By Marianne Otterstad, Trainee Clinical GI Physiologist
Inflammatory bowel disease (IBD) is a group of idiopathic diseases characterised by inflammation of the gastrointestinal tract with prevalence up to 0.3%, the two most common being Crohn’s disease (CD) and ulcerative colitis (UC)1.
Following a diagnosis of CD or UC, the main priority of healthcare professionals is to get the acute situation under control. However, it has been reported that 39% of patients with CD, both in remission and on a stable medical regimen, experience irritable bowel syndrome (IBS)-like symptoms2. IBS is a diagnosis based on a collection of symptoms, often without a known aetiology. IBD and IBS can co-exist, however treatment and prognosis of IBD and IBS are different, so the right diagnosis is crucial3.
Dysbiosis and small intestinal bacterial overgrowth
New publications suggest that IBS-type symptoms seen in IBD patients may be due to small intestinal bacterial overgrowth (SIBO) in a portion of patients2. It is established that an alteration of the gut microbiome occurs in IBD patients4, however the link between IBD and SIBO has only recently been demonstrated2. SIBO is a form of microbial dysbiosis, where an overgrowth of bacteria in the small bowel can cause symptoms of bloating, abdominal pain and diarrhoea5.
Protective factors preventing SIBO:
To prevent bacteria form migrating to the small bowel, the gastrointestinal system has multiple protection mechanisms. Low gastric pH, the migrating motor complex of the small intestines and intact integrity of the small bowel are the most important protective factors that prevent SIBO. Examples of other protective factors include integrity of the mucosa, normal commensal intestinal microbiota, enzymatic secretions from the pancreas and gallbladder, systemic immunity and an intact ileocecal valve2.
Many of these protective factors are compromised in IBD patients due to pathology associated with progression of the disease, was well as surgical and medical therapy used to manage these conditions2. An example of surgical interventions that can increase the risk of SIBO are those which effect the ileocecal (IC) valve, mainly used in CD2. This is due to the IC valve’s ability to prevent reflux from the colon to the small intestines, which may include bacteria. Surgery on the IC valve can impair this mechanism and potentially cause SIBO6.
Fibrostenosing disease is seen in many patients with CD and is also linked to higher prevalence of SIBO because it can adversely affect small intestinal motility, leading to stagnation of luminal content. Dysbiosis is thought to be both a cause of fibrostenosing disease, as well as a consequence7.
IBD and SIBO can produce similar symptoms sometimes leading to misinterpretation of active IBD when the actual cause of symptoms may be SIBO3. Therefore, SIBO testing can be useful in otherwise well managed IBD patients.
Presence of >103 colony forming units/ml in jejunal aspirate is the gold standard for diagnosing SIBO, however this procedure is highly invasive and expensive to perform. Therefore, the non-invasive and significantly less expensive hydrogen and methane breath test (HMBT) is frequently used. HMBT is a relatively simple test that detects gasses in expelled breath, which is a secondary consequence of gut bacterial fermentation of ingested carbohydrates5.
A systematic review with meta-analysis from 2019 used validated clinical IBD activity indices to assess symptoms in IBD patients with and without SIBO2. In SIBO positive IBD patient, there was an increase in abdominal symptoms such as bloating, flatulence, loose stools and increased stool frequency compared to SIBO negative IBD patients2.
In 2018, research was conducted to assess the effectiveness of SIBO treatment in IBD patient8. A significant improvement of symptoms was reported post treatment, which demonstrates the importance of diagnosing SIBO in this patient group to ensure that the correct condition is treated. The majority of IBD patients with SIBO also had a normalisation of SIBO breath tests after treatment with broad spectrum antibiotics8. Antibiotics has also been used to treat patients with active IBD, and a reduction in Crohn’s Disease Activity Index and calprotectin has been reported after courses of azithromycin and metronidazole9.
Prevalence of SIBO in IBD:
Multiple studies have calculated the prevalence of SIBO in IBD, but with conflicting results. A systematic review with meta-analysis was therefore recently performed which assessed 11 studies conducted worldwide including data from 1582 individuals2. SIBO prevalence was calculated to 22.3% in IBD patients, with an odds ratio of 9.51 compared to SIBO prevalence in non-IBD control2. When separating ulcerative colitis and Crohn’s disease, SIBO prevalence was 14.3% and 25.4% respectively2. These frequencies have been calculated using data from all IBD patients, regardless of whether they are symptomatic or not. It is more clinically significant to calculate the prevalence of SIBO in IBD patients who experience IBS-like symptoms. This was done recently by Gu et al. who found a SIBO prevalence of 45% and 46% in UC and CD respectively10.
The majority of Crohn’s patients will in their lifetime have fibrostenosing disease or have undergone bowel surgery. This increases the risk of SIBO even further with odds ratios of 7.47 and 2.38 respectively, compared to IBD patients without fibrostenosing/bowel surgery2. It has also been suggested that disease location and increased oroceacal transit time (OCTT) increase the chance of developing SIBO. However, only a few studies have found a correlation between SIBO and CD in both the large and small bowel combined2. Only few studies found an increased transit time in IBD patients with SIBO compared to IBD patients without SIBO2.
Breath tests used to diagnose SIBO can also detect presence of intestinal methane production. Methane detected in humans is produced by methanogenic archaea species and is associated with slowing of gut transit5. 8-25% of the non-IBD population produce methane, but prevalence is significantly lower in IBD patients (OR=0.72)2. Methane production can therefore in most cases not explain the slow OCTT seen in many IBD patients. Methane production is more often seen in patents with constipation predominant conditions compared to patients with loose stools, which can explain the lower prevalence in IBD11.
Hydrogen sulphide (H2S) can be produced by both endogenous and exogenous factors in the human body. The gas is involved in many physiological processes which includes regulation of blood pressure, metabolism and inflammation12. Regulation of inflammation in the intestines can become pathological and a link between H2S and IBD has been demonstrated. High levels of H2S has been detected in breath as well as presence of sulphate reducing bacteria in the colon of both CD and UC patients13. In the gastrointestinal tract, H2S can increase secretion and relax smooth muscles12. With impaired mucosa, as seen in IBD, H2S can more easily access muscular layers and potentially inhibit motor patterns in the colon which could be another cause of higher SIBO prevalence in IBD patients14. Publications that have found evidence for a pathological effect of H2S in IBD emphasise the potential role of this gas as a target for IBD treatment15.
Hydrogen sulphide production is dependent on sulphate intake as well as metabolism. This indicates that reducing sulphate intake can possibly help control IBD. Sulphate containing foods include sausages, beer, wine, bread, dried fruit and soya flour16. Whilst assessing hydrogen sulphide in breath samples is not easily available, a flat line HMBT test in the presence of SIBO symptoms and mal-odorous (eggy) flatulence can provide indirect evidence of the presence of hydrogen sulphide producing bacteria17.
IBD and Diet
There has been no compelling evidence to link dietary factors and causation of IBD. However, certain foods can be anti- or pro-inflammatory and diet can help manage symptoms of IBD which is why individualised dietary changes are often utilised18. In many patients the disease changes over time and dietary changes should also be re-evaluated. Multiple dietary approaches have been described in the literature, two of the most common diets being the low fermentable oligo-, di-, mono-saccharides and polyol diet (low FODMAP) and the specific carbohydrates diet (SCD)18.
The low FODMAP diet is base don theory that by reducing ingestion of complex carbohydrates, less gas is produced by the intestinal microbiota which can reduce IBS-like symptoms in IBD patients. On this diet, the patient avoids ingesting lactose, fructose, fructans, galactans and polyols19. There is more evidence supporting the use of this diet for controlling IBS rather than IBD, and some dietitians are concerned that the low FODMAP diet excludes some prebiotics which can potentially promote more dysbiosis in IBD patients18. A diet more commonly used by IBD patients, which is base don similar principles as the low FODMAP diet, is specific carbohydrates diet.
On the SCD diet, patients consume carbohydrates that are fully absorbed in the intestines, which limits the microbiota’s access to undigested carbohydrate. This decrease organic acid production by bacterial fermentation. Organic acids can injure intestinal mucosa and exacerbate symptoms of IBD18. The SCD diet excludes processed food, lactose, sucrose, grain-derived flours and potatoes among others but allows for example most fruits and vegetables, nuts and low lactose dairy. However, this diet is not simply a list of approved and disapproved foods and other considerations have to be made. For example, severity of symptoms and duration of the diet affect which foods are permitted18.
Approximately 70% of IBD patients are lactase deficient20. The majority of this group are suffering from CD and lactase deficiency is also seen in patients in remission. This is a result of insufficient lactase production on the damaged or surgically removed small intestinal brush border. When lactose is not broken down and absorbed in the small intestines, bacteria in the large intestines ferment the lactose and produce various metabolites which can cause abdominal symptoms. Hydrogen gas is one of the metabolites produced in response to lactose malabsorption and can be detected in a hydrogen breath test after ingestion of lactose. Lactose breath tests are therefore useful diagnostic tests for lactase deficiency and can explain troublesome symptoms in CD patients. Avoidance of products containing lactose can potentially improve symptoms in this patient group20.
Many IBD patients, including those in remission experience IBS-like symptoms. The prevalence of small intestinal bacterial overgrowth is higher in IBD compared to the non-IBD population because of impaired protection mechanisms. Both the progression of IBD and surgery can impair these factors that usually prevent SIBO. Diagnostic testing, for example hydrogen and methane breath testing, can be utilised to find out if the cause of bothersome IBS-type symptoms in IBD patients are due to SIBO.
Treatment with antibiotics has been successful at both improving symptoms and normalising HMBTs in IBD patients diagnosed with SIBO. Research suggests that targeting hydrogen sulphide production is another possible treatment that can reduce IBS-like symptoms in IBD patients. H2S production is increased in IBD patients compared to controls, however a treatment for this is not available yet. For many IBD patients, dietary plans can help manage abdominal symptoms and multiple diets are available with varying scientific evidence.
Learn more about hydrogen and methane breath testing
- Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390(10114):2769-78.
- Shah A, Morrison M, Burger D, Martin N, Rich J, Jones M, et al. Systematic review with meta-analysis: the prevalence of small intestinal bacterial overgrowth in inflammatory bowel disease. Aliment Pharmacol Ther. 2019;49(6):624-35.
- Abdul Rani R, Raja Ali RA, Lee YY. Irritable bowel syndrome and inflammatory bowel disease overlap syndrome: pieces of the puzzle are falling into place. Intest Res. 2016;14(4):297-304.
- Sokol H, Seksik P, Rigottier-Gois L, Lay C, Lepage P, Podglajen I, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis. 2006;12(2):106-11.
- Rezaie A, Buresi M, Lembo A, Lin H, McCallum R, Rao S, et al. Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus. The American journal of gastroenterology. 2017;112(5):775-84.
- Roland BC, Ciarleglio MM, Clarke JO, Semler JR, Tomakin E, Mullin GE, et al. Low Ileocecal Valve Pressure Is Significantly Associated with Small Intestinal Bacterial Overgrowth (SIBO). Digestive Diseases and Sciences. 2014;59(6):1269-77.
- Li J, Mao R, Kurada S, Wang J, Lin S, Chandra J, et al. Pathogenesis of fibrostenosing Crohn’s disease. Transl Res. 2019;209:39-54.
- Cohen-Mekelburg S, Tafesh Z, Coburn E, Weg R, Malik N, Webb C, et al. Testing and Treating Small Intestinal Bacterial Overgrowth Reduces Symptoms in Patients with Inflammatory Bowel Disease. Digestive Diseases and Sciences. 2018;63(9):2439-44.
- Levine A, Kori M, Kierkus J, Sigall Boneh R, Sladek M, Escher JC, et al. Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn’s disease : a randomised controlled trial. Gut. 2019;68(2):239-47.
- Gu P, Patel D, Lakhoo K, Ko J, Liu X, Chang B, et al. Breath Test Gas Patterns in Inflammatory Bowel Disease with Concomitant Irritable Bowel Syndrome-Like Symptoms: A Controlled Large-Scale Database Linkage Analysis. Digestive Diseases and Sciences. 2019.
- Triantafyllou K, Chang C, Pimentel M. Methanogens, methane and gastrointestinal motility. J Neurogastroenterol Motil. 2014;20(1):31-40.
- Guo FF, Yu TC, Hong J, Fang JY. Emerging Roles of Hydrogen Sulfide in Inflammatory and Neoplastic Colonic Diseases. Front Physiol. 2016;7:156.
- Dryahina K, Smith D, Bortlík M, Machková N, Lukáš M, Španěl P. Pentane and other volatile organic compounds, including carboxylic acids, in the exhaled breath of patients with Crohn’s disease and ulcerative colitis. Journal of Breath Research. 2017;12(1):016002.
- Gallego D, Clave P, Donovan J, Rahmati R, Grundy D, Jimenez M, et al. The gaseous mediator, hydrogen sulphide, inhibits in vitro motor patterns in the human, rat and mouse colon and jejunum. Neurogastroenterol Motil. 2008;20(12):1306-16.
- Ijssennagger N, van der Meer R, van Mil SWC. Sulfide as a Mucus Barrier-Breaker in Inflammatory Bowel Disease? Trends Mol Med. 2016;22(3):190-9.
- Kushkevych I, Dordevic D, Kollar P, Vitezova M, Drago L. Hydrogen Sulfide as a Toxic Product in the Small-Large Intestine Axis and its Role in IBD Development. J Clin Med. 2019;8(7).
- Birg A, Hu S, Lin HC. Reevaluating our understanding of lactulose breath tests by incorporating hydrogen sulfide measurements. JGH Open. 2019;3(3):228-33.
- Kakodkar S, Mutlu EA. Diet as a Therapeutic Option for Adult Inflammatory Bowel Disease. Gastroenterol Clin North Am. 2017;46(4):745-67.
- Gearry RB, Irving PM, Barrett JS, Nathan DM, Shepherd SJ, Gibson PR. Reduction of dietary poorly absorbed short-chain carbohydrates (FODMAPs) improves abdominal symptoms in patients with inflammatory bowel disease-a pilot study. J Crohns Colitis. 2009;3(1):8-14.
- Eadala P, Matthews SB, Waud JP, Green JT, Campbell AK. Association of lactose sensitivity with inflammatory bowel disease–demonstrated by analysis of genetic polymorphism, breath gases and symptoms. Aliment Pharmacol Ther. 2011;34(7):735-46.