Rethinking SIBO in the microbiome era
Small intestinal bacterial overgrowth is thought of as very rare, but in an era of booming microbiome research, gastroenterologists and other physicians are starting to become more aware of SIBO in the general population and provide effective treatment
The small intestine isn't supposed to contain too many bugs, but in patients with small intestinal bacterial overgrowth (SIBO), bacteria can be a real pain in the gut. In recent years, research on the microbiome has shed light on SIBO as a condition potentially related to irritable bowel syndrome (IBS).
For various reasons, too much bacteria can accumulate in the small bowel of patients with SIBO, and this disruption of the normal flora can produce all-too-common nonspecific gastrointestinal (GI) symptoms, such as bloating, flatulence, diarrhea, and abdominal pain.
While statistics on the prevalence of SIBO are hard to come by, estimates of the proportion of IBS patients who also have SIBO range from about 30% to 80%, experts said. Sometimes, patients with IBS will see Hazel Veloso, MD, as their fourth or fifth gastroenterologist. She said that they're often surprised when she can figure out their symptoms and develop a treatment plan in 10 minutes.
“[SIBO] was thought of as very rare before. In fellowship, the way we were trained was that this is something rare, like in those who've had surgeries causing a blind loop syndrome or have connective tissue disease such as scleroderma,” said Dr. Veloso, who is part of the faculty of the division of gastroenterology at Johns Hopkins University in Baltimore. “We were just labeling patients [without classic risk factors] with IBS before, and they were not better because there was actually an underlying cause.”
Now, in an era of booming microbiome research, gastroenterologists and other physicians are starting to become more aware of SIBO in the general population and provide effective treatment. Even if the condition can't be cured, a diagnosis can provide patients with an explanation for chronic, troublesome symptoms that may have gotten short shrift from physicians in the past.
Making the diagnosis
SIBO is not a new disease. However, in the past decade, physicians have come to recognize the relationship between bacterial overgrowth in the small bowel and different conditions, said Jack A. Di Palma, MD, FACP, professor of medicine and director of the division of gastroenterology at the University of South Alabama College of Medicine in Mobile. “We would all think of scleroderma, we would all think of structural disorders from surgery, but we wouldn't think about IBS, medication, narcotics, or older patients,” he said.
The small intestine has two key ways of keeping bacteria at an optimal level, motility and acid, so anything that affects them is going to promote bacterial overgrowth, said Dr. Di Palma. For example, patients with diabetes or chronic opioid use are at increased risk for developing SIBO because of dysmotility, and older patients and those on proton-pump inhibitors (PPIs) are at increased risk due to altered pH, according to a primary care review published in the December 2016 Mayo Clinic Proceedings.
Unfortunately, doctors are probably not curing much in IBS or SIBO, said Richard W. McCallum, MD, FACP, professor and founding chair of the department of medicine at Texas Tech University Health Sciences Center in El Paso. “But we're not aiming at cure here,” he said. “We're aiming at minimizing the bad days and trying to maximize good days by identifying risk factors, problems, and areas where we can intervene.”
To diagnose SIBO, physicians have essentially two options: measuring products of fermentation with breath testing or providing empiric therapy, said Dr. Di Palma. (Aspirating the jejunum for bacteria is doable but more cumbersome, and nuclei tests for SIBO are only available for research, he said.) While many gastroenterologists advocate empiric therapy based on clinical suspicion, breath testing has its advantages. “I'm a breath testing fan,” Dr. Di Palma said. “If positive, it gives you the verve and initiative to re-treat in the future should the symptoms recur.”
Dr. Veloso agreed, adding that empiric treatment with antibiotics puts patients at risk for developing potential drug resistance or Clostridium difficile infection. In addition, patients who test positive for bacteria that produce hydrogen will require different treatment than those who have methane-producing bacteria, or both, she said. “That's why we're proponents of doing the breath testing rather than just empirically treating.”
Internists who wish to do breath testing in the clinic can use a send-out kit, but a greater number may choose to refer patients to a local gastroenterologist who does testing or to a university or hospital with a motility center, said Dr. McCallum, who coauthored an expert consensus on interpreting breath tests for GI disorders, which was published in the May 2017 American Journal of Gastroenterology. The consensus statement suggests using breath testing to diagnose SIBO, defined at a threshold of greater than 103 colony-forming units per mL.
There are two main breath testing methods for SIBO diagnosis, one utilizing a challenge with lactulose, the other with glucose. The appropriate doses of each are 10 grams and 75 grams, respectively, the consensus statement said. The sensitivity and specificity of lactulose breath testing in diagnosis of SIBO range from 31% to 68% and from 44% to 100%, respectively, and the sensitivity and specificity of glucose breath testing range from 20% to 93% and from 30% to 86%, respectively, according to a systematic review and meta-analysis published in the June 2008 Digestive Diseases and Sciences.
Test preferences vary among physicians. At Johns Hopkins, Dr. Veloso uses lactulose breath testing more often because “You may get false positives with the glucose breath testing.” At Mayo Clinic in Rochester, Minn., gastroenterologist Stephanie Hansel, MD, prefers to use glucose breath testing in most patients, reserving lactulose breath testing for those with diabetes. Jejunal aspirates may be difficult to get, but a duodenal aspirate is attainable and can replace breath testing if a patient needs an upper endoscopy for some reason, such as suspected celiac disease, she said.
After a diagnosis is made, try to eliminate risk factors as you're able, recommended Dr. Hansel, who coauthored the 2016 primary care review on SIBO. One example might be minimizing or discontinuing PPIs, although supporting evidence for minimizing or discontinuing them is low quality overall, she said.
“There are many people who started taking it on their own or say, ‘I don't know why I'm on this,’ so if I find somebody and I can't convince myself that they have reflux symptoms or have a good reason to be on a PPI, I'll probably try and discontinue that first and see, because side effects of that can be diarrhea,” said Dr. Hansel, also an associate professor of medicine at the Mayo Clinic College of Medicine and Science.
At least 25% to 30% of any given population of people are on a PPI, which is one of the most common causes of gas and bloating in the world, said Dr. McCallum. “We have an acidified small bowel, and that wards off bad guys—either ingested bad guys or some that are trying to come up from the colon through the ileocecal valve. … The small bowel has to keep these bad guys at bay, and acid is a major player in making it hostile country. If you go on a PPI for a few months or maybe years, then you've really taken away a major defensive unit,” he said.
Dr. McCallum suggested trying to minimize loss of acid with a few strategies, such as going to PPIs every other day or using weaker antacids (calcium carbonate, H2 blockers). He added that drinking apple cider vinegar every day can help bring acid down into the small bowel. “That's been an old trick out there with the alternative medicine and homeopathic world.”
Treatment strategies
After addressing risk factors, internists may consider antibiotic therapy. “If I had to give one message to general internists, it's to think about using nonabsorbable antibiotics … early in the course,” said Dr. Di Palma. In a systematic review and meta-analysis of 10 studies of patients with SIBO, antibiotics in general were more effective than placebo, with a combined breath test normalization rate of 51.1% compared to 9.8%. Rifaximin was by far the most commonly studied antibiotic, with an overall breath test normalization rate of 49.5%, according to the review, published in the October 2013 Alimentary Pharmacology & Therapeutics.
The FDA approved rifaximin in May 2015 for the treatment of IBS with diarrhea, but the drug is not indicated to treat SIBO. Rifaximin is very expensive, experts said, and the lack of indication to treat SIBO means that it can be hard to get insurance coverage for patients who don't have an IBS-D diagnosis. Still, “We can sometimes get patient assistance, we can sometimes get discount cards, and some insurers will cover it,” Dr. Di Palma said.
In a small study published in May 2016 by the Southern Medical Journal, his team showed that out of 100 patients with suspected SIBO, 74.2% reported a response to a rifaximin regimen. While the antibiotic is effective, patients sometimes require re-treatment. “When we use the rifaximin medicine, we usually get a sustained response, but it's not unusual for us to have to re-treat a year to 18 months later, with good response,” he said.
To be clear, the link between IBS and SIBO is a theoretical one, especially since the rifaximin studies that were adequate for FDA approval did not test participants for SIBO, Dr. Di Palma noted. “We are not sure why this medicine works. … I personally believe there is an element of SIBO in IBS patients, but the science for that is still forthcoming,” he said.
With IBS patients, one point to remember is that they may be on a gut antispasmodic like dicyclomine, which affects motility, said Dr. Veloso. “You have to be careful because that slows down the small bowel. So if it's SIBO, you should actually be wary about that,” she said. And patients who have IBS with constipation, if they have methane-predominant SIBO, require a different treatment strategy to address their methane-producing bacteria, noted Dr. Veloso. These patients don't respond to rifaximin alone, but adding neomycin (which tends to kill methane-forming bugs) to rifaximin works well, she said.
Other antibiotics used for SIBO include metronidazole, ciprofloxacin, tetracycline, neomycin, and sulfamethoxazole/trimethoprim, said Dr. McCallum, who prefers these agents over rifaximin as first-line therapies. “My patients call me with sticker shock [about rifaximin] … so I use a lot of other things in the name of reality,” he said.
Although rifaximin is effective, Dr. Hansel also doesn't use it right away due to the cost. The drug has no generic alternatives and an average retail price of more than $2,500 for a bottle of 60 tablets, according to the prescription drug-pricing website GoodRx. In addition, she said metronidazole is usually not well tolerated because of the side effect of nausea, and she has some patients who've done well on low-dose ciprofloxacin (250 mg twice daily for 10 days). “They do that three times a year, and they do quite well with it,” she said, although she is wary about the risk of tendonitis with the fluoroquinolone. Doxycycline is cheap and well tolerated and could also be used, Dr. Hansel added.
Herbal antibiotics may hold some promise in the future, Dr. Veloso noted. A retrospective study, published in the May 2014 Global Advances in Health and Medicine, found that 46% of patients who received commercial herbal preparations had a negative follow-up lactulose breath test at four weeks, compared to 34% of rifaximin users. “That's just one study, though,” said Dr. Veloso. “We are going to do a prospective study, but based on experience, I've noticed that patients do respond to herbal antibiotics.”
In addition, while not a major risk factor in the literature, prior prolonged exposure to antibiotics appears to predispose patients to developing SIBO, she said. “Each time we give antibiotics, we also change their gut microbiome,” Dr. Veloso said. “I have young patients that have none of those risk factors but were put on medications for acne for a year, and then they developed this.”
One nonantibiotic treatment is dietary manipulation, which may help patients with IBS in general and those with SIBO in particular, according to a comprehensive review article published in March 2017 by Gut and Liver. It is common for patients with SIBO to have carbohydrate intolerance or sensitivities to certain foods, said Dr. Veloso.
Studies have shown that restricting fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs) may help reduce gas and associated symptoms, but adherence is a challenge, said Dr. McCallum. Some high-FODMAP foods are omnipresent ingredients (garlic, onions, and wheat, for example), and many are beloved fruits and vegetables, such as watermelon, apples, peas, and several types of mushrooms. Portion size and ripeness count, with smaller amounts and less ripeness occasionally making a high-FODMAP food a low- or moderate-FODMAP food.
“As I tell my patients, only someone living in a monastery could stay on the low-FODMAP diet. It's meant to be a guide” that patients can use to determine their sensitivities and then tailor their diet to their individual needs, he said. “Ideally, you have a dietitian in your office. Most people don't … but a good dietitian could spend an hour with these patients, and ideally they should,” Dr. McCallum said.
Overall, many patients with SIBO will not be cured with antibiotics alone, and re-treatment is based on symptoms, Dr. Hansel said. In her worst case, a patient with poor motility had to have a seven-day course of antibiotics every three or four weeks.
“The patient kind of drives when they get the therapy. They can call and say, ‘I have the same symptoms,’ and you can decide whether or not you want to see them or just prescribe and see them once a year or something like that,” she said. “I think once the diagnosis is established and everybody's comfortable with it, primary care is a perfect place for it to be taken care of.”
