Tag Archives: microbiome

PPIs Alter the Microbiome

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A couple of comments –today’s blog (below) and yesterday’s blog both point out potential concerns with proton pump inhibitors (PPIs).  There is a danger that when publications emphasize the potential consequences of PPI use (including NPR’s recent piece on kidney disease and PPIs) that physicians and families will overlook the value of these medications.

With regard to the benefits of PPIs, there are a large number of studies supporting the effectiveness of PPIs for various GI conditions.  As a result, there is little being published on drug effectiveness at this time.  On a daily basis, these medications prevent a great deal of suffering, heal esophagitis, heal ulcers and contribute to improved health.  If one looks only at the negative side of the ledger, this could create harm.

My personal belief is that when PPIs are used, that it is important to consider both the advantages and the disadvantages.  If the benefits are unclear, this increases the necessity of evaluating the risks, especially in vulnerable populations.  In addition, when the benefits are unclear, determining the length of therapy and/or performing appropriate diagnostic workup becomes essential.

Also, for pediatric gastroenterologists reading this blog, it is important to realize that my blog’s following is tiny in comparison to the circulation of the Journal of Pediatrics and news organizations like NPR.  Therefore, we need to engage our pediatrician/family medicine colleagues to help make sure that PPIs are used effectively.  I am looking forward to the January 26 NASPGHAN webinar on this topic.

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The degree to which proton pump inhibitors (PPIs) affect the gut microbiome is unclear.  A recent study of 12 healthy volunteers (DE Freedberg et al. Gastroenterol 2015; 149: 883-85, Clearing Out My Desk | gutsandgrowth) indicated that this was not much; however, an even more recent study (F Imhann et al. Gut 2015 December 9 (Gut doi:10.1136/gutjnl-2015-310376))  suggests otherwise (abstract below) -their conclusion: “On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.”  

Link: Proton pump inhibitors affect the gut microbiome

Abstract

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome.

METHODS: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis.

RESULTS: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon’s diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli.

CONCLUSIONS: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.

My take: It is likely that the effects on the microbiome are even more notable in infants/younger children; in neonates, the changes in the microbiome could increase the risk of serious diseases like necrotizing enterocolitis.

Related blog posts:

Yosemite

Yosemite

Why Does Enteral Nutrition Work for Crohn’s Disease? Is it due to the Microbiome?

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A recent study (K Gerasimidis et al. Am J Gastroenterol advance online publication 3 November 2015; doi: 10.1038/ajg.2015.357. Full Text: Extensive Modulation of the Fecal Metagenome in Children With Crohn’s Disease During Exclusive Enteral Nutrition) finds that treatment with Exclusive Enteral Nutrition further reduces microbiome diversity compared to healthy controls. This was an unexpected finding as the authors state: “we would expect EEN treatment to normalize the perceived ‘dysbiotic’ microbiota toward a healthier state.”

Reference from KT Park’s twitter feed. Here’s the abstract:

OBJECTIVES:

Exploring associations between the gut microbiota and colonic inflammation and assessing sequential changes during exclusive enteral nutrition (EEN) may offer clues into the microbial origins of Crohn’s disease (CD).

METHODS:

Fecal samples (n=117) were collected from 23 CD and 21 healthy children. From CD children fecal samples were collected before, during EEN, and when patients returned to their habitual diets. Microbiota composition and functional capacity were characterized using sequencing of the 16S rRNA gene and shotgun metagenomics.

RESULTS:

Microbial diversity was lower in CD than controls before EEN (P=0.006); differences were observed in 36 genera, 141 operational taxonomic units (OTUs), and 44 oligotypes. During EEN, the microbial diversity of CD children further decreased, and the community structure became even more dissimilar than that of controls. Every 10 days on EEN, 0.6 genus diversity equivalents were lost; 34 genera decreased and one increased during EEN. Fecal calprotectin correlated with 35 OTUs, 14 of which accounted for 78% of its variation. OTUs that correlated positively or negatively with calprotectin decreased during EEN. The microbiota of CD patients had a broader functional capacity than healthy controls, but diversity decreased with EEN. Genes involved in membrane transport, sulfur reduction, and nutrient biosynthesis differed between patients and controls. The abundance of genes involved in biotin (P=0.005) and thiamine biosynthesis decreased (P=0.017), whereas those involved in spermidine/putrescine biosynthesis (P=0.031), or the shikimate pathway (P=0.058), increased during EEN.

CONCLUSIONS:

Disease improvement following treatment with EEN is associated with extensive modulation of the gut microbiome.

My take: We really don’t know why EEN works and we have a lot to learn about a ‘healthy’ microbiome.

Related blog posts:

Is It a Good Idea for Pregnant Mothers to Take Probiotics?

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A previous study has indicated that maternal probiotic administration was associated with a lower rate of atopic dermatitis.  The overall quality of evidence supporting this association is considered low.

A recent study (CK Dotterud et al. JPGN 2015; 61: 200-7) examined the effect on the intestinal microbiota in both mother and child following maternal perinatal probiotic supplementation. This randomized, double-blind trial examined the effect of probiotic administration (or placebo) from 36 weeks of gestation up to 3 months postnatally while breastfeeding. Stool microbiome was examined in both mother and child.

Key findings:

  • The changes in the infants microbiome were quite limited. “Only the Lactobacillus rhamnosus GG bacteria colonized the children at 10 days and at 3 months of age. There were no significant differences in the abundance of administered probiotic bacteria between the groups at 1 and 2 years of age.”

My take: We know very little about probiotics and their effects on the GI tract. We often do not even the basics: which strains? which dosage?  optimal timing/when to use?  Given the lack of persistent change in the infant’s microbiome, does administration to pregnant mothers really make any sense (outside of research endeavors)?

How High Can You Go with Adalimumab?

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A recent study (Inflamm Bowel Dis 2015; 21: 1047-53) explored the “Efficacy and Safety of Adalimumab 80 mg Weekly in Luminal Crohn’s Disease.”

Methods: Between 2011-2012, 42 adults with active Crohn’s disease, defined by CDAI > 150 and an objective marker of inflammation, had a dose escalation of adalimumab to 80 mg weekly in prospective multi center study.

  • Objective markers could include CRP >0.5 mg/dL, fecal calprotectin >300 mcg/g, radiologic evidence or endoscopic evidence
  • Only 4 patients were receiving concomitant immunomodulators (& none were started)
  • There were no reports of adalimumab drug levels

Findings: At 14 weeks, 33.3% achieved a clinical remission (CDAI <150) and 23 (54.8%) had a clinical response.  These patients had associated improvements in CRP.  The authors do not report on serious adverse events; all AEs “were consistent with previous experience with this drug.”

Take-home point: The authors do not recommend this approach in routine clinical practice at this time.  However, it would seem that some patients with low adalimumab trough levels (and no anti-drug antibodies) may benefit from high doses of adalimumab

Briefly noted:

Fumery M, et al. JPGN 2015; 60: 744-48.  This retrospective study identified 27 children who received adalimumab (ADA) after infliximab failure.  Though ADA was well-tolerated, 8 (30%) had primary nonresponse to ADA and an additional 5 (26%) had ADA failure by 1 year.

Huang EY, et al. Inflamm Bowel Dis 2015; 21: 963-72.  “Exposure to dexamethasone in mice led to substantial shifts in gut microbiota over a 4-week period.” Take-home point: Corticosteroids may have both direct and indirect impacts on the microbiome as one mechanism of influencing disease response

Related blog posts:

Zoo Atlanta

Zoo Atlanta

Preterm Neonatal Microbiota and Effect of Perinatal Antibiotics

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A recent study (Arboleya, S et al. J Pediatr 2015; 166: 538-44) provide sequential data regarding the intestinal microbiome in preterm infants in comparison to full-term infants; in addition, this study offers some insight into the changes that occur with perinatal antibiotics.

The researchers examined fecal samples at approximately 2 days of life, and then days 10, 30, and 90 in 27 preterm infants and 13 full-term babies. The study figures show the progression and changes of the microbiota over the first 90 days. In Figures 1, the profiles are the most similar between the full-term and preterm infants but there remains significant differences.

Key findings:

  • Preterm infants had higher initial percentage of Lactobacillaceae and reduced Bacteroidacease.
  • Perinatal antibiotics (including intrapartum antimicrobial prophylaxis) were noted to affect gut microbiota with increased Enterobacteriaceae organisms in these infants.

There were many confounding variables noted, including different diets, which make interpretation of the data difficult.  The full-term infants received exclusive breast milk whereas the preterm infants received mixed feedings.

A recent review (Houghteling, PD, Walker, WA.”Why Is Initial Bacterial Colonization of the Intestine Important to Infants’ and Children’s Health?” JPGN 2015; 60: 294-307) had a relevant figure:

From NASPGHAN Twitter Feed

From NASPGHAN Twitter Feed

Bottomline: Overall, Arboleya et al provide some additional baseline data but much more is needed to ascertain what factors will make children healthier –starting from before birth. The understanding of the microbiome is truly in its infancy.

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NPR: “Craptastic Voyage” and Fart Analysis

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Surely a story for every gastroenterologist: “Before The Gas is Passed, Researchers Aim to Measure it in The Gut.”

An excerpt:

Kalantar-Zadeh and his colleagues propose in a paper in Trends in Biotechnologyonline Thursday two new devices that could keep a vigilant eye, or a nose in this case, on what’s going on deep in the gut….

The jar is pretty straightforward. A spoonful of poop goes in and a technician squeezes on a lid containing a sensor that detects the molecules of gas fuming inside and at what concentration…but he’s most excited about their other invention.

It’s a robotic pill that sniffs its way along a craptastic voyage through the gut. As the pill tumbles through, a membrane on the pill lets gasses pass onto a small molecular sensor inside that serves as its nose. The membrane blocks the other stuff sloshing around in the gut.

The pill notes the gasses that gut microbes produce, including oxygen, methane, hydrogen and hydrogen sulfide, which smells like rotten eggs. The pill’s sensor figures out how much of each gas is present, and beams the information out of the patient’s body through a tiny antenna…

The researchers aim to detect changes in gas content. As people’s health waxes or wanes because of stress or disease their intestinal ecosystems change too. Certain microbes may thrive in the new conditions while others struggle. As the populations shift, so will the concentrations of their distinctive gassy waste products.

My Take: This story reminds me about the joke I heard from a mentor about how can you tell if a person is an optimist.  An optimist is a person who finds a pile of manure under the tree on Christmas morning and declares: ‘Oh boy, I’m getting a pony.’

This story shows us that some researchers are true optimists as well; they see a lot of opportunity in studying stool and intestinal gases. Will this research will be useful or wind up being a pile of stool?

Also on NPR: Why Is Insulin So Expensive in the U.S. -summarizes recent commentary (N Engl J Med 2015; 372:1171-1175). This article is important for anyone concerned about escalating medicine costs.

Related blog post: “There is No ‘Healthy’ Microbiome” | gutsandgrowth

Gut Microbiome, Crohn’s Disease and Effect of Diet

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At this past year’s NASPGHAN conference, Bob Baldassano indicated that a low-residue diet probably does not makes sense for the majority of patients with Crohn’s disease because it would not promote a ‘healthy’ gut microbiome.  Another article (Walter SS, Quiros A, et al. SOJ Microbiol Infect Dis 2014; 2: 1-13) supporting this argument has been published. (Thanks to Ben Gold for giving me this reference.)

In this study, the authors examined the gut microbiome from two healthy volunteers and compared them to six patients with Crohn’s disease (CD) (ages 16-50).  The CD cohort were in clinical remission and were not receiving probiotics.  Subjects were randomized to either a low-residue diet (LRD) or a specific carbohydrate diet (SCD).

Besides having some cool figures to explain their results, the key points:

  • The complexity of the gut microbiome was lower in IBD patients compared to healthy controls
  • Bacteroides fragilis was increased in fecal samples of IBD positive patients
  • There was a temporal response of gut microbiome to SCD with increased microbial diversity while the LRD diet was associated with a reduced diversity of the microbiome in patients with CD

While the number of patients participating in this study are low, the affects of these diets can still be measured due to the trillions of microbes in the gut microbiome.

Also noted: Church PC, Turner D, et al. Aliment Phamacol There 2015; 41: 153-66. “Systematic review with meta-analysis: magnetic resonance enterography for the detection of inflammation and intestinal damage in Crohn’s disease.”

How the gut micro biome may affect other diseases including Multiple Sclerosis: Study Hints Gut Microbiome Plays a Role in Multiple Sclerosis (Link to Gastroenterology & Endoscopy News)

Related blog posts:

From NASPGHAN:  Introducing New Website for Teens with Inflammatory Bowel Diseases: JustLikeMeIBD.org  PRESS RELEASE

New York, NY- January 20, 2015 – The number of inflammatory bowel disease (IBD) patients in the U.S. has now increased to an estimated 1.6 million, with approximately 5 percent of that patient population under the age of 18. In response to the growing number of kids with IBD, the Crohn’s & Colitis Foundation of America (CCFA) along with the NASPGHAN Foundation for Children’s Digestive Health and Nutrition, has launched a new website called “Just Like Me” for teenagers with Crohn’s disease and ulcerative colitis.

The interactive site will feature stories and videos from teens with IBD as well as information on school, dating, stress, diet, and research.

 

 

Can an Altered Microbiome Explain Persistent Symptoms in Treated Celiac Disease?

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A recent study (Am J Gastroenterol dii:10.1038/ajg.2014.355) from Helsinki examined 177 patients with celiac disease.  Their goal was to investigate whether altered intestinal microbiota may be associated with persisting gastrointestinal symptoms in celiac patients who had been following a strict gluten-free diet (GFD) for at least 3 years.

After administering a questionnaire (Gastrointestinal Symptom Rating Scale or GSRS) to those with negative celiac antibodies and normal small bowel mucosa (n=164), the researchers identified the 18 subjects with the highest total score (persistent symptom group) and compared them to the 18 subjects with the lowest total score.  Three duodenal biopsies during endoscopy had been frozen and were subsequently analyzed for their microbial DNA.  In each group, one microbial profile was unsuccessful.

Key findings:

  • In the persistent symptom group, there was lower relative abundance of Bacteroidetes (15% vs. 25%, P=0.01), lower Firmicutes (33% vs 46%, P=0.05) and higher relative abundance of Proteobacteria (40% vs 21%, P=0.04).
  • The “microbial richness,” measured as a number of detected genera or operational taxonomic units (OTUs), was reduced in patients with persistent symptoms.  On average, patients with persistent symptoms had 32 genera and 72 OTUs per sample; in contrast, those without symptoms, on average had 37 genera and 106 OTUs.

Some of the strengths of this study include the normal villous architecture for all of the patients; this helps exclude refractory celiac disease as an etiology for the persistent symptoms.  In the discussion, the authors note that the “intestinal microbiota composition in healthy adults is relatively stable and can tolerate normal stress in the intestine caused by, e.g. daily changes in diet.” The speculate that long-term untreated celiac disease “may disrupt a stable intestinal microbiota community that, in some patients, could then reform in a dysbiotic state.”

The limitations of this study include the difficulty of excluding small intestinal bacterial overgrowth which could be related and the difficulty of excluding coexisting irritable bowel syndrome.  Like most studies regarding the micro biome, this study cannot “show causality or distinguish the effects of different bacteria to the persistent symptoms.”

Bottomline: Treated celiac patients with persistent symptoms have a different duodenal microbiome compared to treated celiac patients whose symptoms resolved with a gluten-free diet.

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“There is No ‘Healthy’ Microbiome”

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While thinking about what you might eat later today and pondering how this may affect your GI tract, perhaps a recent editorial may provide some reassurance.

A recent editorial provides an insightful view regarding a ‘healthy’ microbiome.  Despite all of the publications on this subject (and the numerous posts on this blog), there is not a one-size fits all microbiome.

Here’s the link  “No Healthy Microbiome” and an excerpt:

These microscopic partners help us by digesting our food, training our immune systems and crowding out other harmful microbes that could cause disease. In return, everything from the food we eat to the medicines we take can shape our microbial communities — with important implications for our health. Studies have found that changes in our microbiome accompany medical problems from obesity to diabetes to colon cancer.

As these correlations have unfurled, so has the hope that we might fix these ailments by shunting our bugs toward healthier states. The gigantic probiotics industry certainly wants you to think that, although there is little evidence that swallowing a few billion yogurt-borne bacteria has more than a small impact on the trillions in our guts….

But how can you tell when it needs replacing? A bloom of C. difficile is an obvious problem, but most other communities are not so easily classified. The microbiome is a teeming collection of thousands of species, all constantly competing with one another, negotiating with their host, evolving, changing. While your genome is the same as it was last year, your microbiome has shifted since your last meal or sunrise.

We need to start thinking about it as an ecosystem, like a rain forest or grassland, with all the complexities that entails. And just as the gorillas and leopards of African forests differ from the wolves and moose of American ones, so, too, do microbiomes vary around the world.

Microbial Signature in Crohn’s

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This recent study (summarized in earlier post today/Dr. Barnard’s talk) provides more information on the microbiome in patients with pediatric Crohn’s.  Here’s a link to full article: Specific transcriptome and microbiome signature in pediatric Crohn’s   Here’s the abstract:

Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.

From Cincinnati Children’s Pediatric Insights (summary of findings):

“The discovery of specific bacterial populations and a core gene signature associated with Crohn’s disease could lead to new diagnostic testing and improved treatment for inflammatory bowel disease (IBD), according to a study led by researchers at Cincinnati Children’s.

‘This study identifies a set of bacteria that are associated with symptoms, and a group of anti-inflammatory genes that are associated with intestinal damage in children with Crohn’s disease,’ says Lee (Ted) Denson, MD, Medical Director of the Inflammatory Bowel Disease Center, senior investigator for the study, published online July 8 in the Journal of Clinical Investigation. Yael Haberman Ziv, MD, was the study’s first author.

Denson’s team studied tissue samples from the ileum, the lowermost portion of the small intestine, in a large number of children with Crohn’s disease. They found specific types of bacteria and a “core” gene expression signature, both of which appear to affect inflammatory changes in the gut. Certain genes in the core signature appeared to be specifically associated with intestinal damage from deep ulcers.”