of H2S production are “rotten egg” odor to the belching or flatus as well as possible urinary irritation associated with interstitial cystitis (Weinstock and Mullin – add this citation.
Preparation for the test varies from lab to lab, but a typical prep diet is limited to white rice, fish/poultry/meat, eggs, hard cheeses, clear beef or chicken broth (not bone broth or bouillon), oil, salt, and pepper. The purpose of the prep diet is to get a clear reaction to the lactulose solution by eliminating fermentable foods the day prior to testing. In cases of constipation, two days of prep diet may be needed to reduce baseline gases to negative. Antibiotics should not be used for at least 2 weeks prior to an initial test although some sources recommend 4 weeks 68 (Eisenmann, 2008.) If symptoms allow, proton pump inhibitors should also be eliminated for at least seven days before testing 69 (Costa MB, 2012.)
Interpretation of the test varies among practitioners. The criteria provided by Quintron for a positive test are as follows:
· A rise over baseline in hydrogen production of 20 parts per million (PPM) or greater within 120 minutes after ingesting the test substrate.
· A rise over baseline in methane production of 12 PPM or greater within 120 minutes after ingesting the test substrate.
· A rise over baseline in the sum of hydrogen and methane production of 15 PPM or greater within 120 minutes after ingesting the test substrate.
Additional testing and interpretation parameters:
· Hydrogen sulfide SIBO may be suspected when the typical symptoms are present but the breath test shows “flat-line” hydrogen and methane levels. 70 (Pimentel M, 2014)
· Modest levels of methane gas at any level equal or greater than 3 PPM at any sample on a 3 hour lactulose breath test may be a cause of methane-induced constipation 71 (Pimentel M, 2014).
· A “spot methane” level may be used for follow-up testing in methane positive individuals. When testing methane alone there is no need for a preparatory diet or fasting prior to this single breath sample.
IBS subjects who have elevated breath methane are constipated in most cases. In murine studies, methane infusion prolongs intestinal transit time 72 (Attaluri A, 2010).
We have found that an absolute level of gases, without a rise over baseline, correlates well with clinical SIBO. This is especially true for methane gas, which can have a pattern of elevated baseline which remains elevated for the duration of the test. In cases such as these, methane may only rise a few PPM over baseline, but the level is consistently above positive. Interpretation of elevated hydrogen or methane on the baseline specimen (pre-lactulose ingestion) is controversial, but at the SIBO Center we prefer to consider a high baseline methane to be a positive test 73 (Quigley E, 2006.)
The classic positive for SIBO has been considered to be a double peak, with the first peak representing the small intestine and the second peak representing the normal large intestine bacteria. It is not essential to have a second peak in order to have an accurate test. We find that a single peak which rises highest in the third hour may also represent distal SIBO followed by the normal colonic gas levels.
Breath testing may be used in pediatric cases, so long as the child can follow instructions to collect the samples. For those under 3 years old, testing is best done on site at a lab due to differences in collection methods versus at-home kits. Pediatric lactulose dosing is 1g/kg body weight with a maximum of 10 g (22 pounds and above receive the max/adult dose of 10 g) 74(Quin Tron, 2012). Lactulose is available only by prescription.
Treatment of SIBO
In 2006, Dr. Pimentel shared his treatment algorithm for SIBO which included the use of antibiotics, elemental diet or both 75 (Pimentel M, 2006). Our approach offers two additional options: diet and herbal antibiotics (Figure 8.4: SIBO Treatment Protocol).
Diet
We advise the use of the Specific Carbohydrate Diet™ or the SIBO Specific Foodguide 76(Gottschall E, 1994 and Siebecker A, 2014). The SIBO Specific Foodguide (see www.siboinfo.com/diet.html) is a combination of the Specific Carbohydrate DietTM, the low FODMAP diet and the clinical experience of Dr. Siebecker in the treatment of SIBO with diet. Bacteria use carbohydrates as their energy source and ferment them to gases, therefore a low carbohydrate diet can directly reduce symptoms by decreasing the amount of gas produced 77(Ong DK, 2010). Reducing carbohydrates may also decrease the overall microbial load, though formal studies to validate this are lacking. The Specific Carbohydrate DietTM and the SIBO Specific Foodguide greatly reduce the intake of polysaccharides, oligosaccharides and disaccharides by eliminating all grains, starchy vegetables, lactose, and sweeteners other than honey or dextrose. Legumes are often avoided in initial phases of these diets. Many patients experience a rapid and significant decrease in symptoms after starting a SIBO diet. The Specific Carbohydrate Diet has been reported to have an 84% success rate for Inflammatory Bowel Disease 78(Nieves & Jackson, 2004), a condition commonly associated with SIBO 79(Choung RS, 2011). Patients that find the Specific Carbohydrate Diet™ or SIBO Specific Foodguide approach to be too restrictive can follow the Cedars-Sinai diet as described at http://www.gidoctor.net/diet-ibs-sibo.php.
The Low FODMAP Diet™ is a nutritional plan that greatly reduces the fermentable levels of carbohydrate containing foods and has a success rate of 76% in IBS80,81(Shepherd SJ, 2014 and Staudacher HM, 2011.) The low FODMAP Diet™ is not specifically designed for SIBO and therefore does not eliminate polysaccharide and disaccharide sources such as grains, starch, starchy vegetables, and sucrose. Eliminating these poly and disaccharides is helpful in SIBO because these carbohydrates - which normally feed the host - also feed the increased numbers of microflora in the small intestine (Figure 13.1: SIBO Pathophysiology I.)
Diet alone has proven successful for infants and younger children, but for older children and adults one or more of several treatment options are often needed to reduce bacteria quickly, particularly in cases in which the patient’s diet become excessively limited in order to obtain symptomatic relief. Additionally any of the diets discussed above need to be customized to the individual by trial and error over time.
Low carbohydrate diets often induce weight loss. Particular attention must be paid to underweight patients. Increased intake of winter squash, glucose or honey may be recommended in these circumstances. White rice (jasmine/sticky variety is best) or white potato may also be needed to maintain weight along with medium chain triglyceride sources such as coconut and other oils.
Diet is also essential for prevention of relapse following successful SIBO eradication. Pimentel recommends postponing any dietary changes until after the effective treatment of the microbial overgrowth, rather than during the treatment phase 82 (Pimentel M, 2014). Our clinical experience with the SIBO Specific Foodguide is that it is beneficial for both the treatment and prevention phases.
Elemental diet
An elemental diet can be used in place of antibiotics or herbal antibiotics to rapidly decrease bacteria. In the treatment of SIBO elemental diet is used to the exclusion of all other food sources. These products are a powdered mix of free form amino acids, fat, vitamins and minerals as well as rapidly absorbed carbohydrates. The concept behind this treatment is that the nutrients will be absorbed before reaching the involved organisms, thus feeding the patient but starving the flora. It is used in place of all meals, for 2-3 weeks, and has a success rate of 80-85% 83 (Pimentel M, 2004) using the Nestle product Vivonex Plus™). Two versions of a homemade recipe for elemental diet can be found at http://www.siboinfo.com/elemental-formula.html Elemental diets are not protein powders or typical detoxification formulas. They are available over the counter and are not reimbursed by most insurance coverage, which can make this treatment costly. Patients should be warned that vivonex plus or homemade elemental diets are very bitter tasting. Elemental diet may not be suitable to underweight patients who cannot afford to lose weight.
Herbal Antibiotics
While there have only been two published reports of herbal antibiotics in the treatment of SIBO 84 (Logan A, 2002) and 85 (Chedid V, 2014), our experience is that they have similar effectiveness to antibiotics. Chedid et al studied patients with SIBO based on a positive lactulose breath test. A negative breath test after treatment was seen in 34% of the rifaximin or triple antibiotic treated group vs. 46% of the herbal treated group.
The study employed a pair of herbal formulas. The dosage was 2 capsules of each BID for 30 days.
At our center we have used the following botanicals: Allium sativum (garlic), Hydrastis canadensis and other berberine containing herbs, Origanum vulgare (oregano) and Azadirachta indica (neem). We have used these as both single agents and in various combinations at dosages that are at the upper end of label suggestions x 30 days. Specific single dosages we have used include allicin extract of garlic: 450mg bid-tid, goldenseal /berberine: 5g qd in split dosage, emulsified oregano: 100mg bid and a formula which contains 300 mg of neem plus a proprietary blend containing a total of 200 mg of the following: Emblica officinalis, Terminalia chebula, Terminalia belerica, Tinospora cordifolia, Rubia cordifolia. The latter formula is dosed at 1 capsule tid. Researchers at Johns-Hopkins have studied other herbal combinations which are listed in Chart 8.1. Our breath testing has validated the need for the longer treatment period of 30 days for herbal antibiotics compared to 14 days for prescription antibiotics. Note that although whole garlic is a high FODMAP food, we do not observe purified allicin to provoke symptoms in our patients. Allicin is the only herb we have noted so far that can reduce breath methane levels. We have also observed that some patients experience prolonged die off reactions with herbal treatment which can last for the duration of the treatment course. More studies on herbal antibiotics for SIBO are needed, particularly to identify botanicals effective in reducing methane.
Antibiotics
The most studied and successful prescription antibiotic for SIBO is rifaximin (brand name xifaxan). It has a broad spectrum of activity and is non-absorbable. Its luminal action allows it to act locally and it is therefore less likely to cause systemic side effects common to other antibiotics 86 (Scarpignato C, 2006). Rifaximin has up to a 91% success rate 87 (Lombardo L, 2010) and is given at 550mg TID x 14 days 88 (Pimentel M, 2011). Many physicians continue to prescribe a lower dosage of 1200 mg bid x 10 days although research shows a 22% increase in breath test normalization with the higher dosage. Suggested pediatric dosages are 200 mg TID x 7 days for ages 3-15 89 (pediatric SIBO study- Scarpellini E, 2013) or 10-30 mg/Kg90 (pediatric inflammatory bowel disease study- Muniyappa P, 2009.)
Additionally, rifaximin has several unique benefits: it purportedly does not cause yeast overgrowth 91 (Scarpignato C, 2006) and it decreases antibiotic resistance in bacteria by reducing plasmids 92 (Debbia EA, 2008). Antibiotic resistance does not develop to rifaximin, making it effective for re-treatments 93(Yang J, 2008) and it has anti-inflammatory properties, decreasing intestinal inflammatory cytokines and inhibiting NF- Κβ via the PXR gene 94 (Mencarielli A, 2011). Rifaximin as a solo antibiotic is best used for SIBO when only the hydrogen levels are elevated. When methane gas is also increased, double therapy of rifaximin plus neomycin (500mg bid x 14 days) is more effective 95(Low K, 2009). Many gastroenterologists use metronidazole (250mg tid x 14 days) as an alternative to neomycin (unpublished). Since different antibiotic regimens are recommended based on the gas type, breath testing is necessitated when considering this treatment.
Furnari et al compared the percentage of breath test normalization using rifaximin 1200 mg qd vs. rifaximin 1200 mg qg plus partially hydrolysed guar gum (5 g qd) for 10 days. The combination treatment was proven to be 23% more effective than rifaximin monotherapy 96 (Furnari M, 2010). If hydrogen sulfide SIBO is suspected the same treatments as those used for methanogen overgrowth are indicated.
Biofilm Disruptors
Mucosal methanogenic organisms are able to elaborate biofilms 97 (Bang C, 2014). The use of N-acetyl cysteine, nattokinase, serrapeptase,or lumbrokinase may be considered in addition to herbal or prescription antibiotic treatment to provide mucolytic and biofilm disruption effects. As mentioned earlier in this chapter – there is evidence both for and against enteric mucosal biofilms and SIBO.
Prevention of SIBO
SIBO is a disease that relapses because eradication itself, does not always correct the underlying cause 98,99 (Pimentel M, 2009; 2010). Pimentel’s 2006 treatment algorithm includes 2 essential preventions: diet and a prokinetic (motility agent). Our approach offers additional options: hydrochloric acid, probiotics, and brush border healing supplements. Also worth consideration are physical exercises, breathing techniques, acetylcholine precursors and modulators of neural inflammation.
Prokinetics
A key underlying cause of SIBO is thought to be deficient activity of the migrating motor complex (MMC). An intact MMC moves debris and bacteria down into the large intestine during fasting at night and between meals 100 (Pimentel M, 2009). Prokinetics stimulate the MMC, symptomatically correcting this underlying cause. Iberogast is a German compound botanical tincture with possible prokinetic action101 (Ochoa-Cortes F, 2014). This formula includes alcoholic extracts of Iberis amara totalis recens, Angelicae radix, Cardui mariae fructus, Chelidonii herba, Liquiritiae radix, Matricariae flos, Melissae folium, Carvi fructus and Menthae piperitae folium. It has been used to treat functional dyspepsia and IBS since the 1960s. One study found symptom improvement, but no increase in gastric emptying, which suggests that if this formula is prokinetic, it is likely not the only mechanism underlying its action in IBS 102 (Braden B, 2009.) A double blind controlled trial compared iberogast to cisapride (a prescription prokinetic with limited special use in the U.S. due to cardiovascular side effects). The herbal formula performed as well as the prokinetic drug for functional dyspepsia 103 (Rösch W, 2002) and was superior to metaclopramide in a retrospective cohort study of 961 patients 104 (Raedsch R, 2007). It has also been shown to be effective for IBS in children 105,106 (Leichtle K, 1999 and Gundermann KJ, 2004.)
Prescription prokinetics studied for SIBO include: low dose naltrexone 2.5mg qhs for IBS-D or 2.5 mg bid for IBS-C 107 (Ploesser J, 2010), low dose erythromycin 50mg qhs, and tegaserod 2-6mg qhs 108 (Pimentel M, 2009). Tegaserod has a higher success rate for SIBO prevention versus erythromycin 109 (Pimentel M, 2009), but has been withdrawn from the US for safety reasons. Prucalopride (resolor, motegrity) 0.5-2mg qhs, is not yet available in the US but is a safer alternative to Tegaserod 110 (Manabe N, 2010). It is presently available in Canada and Europe. A trial removal of a prokinetic at ≥ 3 months is suggested but continued long term use may be needed for some patients 111(Pimentel M, 2006).
Diet
A lower carbohydrate diet is used in combination with a prokinetic to discourage a return of bacterial overgrowth. Once the breath test has normalized and small intestine damage has healed, the diet can be expanded beyond the strictness of the Specific CarbohydrateTM and SIBO Specific Foodguide. The timeframe for this is uncertain. Two studies have examined the rate of healing post-SIBO, and found that intestinal permeability normalized four weeks after successful SIBO eradication in 75-100% of patients 112 (Lauritano EC, 2010, irdan.PM9200287) While these reports are very encouraging, they may or may not reflect the other repair needed post-SIBO. Therefore we currently suggest continuing a SIBO diet for one to three months post successful eradication. At this point, the Cedars-Sinai Diet 113 (Pimentel M, 2006), lowFODMAP Diet 114 (Gibson PR, 2010) or a similar diet may be adopted long term, as the patient tolerates. These diets allow more carbohydrates in the form of grains, gluten free grains, cane sugar, and soy, though they still limit overall carbohydrate load.
Spacing meals four to five hours apart, with nothing ingested but water, allows for activity of the MMC 115 (Pimentel M, 2006). We have found this to be very helpful clinically. If a low carbohydrate SIBO diet does not correct hypoglycemia, this strategy will need to be altered to allow for more frequent meals.
Optional Supplements
Hydrochloric acid or herbal bitter supplements, which encourage hydrochloric acid (HCl) secretion 116 (Bowman G, 2010) may be used to decrease the load of incoming bacteria. When considering HCl supplementation, Heidelberg testing for HCl levels and response to treatments is the gold standard. Heidelberg testing reveals achlorhydria, frank hypochlorhydria and hidden hypochlorhydria and allows individualization of dosing.
Probiotics are a controversial intervention in SIBO because lactobacilli have been cultured in SIBO 117 (Bounik Y, 1999) and there is also concern about adding to the bacterial overload. Despite this, the few studies that have focused directly on probiotics for treatment of SIBO have shown good results. Bacillus clausii as a sole treatment normalized the breath test in 47% of cases 118 (Gabrielli M, 2009). An 82% clinical improvement in SIBO was found using a combination of Lactobacillus casei and plantarum, Streptococcus faecalis, and Bifidobacter brevis (Bioflora)119(Soifer LO, 2010). Probiotic yogurt containing Lactobacillus johnsonii normalized cytokine responses thereby reducing the low grade chronic inflammation found in SIBO after 4 weeks 120(Schiffrin EJ, 2009). We have used various multi-strain and single probiotics as well as yogurt and cultured vegetables with our SIBO patients with good results. A key point for the use of probiotic supplements in SIBO is to avoid prebiotics as main ingredients. Prebiotics are fermentable food for bacteria which can exacerbate symptoms during active SIBO and encourage bacterial growth post-SIBO. Common prebiotics found in probiotic supplements include: FOS (fructooligosaccharide), inulin, arabinoglactan, MOS (mannoseoligosaccharide) and GOS (galactoligoosaccharide). Prebiotics may be tolerated in small amounts used as base ingredients, but this depends on the individual.
Brush border healing supplements may be given to assist the repair of small intestine tissue. While mucilaginous herbs are traditionally employed for this purpose (licorice, slippery elm, aloe vera, marshmallow), their use is controversial post-SIBO, due to their high level of mucopolysaccharides which are fermentable and could encourage bacterial re-growth. Specific nutrients we have used include lactose-free colostrum: 2-6 g qd, L-glutamine: 375mg- 1500mg qd, zinc carnosine: 75mg bid, vitamins A and D, often given as cod liver oil: 1 Tbsp qd, curcumin: 400mg- 3 g qd, resveratrol: 250mg-2 g qd, glutathione (oral liposomal): 50-425mg qd or glutathione precursor N-acetyl cysteine 200-600mg qd. Supplements are given for one to three months, though may be continued long term for general benefit if desired. Higher dosages of curcumin and resveratrol are given for two weeks for the purpose of down-regulating NF-Κβ, a mediator of increased intestinal permeability, and then reduced to maintenance levels 121,122,123 (Ruland J, 2011; Al-Sadi RM, 2007; Csaki C, 2009.)
Herbal cholinergic support may include phosphatidyl choline, pantothenic acid, huperzine A (from Huperzia serrata), and N-aceytl L-carnitine 124(Kharazian D, 2014). Pranayama (yogic alternate nostril breathing) has been shown to have benefits in IBS-D by normalizing parasympathetic tone 125(Taneja I, 2004.)
If dampening of CNS inflammation is indicated consider the use of Green tea catechins, Curcuma longa, bioflavonoids, Scutellaria, resveratrol, Chrysanthemum morifolium leaf and Matricaria chamomilla 126(Kharazian D, 2014).
In our practices we have found that the following circumstances increase the chances for an unsatisfactory patient outcome:
· Failure to continue treatment courses until SIBO is eradicated (negative breath test or patient ≥90% better). This crucial process of successive treatment is indicated by the long go-back arrow on the right side of our algorithm (Figure 8:4 - SIBO Treatment Protocol).
· Failure to use double antibiotic therapy for methane producers. Methanogenic flora need different antibiotic treatment than hydrogen producing bacteria.
· Failure to utilize breath testing to identify if the patient has SIBO, the type of gas they produce, and the overall level of gas. This information is necessary for diagnosis, treatment choice/duration and prognosis.
· Failure to use a prokinetic immediately following treatment. Prokinetics along with diet are needed to prevent relapse of this commonly recurring condition. Antibiotic treatment as a sole therapy typically leads to recurrence of hydrogen SIBO within three months and methane SIBO within one month 127(Pimentel M, 2014)
· Failure to use a low carb preventative diet following treatment. Diet along with prokinetics are needed to prevent relapse of this commonly recurring condition.
· Failure to tailor diet to individual tolerances with personal experimentation. No fixed diet can predict an individual’s complex bacterial, digestive, absorptive, immunological and genetic circumstances, therefore customizing is necessary.
· Failure to identify underlying causative conditions. One report found the following conditions led to a poor response to antibiotics: anatomical abnormalities (adhesions, blind loops, diverticuli, superior mesenteric artery syndrome, etc.), chronic narcotic use, Addison’s disease, scleroderma, colonic inertia, inflammatory bowel disease, and NSAID-induced intestinal ulceration 128(Chou J, 2010). Some of these patients will need long term cyclical rotation of herbal treatments or, very rarely, a 550 mg single dose of rifaximin every other day in order to stay asymptomatic.
· Failure to find the underlying causes and repair or modulate the MMC will lead to a less desirable outcome
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