Proton pump inhibitors affect the microbiome

Proton pump inhibitors (PPI) are used to reduce gastric acid production in individuals’ guts and are prescribed to treat ulcers, gastroesophogeal reflux disease (GERD), and other conditions associated with acid production. It is one of the most commonly used drugs in the world. We know (and have written about) that PPIs are associated with increased intestinal infections, specifically Clostridium difficile, and the gut microbiome plays an important role in infections of the intestine. A recent study looked at the influence that PPIs had on the gut microbiome.

The team of researchers studied the gut microbiome of 1815 individuals. They looked at PPI users vs non-users. Of those sampled, 215 of them were taking a PPI at the time that a sample was taken. It was found that those taking the PPIs had lower microbial diversity compared to those not taking PPIs. They also found that bacteria usually found in the mouth was over-represented in the fecal samples of those taking PPIs, including those in the Rothia genus. They also observed an increase in Enterococcus, Streptococcus, Staphylococcus, and Escherichia coli, a potentially pathogenic bacterium.

PPI usage effects are more prominent than those of most other drugs, including antibiotics. The results of this study are consistent with a less healthy microbiome and allow us to better understand why PPIs may lead to an increase of susceptibility to intestinal infections like C. diff.

Sepsis-like syndrome in a patient after Fecal Microbiota Transplant

Clostridium difficile infection causes pain and diarrhea, is sometimes fatal, and normally occurs after a course of antibiotics leaves the gut in a state of dysbiosis where the C. diff can thrive.  Doctors normally prescribe antibiotics to cure this infection, but this can sometimes exacerbate the problem, making the gut even more prone to infection.  Fecal microbiota transplants (FMT) are the most successful therapy to treat the condition and have been seen to be successful in as many as 95% of treatments. 

A group of doctors in California chronicled the story of a 56-year-old woman who suffered from C. diff after she took a 10-day course of amoxicillin after she became sick with bacterial sinusitis. She went to the doctor after getting very sick and reporting 8-10 bowel movements per day. She was then prescribed various other antibiotic regimes that did not improve her condition over several days and a stool analysis found that she had C. diff.

While admitted at the hospital she was prescribed more antibiotics including metronidazole, vancomycin, and fidaxomicin however this only exacerbated her problems. Finally, her husband was identified as a potential stool donor and on Day 15 she underwent an FMT.

Six hours after the FMT, the woman developed sepsis-like syndrome and had a fever, tachycardia, and hypotension. After the woman was transferred to ICU, it was decided that no further antibiotics would be initiated as this could prevent the FMT from being effective and she did not clinically appear to be severely ill despite her vitals.  The following morning she was recovering and her vital signs normalized. Three days later, she was discharged and six weeks later, her stool frequency had reduced to 2-3 times per day and there was no C. diff recurrence.

Why was it that, this woman suffered from a condition that looked like sepsis after the FMT? The hypotheses included that it could have been a result of another pathogen derived from the donated stool. Second, it could have been a compilation from the procedure such as a perforated colon. Third, the FMT may have been unsuccessful resulting in untreated infection after the cessation of antibiotics the day prior. And finally, it could have been a result of the representation of an immune response as a result of a new gut microbiota.

While this was only an example of one patient and they did not discover the reason for her sepsis-like symptoms, this was an example of the harm that an FMT can cause. The authors state that well designed, executed, and interpreted clinical trials should be conducted if FMTs are to be used for higher risk/benefit conditions.

Proton pump inhibitors increase risk of C. diff in children

Alka seltzer treats acid reflux without proton pump inhibitors

Acid reflux is a common problem among adults, and is often treated with acid suppression medication such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). Acid suppression medication is also given to children over long periods of time. While there is a recognized connection between proton pump inhibition in adults and Clostridium difficile infection (CDI), a link between the drug intake by children and CDI has not been studied. As we’ve discussed on the blog before, infection by the bacteria C. difficile can cause serious harm to the intestinal tract and immune system. An article published by Clinical Infectious Diseases looks further into the relationship between acid suppression and CDI in children.

          Researchers at Columbia University Medical Center conducted a study using data from the Health Improvement Network, a medical records database. Data from 1995 to 2014 was used, and subjects were selected if they were aged 0-17 at the time of CDI diagnosis. The patients also needed the following requirements:  3 follow-up visits for patients younger than 1 year, and  1 follow-up visit for patients older than 1 year. Children with prior chronic conditions that may be linked to long-term acid suppression, such as neurological disorders and chronic gastrointestinal mucosal diseases, were excluded.

In the end, 650 cases were selected, with 68 of them being infants younger than 1 year. 3200 control cases were selected as well. After statistical analysis, it was found that there was no significant evidence of  age (1 year or 1-17 years) having an effect on the acid suppression-CDI relationship. It was found that the use of stronger proton pump inhibitors, rather than less-strong H2RAs, causes a significantly increased risk for CDI. Additionally, when the acid suppressant was used more recently (8-90 days) than distantly, the likely-hood of CDI was increased.

The researchers point out a potential error diagnosing CDI that could be causing the increase in children with the disease. In children, they say, symptoms of acid-related disorders may be very nonspecific, such as abdominal pain. Physicians then treat this with acid suppression medications, which, as discussed above, would then increase possibility of C. difficile colonization and growth.  However, the original abdominal pains may actually be symptoms of CDI. As a result, treating the CDI with acid suppressants is worsening the infection. With this new research, physicians might want to reconsider their options before treating what they think is an acid-related issue. 

New info on fecal microbiota transplants for C. difficile and ulcerative colitis

"Fecal bacterial communities of recurrent [C. diff]  patients shift towards [healthy] fecal bacterial communities after FMT. Pre-FMT patient samples (red circle); post-FMT patient samples (green circles); trajectory of patient fecal communities after FMT (blue line)."
Image and caption from the C. diff paper: Weingarden et al. Microbiome 2015 3:10   doi:10.1186/s40168-015-0070-0

Two important papers regarding fecal microbiota transplants (FMTs) were published last week.  The first was an examination of a patient’s microbiome over time after he or she undergoes an FMT to treat C. difficile.  The second showed the results of clinical trials that used FMTs in an attempt to treat ulcerative colitis.   The FMT papers, which are described below, improve our understanding of this procedure, which holds promise to treat various microbiome-based diseases.

The C. diff paper, published in the journal Microbiome, attempted to answer the question: Do the microbiome changes that occur after FMT remain long after the procedure?  We know that FMTs are highly effective in treating C. diff because they install a healthy microbiome that can crowd out the infection.  However, it is unknown if these new bugs that take hold are transient, or if they become permanent members of the gut.  The researchers sampled the microbiomes of FMT donors and recipient patients before and up to 84 days after an FMT procedure to treat C. diff.  They discovered that the recipients’ dysbiotic microbiomes stabilized quickly, and after just one day they closely resembled the donors’ microbiomes.  Continued measurements showed that the microbiomes deviated over the next few weeks, but that they remained healthy.

The colitis clinical trial, published in the journal Gastroenterology, attempted to discover if FMTs could treat ulcerative colitis.  Ulcerative colitis is widely considered to somehow be related to a dysbiosis in the microbiome, so can FMTs from healthy donors treat this disease?  The study was a double blind randomized clinical in which 48 people suffering from ulcerative colitis either received stool from healthy donors (treatment) or just an FMT of their own stool (control).  7/23 patients who received stool from a healthy donor were in remission after 12 weeks, while 5/25 patients who received their own stool were in remission at that time.  Unfortunately, this is not a clinically significant result based on the number of patients involved.  The researchers measured the bacterial abundance in all of the patients microbiomes before and after treatment.  Before treatment the microbiomes all had some baseline similarity.  After treatment, though, the patients who responded to treatment from a healthy donor all had an increase in certain Clostridia, and the patients who responded to treatment from their own stool all had in increase in certain Bacilli, Proteobacteria and Bacteriodetes.  The researchers feel that this information warrants further study.

FMTs are an exciting new therapy that may be important in treating some really nasty diseases.  We do want to remind people, though, that it is still an unproven technique that should only be performed under the guidance of a doctor.  As we have written about before, the promise of the microbiome is what makes FMTs both attractive, but potentially dangerous at the same time.

Antibiotic resistant bacteria at UCLA and how the microbiome can prevent similar infections

Endoscopes (the instrument that resulted in infections at UCLA) in sterilization equipment

Over the past few weeks at Ronald Reagan UCLA Medical Center in Los Angeles, California, 179 patients were exposed to Carbapenem-resistant enterobacteriaceae or CRE, resulting in seven patients being infected and two deaths.  This is a lethal bacterium that is very resistant to antibiotics and has resulted in significant discussion in the press. Hospital patients with compromised immune systems are susceptible to infections passed on from other patients and hospital equipment and in the current case of CRE at UCLA, a contaminated endoscope.

Another prominent cause of infection is the bacteria enterococci, specifically vancomycin-resistant enterococci (VRE), which, as the name states, are resistant to the antibiotic vancomycin. In healthy individuals, the bacteria are not a threat and are usually killed by the immune system. In cancer patients, the elderly, transplant recipients, and other patients on antibiotics, the weakened immune system and microbiome colonization cannot fight the colonization of VRE in the gut. The result is an infection of the intestines, and possibly of the urinary tract, blood stream, and heart.

In an article published in FEMS Microbiology Letters in early February, the authors summarize research that is being done to overcome the issue of VRE infection. Infection by enterococci often occurs in patients who have taken antibiotics that deplete beneficial bacteria in the gut. One possible fix for this problem could be the administration of probiotics, live microorganisms that provide a health benefit. Unfortunately, limited research has been done in this area. In one inconclusive study, Lactobacillus rhamnosus appeared to eliminate or at least decrease the presence of VRE in the gut. Other studies suggest that it is easier to prevent infection of, rather than eradicate already present VRE.  

Another area of investigation is the use of commensal bacteria to prevent infection, or the administration of normal gut-colonizing bacteria. A popular topic in microbiome research, and one that often, and recently, appears on our blog is the treatment of infection of Clostridium difficile. One method of treatment that we frequently discuss is fecal microbiota transplant (FMT). The authors of this article suggest the use of FMTs may be able to be applied for the treatment of enterococci infection. 

Many hospital patients get sick from infections passed within the hospital, as their compromised immune systems cannot stave off infection. Hospitals are supposed be a place for getting healthier, yet we know that hospital-acquired infections are a major issue in today’s hospital systems as we have seen over the past few weeks at UCLA. New strategies for overcoming these issues are being pursued and are very important for the prevention of deaths resulting in bacterial infections passed within hospitals.