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Irritable Bowel Syndrome is linked to bacteria in our gut

The antibiotic rifaximin (brand name Xifaxin) was recently approved by the FDA for diarrhea-predominant irritable bowel syndrome (IBSd). You many wonder why doctors would recommend an antibiotic for IBS.

The idea that antibiotics may be helpful for IBS is based largely on the work of Dr. Mark Pimentel, the Director of the Gastrointestinal motility Program at Cedars-Sinai Medical Center. Dr. Pimentel’s book, A New IBS Solution, documents his team’s research linking an overgrowth of bacteria in the gut to irritable bowel syndrome (IBS).  The book and subsequent journal publications provide solid evidence that a technique called hydrogen breath-testing can be used to determine if too many bacteria in the small intestine may be causing a patient’s IBS symptoms. The condition is called SIBO for small intestinal bacterial overgrowth.

SIBO is also a factor in other digestive health conditions including celiac and Crohn’s disease, and may also be involved in systemic conditions including rosacea, asthma, scleroderma, ankylosing spondylitis (a serious autoimmune condition like arthritis), and fibromyalgia. This article also has relevance to chronic acid reflux based on evidence in my book, Fast Tract Digestion Heartburn linking acid reflux to SIBO (Could antibiotics help people with heartburn?).

Hydrogen breath-testing can detect SIBO because gut bacteria (but not human beings) produce hydrogen gas when they ferment carbohydrates. The hydrogen is absorbed into the blood and exhaled in the breath.  Excessive breath hydrogen (the patient blows in a tube and the samples are analyzed at the lab), detected soon after taking a drink of lactulose (a sugar that can’t be digested by humans, but can be fermented by bacteria) is indicative of SIBO.

Dr. Pimentel’s recommended treatment approach for IBS patients diagnosed with SIBO is referred to as the “Cedars-Sinai Protocol”. Once tests are given so celiac disease, thyroid malfunction, and other conditions that could give the same symptoms can be ruled out, the patient is offered a ten day course of antibiotics. The antibiotic most recommended is rifaximin, which is FDA approved for traveler’s diarrhea caused by certain strains of E. coli, to reduce the risk of overt hepatic encephalopathy recurrence (the worsening of brain function when the liver can’t remove toxins from the blood) and now for IBSd. A second antibiotic, neomycin, is sometime recommended as well.

The treatment of SIBO itself with antibiotics is not new. Several antibiotics including metronidazole, levofloxacin, ciprofloxacin, doxycycline, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, cephalexin and norfloxacin have been used for SIBO in the past. A short term study involving ten SIBO patients indicated that norfloxacin and amoxicillin-clavulanic acid could be effective in the treatment of bacterial overgrowth-related diarrhea[1]. Metronidazole (Flagyl), which has potent activity against several bacteria associated with SIBO such as Bacteroides fragilis and Clostridium difficile, has also been used successfully for treating SIBO[2].

 The case for antibiotics

There are many situations that merit the use of antibiotics. Life-threatening infections such as (bacterial) pneumonia or septicemia – a serious bacterial infection of the blood,  come to mind first, but there are many other occasions where bacteria jeopardize our health and antibiotics may be needed. Some types of bacteria, such as Staphylococcus aureus, are particularly virulent meaning they are well adapted to causing disease and an antibiotic may be needed to control the infection. Also, some people have immune deficiencies where even routine infections can be serious. Antibiotics are also used for some chronic infections caused by bacteria, such as H. pylori, which can lead to stomach and duodenal  ulcers, even gastric cancer. Treatment of IBS with antibiotics differs in that the condition is not caused by a single pathogen, but rather a general overgrowth of intestinal bacteria in the small intestine.

There are many other instances where antibiotics are not a wise choice. The best example is taking antibiotics for a cold or other illness caused by a virus. In these cases, antibiotics won’t help at all, and indiscriminate use limits their effectiveness in the future because antibiotic use provides constant pressure for resident bacteria to become resistant to the antibiotics used.

In most cases, antibiotics are prescribed when there is clear evidence that the patient suffers from a bacterial illness that is not expected to resolve on its own. Doctors often prescribe antibiotics empirically without knowing what specific bacterium is causing the problem, but when the causative organism has been isolated in culture there is a much greater chance for success, because the cultured bacterium can be tested for susceptibility to a variety of antibiotics so the most effective one can be selected.

On the surface, it would seem logical to treat SIBO with antibiotics. SIBO after all, is bacteria overgrowing in our small intestine. The logical response would seem to be “kill the bacteria that are causing the problem”. Certainly, there are circumstances where antibiotics are needed for SIBO. Situations where SIBO poses a significant and immediate health threat such as anemia, malnutrition or other serious medical conditions may require intervention with antibiotics. But can antibiotics rise to the challenge? Treatment success means killing the bad bacteria and bringing down the overall number of bacteria while not wiping out all the good bacteria. Unfortunately, antibiotics represent a shotgun approach that often causes more problems than it solves. Though I have great respect for the work of Dr. Pimentel’s team on IBS, I am not sure about the rationale for using antibiotics as a first line treatment for IBS. There may be reasons to reconsider this approach. Let’s look at the pros and cons.

Why the approach might make sense (The Pros)

  • Lots of people with IBS can be helped. If the Cedar-Sinai Protocol works, it stands to help many people. There are an estimated fifty million people in the US who suffer with chronic IBS. Pimentel’s team found that 78 percent of patients with IBS had SIBO[3]. Similar findings were observed in children[4].
  • Reported to be effective and safe. Dr. Pimental states in his book that he recommends rifaximin and neomycin because the antibiotics have been shown to be effective for treating SIBO and both antibiotics are almost completely contained in the GI tract minimizing side effects and drug resistance. Pimentel’s team suggests that the treatment protocol is effective for most IBS sufferers with SIBO noting that “patients’ IBS symptoms significantly decreased after a single ten-day course of rifaximin” and that “the symptom improvement lasted two months after treatment.”
  • Preventing more serious consequences of SIBO. Antibiotic treatment, if successful, could help prevent more serious complications of SIBO from occurring.  Like IBS, the symptoms of SIBO include abdominal pain or cramps, diarrhea, constipation, gas, bloating, acid reflux, flatulence, nausea, dehydration and fatigue.  But SIBO can cause more severe symptoms including weight loss and “failure to thrive,” steatorrhea (the body’s failure to digest fats), anemia, bleeding or bruising, night blindness, bone pain and fractures, leaky gut syndrome, and autoimmune reactions. Preventing SIBO from invoking more serious symptoms and illness is important.

Reasons to reconsider treating IBS with antibiotics (The Cons)

While I support the use of antibiotics for treating serious bacterial infections, including the most serious forms of SIBO mentioned above, I have five basic concerns over the use of antibiotics for the routine treatment of IBS.

  • Antibiotics lack both short- and long-term efficacy for IBS.
  • Antibiotics kill both good and bad bacteria and can lead to C. diff infection.
  • Overusing antibiotics breeds resistant strains of bacteria.
  • Antibiotics are associated with side effects and can cause allergic reactions.
  • There are better ways to control SIBO, using diets that limit fermentable carbohydrates and sugar alcohols.

Antibiotics lack both short- and long-term efficacy for SIBO

In two double-blind (neither investigators nor patients know who receives placebo and who receives the drug) clinical studies funded by Salix called Target 1 and Target 2, similar results were achieved in IBS patients treated with 550 mg or rifaximin three times daily for two weeks[5]. “Adequate relief” of IBS symptoms was 41 vs. 32 percent when both studies were averaged for rifaximin and placebo respectively. “Adequate relief” was defined as relief of symptoms for at least 2 of the first 4 weeks after treatment – not sure why relief for only half of the time is considered adequate. Relief of bloating was also measured as 40 vs. 30 percent when both studies were averaged for rifaximin and placebo respectively. While the results were statistically significant in favor of the antibiotic treatment, based on some earlier work, I had expected more dramatic results. The antibiotic only gave a 10 percent improvement over placebo.

Also antibiotics are not effective for long term treatment of SIBO. A study of eighty patients with SIBO who were treated with rifaximin showed a high recurrence rate six months (27.5 %) and nine months (43.7%) after therapy[6]. Refer to figure1.

IBS Recurrance

Figure 1. SIBO recurrence following rifaximin treatment.

Clearly, this high recurrence rate indicates the underlying problem not being addressed fully in many cases, and the bacteria quickly grow back after treatment. One of the reasons for this lack of efficacy could be that the antibiotic does not inhibit all bacterial types overgrowing in the small intestine. And many gut bacteria involved in SIBO and IBS may quickly develop resistance against the drug (see below).

 

 

 

Antibiotics kill both good and bad bacteria and can lead to C. diff

The antibiotics used in the Cedars-Sinai Protocol are broad spectrum meaning they inhibit a wide range of bacteria. This is important because SIBO is not caused by a single type of bacteria but rather by the overgrowth of many types of bacteria, generally arising from the large intestine. Many of the bacterial types involved will likely be resistant to several less potent antibiotics. But there is a downside.

Broad spectrum antibiotics are indiscriminate bacteria killers. They can disturb the balance of good to bad bacteria in the intestines causing diarrhea and other problems. Whenever people take antibiotics, regardless of the reason, a large number and wide variety of intestinal bacteria are killed. This is likely the reason that broad-spectrum antibiotics can themselves lead to IBS[7] as well as inflammatory bowel disease[8]. In most cases, the natural balance of your intestinal bacteria will be restored over time after you stop taking the antibiotic, but this can take a long time, even years. In some cases the original healthy intestinal microbial population never fully recovers.

When you wipe out the healthy gut bacteria, pathogenic or bad bacteria can take over. The worst of the bunch is Clostridia difficile, known as C diff. According to a CDC press release[9], C diff is linked to approximately 14,000 deaths every year in the US alone, mostly due to a dangerous condition called pseudomembranous colitis (a serious inflammation of the large intestine). Even more powerful antibiotics may be required to treat this condition. The biggest risk factor for C diff is taking antibiotics or staying in a medical facility which may include hospitals, nursing homes or even doctor’s offices. C diff makes difficult-to-kill spores which are able to persist on surfaces and even the hands of medical providers. Most at risk of dying from infection are elderly patients. According to the article, treating C diff infections costs at least one billion dollars each year.

Overusing antibiotics breeds resistant strains of bacteria

One of the biggest challenges in treating SIBO with antibiotics is drug resistance. Many bacteria are naturally resistant to many antibiotics and all bacterial have the ability become resistant either through mutation or by receiving resistance genes from other bacteria. Well known examples of drug resistant bacteria include methicillin-resistant Staph aureus (blood and wound infections and toxic shock syndrome), multidrug-resistant enterococci (urinary tract, blood, and other infections) multi drug resistant Acinetobacter baumannii (pneumonia, blood, urinary tract and other infections) and drug resistant C diff. (diarrhea and pseudomembranous colitis – serious inflammation of the colon). Drug resistance limits the usefulness of all antibiotics whenever they are used, but the problem is most challenging with SIBO because of the sheer number and diversity of bacteria that reside in the small and large intestine.  As resistance to one drug emerges, SIBO and symptoms will persist until another antibiotic or antibiotic combination is found that can effectively treat the condition.

Drug-resistance and C-diff

As mentioned above,C diff often takes over after antibiotic treatment kills the majority of friendly bacteria. C diff infection is so often linked to antibiotic use that it’s commonly referred to as “antibiotic-associated diarrhea (AAD)”.  Having lots of healthy bacteria is the best protection against C diff.

Once established, the bacterium produces several toxins including enterotoxin (toxin A) and cytotoxin (toxin B) that cause inflammation and severe diarrhea. C. diff infection can lead to pseudomembranous colitis, a potentially life-threatening inflammation of the colon. C diff is on the move in hospitals, nursing homes and even doctor’s offices. There are already many C diff strains (some from epidemic outbreaks) that are resistant to a number of antibiotics including rifaximin. This is concerning because not only is rifaximin being recommended for treating IBS, but because it has actually been used as a supplemental drug to treat C diff infection.

A study of C diff strains from a hospital outbreak found that rifampin resistance (rifampin is a close relative of rifaximin) is common (36.8% of 470 recovered isolates and 81.5% of 205 epidemic clone isolates) among C. diff isolates recovered during epidemic outbreaks at the University of Pittsburgh Medical Center–Presbyterian Hospital[10]. The authors stated that “Exposure to rifamycins (which include rifaximin) before the development of C. difficile-associated disease was a risk factor for rifampin-resistant C. difficile infection. The use of rifaximin may (therefore) be limited for treatment of C. difficile-associated disease at our institution”. This finding is supported by other research showing that the same mutations in C. diff that result in rifampin-resistance also result in resistance to the closely related antibiotic, rifaximin[11]. Recently, investigators reported the selection of C. difficile resistant to the rifamycin class of antibiotics in a patient within 32 h of receiving rifaximin for the treatment of recurrent C. difficile diarrhea[12]. And the problem is not limited to the US. In another recent study, more than 10% of C. diff isolates from three major teaching hospitals in Taiwan were resistant to rifaximin[13].

Salix, who makes rifaximin also cautions on their web site with the following statement: “Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued”.

Antibiotics are associated with side effects and can cause allergic reactions

As noted on the Salix company web site, patients experienced the following adverse reactions: edema peripheral, or fluid in the tissues of the extremities causing swelling in 15 percent of patients, nausea was found in 14 percent, dizziness in 13 percent, fatigue in 12 percent, ascites, or fluid in peritoneal cavity between abdominal organs in 11 percent, muscle spasms in 9 percent, pruritus in 9 percent and abdominal pain in 9 percent.

Though some side effects are also noted in people taking placebo, the high percentage of people having side effects is a definite con in my opinion, especially given the limited effectiveness of the antibiotic for IBS. Keep in mind that more serious side effects occur, though at a lower frequency than those listed above. Web MD lists one infrequent side effect, a hernia which protrudes into the abdominal wall and 14 other rare but serious side effects. All antibiotics, including rifaximin, can cause serious allergic reactions. Potentially serious side effects are another reason to use caution and take antibiotics only when they are absolutely needed and expected to provide maximum benefit.

There is a better way to control SIBO

In some cases, correcting SIBO can be fairly simple. For example, a lactose intolerant individual with intermittent diarrhea (caused by SIBO) may recover completely by avoiding lactose or taking the enzyme supplement lactase. But often the problem is more complex and the overgrowing bacteria has become part of the cycle of SIBO and malabsorption (see below). In this case, successful treatment of SIBO requires treatment aimed directly at the bacterial overgrowth as well as treatment to correct or ameliorate the underlying problem that allowed SIBO to become established.

Potential causes of SIBO (you likely suffer from one or more of these if you have IBS, GERD/LPR, celiac or Crohn’s disease, fibromyalgia, rosacea, interstitial cystitis, autoimmune disorder or several other SIBO-related conditions) can be grouped into different categories including:

  • Motility issues
  • Pancreatic insufficiency (lack of digestive enzymes)
  • Intestinal villi damage (finger like projections for nutrient absorption)
  • Antibiotic use
  • Gastric (stomach) acid reduction
  • Immune impairment
  • Low ileocecal valve pressure (separates the small  from large intestine)
  • Carbohydrate malabsorption

If you and your medical provider can determine which of these factors is causing your symptoms you have a good chance to adopt a comprehensive treatment approach that will provide lasting relief. Each of these factors along with treatment guidelines  is covered in my books Fast Tract Digestion Heartburn and Fast Tract Digestion IBS.

There are two basic approaches in treating the bacterial overgrowth itself. We talked about the first approach – killing or inhibiting the growth of the overgrowing bacteria using broad spectrum antibiotics.  The other approach is to limit the growth of overgrowing bacteria by minimizing the malabsorption of carbohydrates, the major fuel source for gut bacteria. The best way to accomplish this is with a diet that limits difficult to digest carbohydrates.  When you remove most difficult-to-digest carbohydrates from your diet, you have the almost magical ability to limit the growth of all intestinal bacteria, yeast and other fungi across the board. Healthy gut bacteria are well adapted (because we evolved with these bacteria) to living in a nutient-limited gut environment and will prevail over bad bacteria which are less well adapted to this environment.

There is one constant in SIBO, carbohydrate malabsorption, which feeds bacterial overgrowth. This issue must be addressed for lasting relief. Two basic types of diet can be used to limit carbohydrate malabsoption. One is an overall low carb diet (Heartburn cured) and the other is a selective diet that limits only the most difficult-to-digest carbs, (Fast Tract Diet described in the Fast Tract Digestion book series).  For a full review on diets for SIBO, read my article on SIBO Diets and Digestive Health – It’s about Fermentable Carbohydrates.

Take home message

My recommendation is to treat all but the most severe forms of IBS with a science-based diet that limits SIBO. Antibiotics should be reserved for IBS/SIBO conditions that either fail to respond to diet or that involve more severe symptoms such as weight loss, failure to thrive, steatorrhea (the body’s failure to digest fats), anemia, bleeding or bruising, night blindness, bone pain and fractures, leaky gut syndrome, and autoimmune reactions, or in cases where SIBO has damaged intestinal villi (the hair like projections in our small intestines which allow us to absorb nutrients).  More severe symptoms which may include vomiting, constant diarrhea, fever or blood in the stool may be indicators of even more serious illness and should be evaluated by your doctor as soon as possible.

What do you think? 

Disclaimer

I am a medical microbiologist, not a medical doctor or gastroenterologist. This article is presented for information only and should not take the place of discussions with your own doctor.

Though I have done my best to present this information objectively, I am the author of diet-based treatments for functional gastrointestinal disorders, SIBO and related conditions including acid reflux and IBS and provide individual consultation based on my 3 pillar approach:

  • Dietary (including supplements)
  • Behavioral
  • Identifying and addressing underlying causes

 

References

[1] Attar A, Flourié B, Rambaud JC, Franchisseur C, Ruszniewski P, Bouhnik Y. Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial. Gastroenterology. 1999 Oct;117(4):794-7.

[2] de Boissieu D, Chaussain M, Badoual J, Raymond J, Dupont C. Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain, or both.  J Pediatr. 1996 Feb;128(2):203-7.

[3] Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503-6.

[4] Scarpellini E, Giorgio V, Gabrielli M, Lauritano EC, Pantanella A, Fundarò C, Gasbarrini A. Prevalence of small intestinal bacterial overgrowth in children with irritable bowel syndrome: a case-control study. J Pediatr. 2009 Sep;155(3):416-20.

[5] Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan 6;364(1):22-32.

[6] Lauritano EC, Gabrielli M, Scarpellini E, Lupascu A, Novi M, Sottili S, Vitale G, Cesario V, Serricchio M, Cammarota G, Gasbarrini G, Gasbarrini A. Small intestinal bacterial overgrowth recurrence after antibiotic therapy. Am J Gastroenterol. 2008 Aug;103(8):2031-5.

[7] Villarreal AA, Aberger FJ, Benrud R, Gundrum JD. Use of broad-spectrum antibiotics and the development of irritable bowel syndrome. WMJ. 2012 Feb;111(1):17-20.

[8] Hviid A, Svanström H, Frisch M. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54. Epub 2010 Oct 21.

[10] Curry SR, Marsh JW, Shutt KA, Muto CA, O’Leary MM, Saul MI, Pasculle AW, Harrison LH. High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital.  Clin Infect Dis. 2009 Feb 15;48(4):425-9.

[11] O’Connor JR, Galang MA, Sambol SP, Hecht DW, Vedantam G, Gerding DN, Johnson S. Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile.  Antimicrob Agents Chemother. 2008 Aug;52(8):2813-7.

[12] Carman RJ, Boone JH, Grover H, Wickham KN, Chen L. In vivo selection of rifamycin resistant Clostridium difficile during rifaximin therapy. Antimicrob Agents Chemother. 2012 Aug 20. [Epub ahead of print].

[13] Liao CH, Ko WC, Lu JJ, Hsueh PR. Characterizations of clinical isolates of clostridium difficile by toxin genotypes and by susceptibility to 12 antimicrobial agents, including fidaxomicin (OPT-80) and rifaximin: a multicenter study in Taiwan. Antimicrob Agents Chemother. 2012 Jul;56(7):3943-9.