Tag Archives: microbiome

Top Lecture: Enteral Nutrition for Crohn’s Disease

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In my opinion, the best lecture from this year’s postgraduate course was from Dr. Baldassano.  Enteral nutrition in Crohn disease: Where should this be in our treatment algorithm?  Robert N. Baldassano, MD (page 115)

Dr. Baldassono has personal experience with improving with enteral therapy after failing methotrexate/remicade.  His conclusion:

Enteral Nutritional Therapy: Where should this be in our treatment algorithm?

  • Should be offered to all newly diagnosed Crohn’s patients who can tolerate Nutritional Therapy
  • Special groups (especially a good idea): Malnourished patients, Younger patients, Growth failure, History of Cancer, Family history of Lymphoma, Consider when failing other therapies

This conclusion is supported by his presentation.

Should we be immunosuppressing our Patients?  Hypothesis: IBD arises from inappropriate handling of intestinal bacteria

Elements of Modern Lifestyle Lead to Changes in Gut Microbiota

  1. Improved sanitation
  2. Less crowded living conditions
  3. Decline in parasites
  4. Vaccinations
  5. Increased antibiotic use
  6. Caesarean section
  7. Refrigeration
  8. Food processing
  9. Diet changes
  10. Improved sanitation

Diet is associated with new onset IBD

  • High dietary intakes of total fats, PUFAs, omega‐6 and meat were associated with an increased risk of CD and UC
  • High fiber and fruit intakes were associated with decreased CD risk
  • High vegetable intake was associated with decreased UC risk.  Reference: Hou JK et al. American Journal of Gastro 2011; 106:563-73
  • The Bacteroides enterotype highly associated with animal protein and saturated fats which suggests meat consumption as in a Western diet
  • The Prevotella enterotype, high values for carbohydrates and simple sugars, indicating association with a carbohydrate-based diet, more typical of agrarian societies.  References: Wu G, et al. Science. 2011 Oct 7;334(6052):105‐8

Partial or Complete Enteral Nutrition?

  • 50% vs 100% of total caloric needs for induction with elemental formula (PCDAI < 10 at 6 weeks)
  • 50% of total caloric needs 15% remission
  • 100% of total caloric needs 42% remission
  • Labs improved only in the 100% group
  • Weight gain similar in the 2 groups. References: Akobeng et al Clin Nutr 2007; Ludvigsson et al Acta Paediatr 2004;Johnson et al Gut 2006;Critch et al. JPGN: 2012 

Pediatric Longitudinal Study of Semi‐Elemental Diet and Stool Microbiome (PLEASE)

Prospective cohort study of children with Crohn disease from Philadelphia (used Peptamen), Toronto (used Modulen) and Halifax (used Osmolite); (n=90)

  • Enteral therapy with defined formula diet (n=38) vs. anti‐TNFα therapy (n=52)
  • Similar drop in PCDAI and calprotectin in TNF group and diet group. 

Other points:

  1. Insurance generally will cover nasogastric feeds
  2. Disease location –not clear that this matters with Crohn’s disease
  3. The reason EN works may be not what you are giving the patient but what the patient is not getting
  4. Bacterial populations in pediatric IBD subjects on semi‐elemental diet (16S rDNA sequencing) develop a rapid change in gut bacterial populations upon initiating diet.
  5. Partial (50%) nutrition, as noted above, helped maintain remission compared to normal diet.

Nutrition Therapy: “European” Protocol

• Induction:  Exclusive enteral nutrition with an elemental, semielemental,or polymeric formula

• Duration: 4 – 12 weeks

• Maintenance Therapy: (either)

– Nutritional therapy: Repeat 4 week cycle of exclusive enteral nutrition every 3– 4 months

OR

– Medical therapy: 6‐MP/AZA/MTX after induction with nutritional therapy

CHOP EN Experience: What if >80% of calories is from Enteral Nutrition?

  • Methods: Semi‐elemental formula, 80%‐90% of patient’s caloric needs from formula, Nocturnal NG feeds (outpatient teaching program), Normal diet as tolerated during the day
  • Duration:  7 days per week for 8‐12 weeks (induction), 5 days per week (maintenance) Reference: Gupta et al. Inflamm Bowel Dis. 2013:1374-8.
  • Induction of remission: 65% (at 8 weeks)
  • Response: 87% (at 8 weeks)
  • Significant improvement in weight and linear growth
  • Protocol is well tolerated:  no serious adverse events

Postgraduate Course Syllabus (posted with permission): PG Syllabus

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Probiotics, Atopy, and Asthma

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Moving from theory to practice with probiotics has been problematic in many areas.  That is, theoretically probiotics by altering the microbiome should have numerous beneficial effects; however, demonstrating these positive effects in practice has been difficult for many conditions.  A recent study (thanks to Mike Hart for this reference) highlights this issue with regard to asthma:  Pediatrics 2013; 132: e666-76. Full article:

http://pediatrics.aappublications.org/content/132/3/e666.full.html

Background: Due to the immune modulating effects of probiotics and mindful of the hygiene hypothesis regarding the rise of atopic diseases, some have proposed the use of probiotics to reduce the risk of atopy and asthma in children.

Methods: In this study, the authors performed a meta-analysis of numerous randomized studies.  Out of a total of 1081 articles, 25 studies met predefined criteria, with a total of 4031 participants (see Table 1 in publication).  Numerous probiotics were administered.  The most common probiotic in these trials, Lactobacillus GG,  was used in 8 of the studies.

Results:

  • For serum immunoglobulin E (IgE) levels, 9 of the trials (n=1103) provided data.  Probiotics were associated with a -7.59 U/mL reduction in total IgE (P= .044).  The effect of probiotics was more pronounced with longer, follow-up periods.
  • Probiotics, in comparison to placebo, were associated with a reduced risk of atopic sensitization based on positive skin prick and/or elevated specific IgE to common allergens.  This was true whether the probiotic was administered prenatally (relative risk 0.88, P=.035) or postnatally (relative risk 0.86, P=.027)
  • Probiotics did not reduce the risk of asthma/wheeze (relative risk 0.96 [95% CI 0.85-1.07]

Study limitations: heterogeneity of clinical trials in meta-analysis, various probiotic strains, variable duration and timing of probiotic use.

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Probiotics for Crohn’s Disease –No Beneficial Effects Noted

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With all the buzz regarding how a patient’s microbiome seems to affect everything from metabolic syndrome and colic to autoimmune diseases and inflammatory bowel disease, more attention has been paid in attempts to alter the microbiome for therapeutic benefits.  In Crohn’s disease (CD), the fact that antibiotics have shown beneficial effects have led to a number of studies of probiotics.  A recent study, like previous ones, did not demostrate any benefit with Saccharomyces boulardii (Clin Gastroenterol Hepatol 2013; 11: 982-87).

In this prospective double-blind, placebo-controlled study of 165 patients who achieved remission after steroids or salicylates, subjects were randomly assigned to groups given S boulardii (1 gram per day) or placebo for 52 weeks.

Results:

  • CD relapse occurred in 80 patients: 38 (47.5%) in the probiotic group  and 42 (53.2%) in the placebo group
  • Time to relapse did not differ significantly: 40.7 weeks in probiotic group vs 39 weeks in placebo group
  • No differences were seen in disease activity scores or serum inflammatory markers
  • In post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse compared with nonsmoker control patients (34.5 % vs. 72%)

One important limitation of this study was not examining the effects of the probiotic on the microbiome of these patients.  Perhaps, other probiotics would be more effective in restoring a “healthy” flora.

Based on these results, and others, the accompanying editorial (pg 988-89), advocates use of probiotics only for prevention of antibiotic-associated diarrhea, prevention of recurrent Clostridium difficile, and treatment/prevention of pouchitis.

Bottom-line: Probiotics have not been demonstrated to be helpful for Crohn’s disease.

Related blog posts:

Could antibiotics make you fat?

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Studies in mice have shown that those exposed to antibiotics had higher total fat mass/body fat without additional weight gain.  In addition, a study of infants indicated that early antibiotic exposure may also be a risk factor for increased weight gain.

From Gastroenterology and Endoscopy News, June 2013: http://www.gastroendonews.com/ViewArticle.aspx?d=In%2bthe%2bNews&d_id=187&i=June+2013&i_id=961&a_id=23385

“Ilseung Cho, MD, MS, assistant professor of medicine, associate program director, Division of Gastroenterology, NYU School of Medicine, New York City, said, “Many investigators who study the gut microbiome think that it plays a significant role in the obesity epidemic in concert with a variety of other risk factors, such as poor dietary habits or a sedentary lifestyle. The microbiome plays a key role in a variety of host functions, including immune response and metabolism.”

Effect of Antibiotics

Dr. Cho was the lead investigator on a study in mice that demonstrated that antibiotics altered the gut microbiome in such a way as to affect murine metabolism and cause increased adiposity (Cho I et al. Nature 2012;488:621-626). Investigators administered subtherapeutic doses of penicillin, vancomycin, penicillin plus vancomycin, or chlortetracycline to young mice in their drinking water; a control group received no antibiotics. There were 10 mice per group. After an exposure period of seven weeks, the mice did not differ significantly in weight gain, but all four antibiotic-exposed groups had significantly higher total fat mass (P<0.05) compared with controls, and most (with the exception of the vancomycin group) had higher percent body fat (P<0.05).

The antibiotic exposure caused taxonomic changes in the microbiome, with the ratio of the phylum firmicutes to the phylum Bacteroidetes elevated in the antibiotic-exposed mice. Additionally, there was evidence of metabolic changes. For example, glucose-dependent insulinotropic polypeptide was elevated in the antibiotic-exposed mice, and glucose tolerance tests showed a trend toward hyperglycemia.

“In our paper, we describe a model where, by exposing mice to low-dose antibiotics, we were able to alter their microbiome,” said Dr. Cho. “Altering their microbiome resulted in a metabolic change in the mice that led to increased adiposity. The paper demonstrates that we are able to affect host metabolism by altering the gut microbiome.”

Around the same time that Dr. Cho and his colleagues published their results, a related paper about antibiotic exposure in infants was published in advance online (Trasande L et al. Int J Obes 2012 Aug 21 [Epub ahead of print]).

“Knowledge of the importance of the microbiome in human development raises new issues about antibiotic use in children, as such exposures may disrupt the microbial ecology,” the authors wrote.

In the longitudinal birth cohort study, investigators analyzed data from 11,532 children. Exposure to antibiotics during three early-life time periods (ages <6 months, 6-14 months, 15-23 months) was assessed by questionnaires that had been administered to the parents near the measured time interval. Body mass indices (BMIs) were examined at five time points (six weeks, 10 months, 20 months, 38 months and seven years).

Exposure to antibiotics during the period before 6 months of age—and only during that period, of those studied—was consistently associated with increases in BMI from 10 to 38 months. At 38 months, children who had been exposed to antibiotics before 6 months had significantly higher standardized BMI scores (P=0.009) and were 22% more likely to be overweight than children who had not been exposed (P=0.029). The researchers controlled for known social and behavioral risk factors for obesity.”

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What really causes Celiac disease?

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A fascinating article in the NY Times delves into a number of environmental factors that are likely playing a role in the increasing incidence of celiac disease. Here’s the link (thanks to Kayla Lewis for this reference):

Some excerpts:
“Scientists are pursuing some intriguing possibilities. One is that breast-feeding may protect against the disease. Another is that we have neglected the teeming ecosystem of microbes in the gut — bacteria that may determine whether the immune system treats gluten as food or as a deadly invader.Celiac disease is generally considered an autoimmune disorder. The name celiac derives from the Greek word for “hollow,” as in bowels. Gluten proteins in wheat, barley and rye prompt the body to turn on itself and attack the small intestine. Complications range from diarrhea and anemia to osteoporosis and, in extreme cases, lymphoma. Some important exceptions notwithstanding, the prevalence of celiac disease is estimated to range between 0.6 and 1 percent of the world’s population….Yet the more scientists study celiac disease, the more some crucial component appears in need of identification. Roughly 30 percent of people with European ancestry carry predisposing genes, for example. Yet more than 95 percent of the carriers tolerate gluten just fine. So while these genes (plus gluten) are necessary to produce the disease, they’re evidently insufficient to cause it….

A recent study, which analyzed blood serum from more than 3,500 Americans who were followed since 1974, suggested that such a trigger could strike adults at any time. By 1989, the prevalence of celiac disease in this cohort had doubled.

“You’re talking about an autoimmune disease in which we thought we had all the dots connected,” says Alessio Fasano, head of the Center for Celiac Research and Treatment at the Massachusetts General Hospital for Children in Boston, and the senior author of the study. “Then we start to accumulate evidence that there was something else.”

Identifying that “something else” has gained some urgency. In the United States, improved diagnosis doesn’t seem to explain the rising prevalence. Scientists use the presence of certain self-directed antibodies to predict celiac disease. They have analyzed serum stored since the mid-20th century and compared it to serum from Americans today. Today’s serum is more than four times as likely to carry those antibodies…

your microbes change you, but your genes also shape your microbes — as do environment, breast milk, diet and antibiotics, among many other factors.

Such complexity both confounds notions of one-way causality and suggests different paths to the same disease. “You have the same endpoint,” Dr. Jabri says, “but how you get there may be variable.”…

In a far-flung corner of Europe, people develop celiac disease and other autoimmune diseases as infrequently as Americans and Finns did a half-century ago. The same genes exposed to the same quantity of gluten do not, in that environment, produce the same frequency of disease.

“We could probably prevent celiac disease if we just give the same environment to the Finnish children as they have in Karelia,” says Dr. Hyoty. “But there’s no way to do it now, except to move the babies there.”

Author of NY Times article:

Moises Velasquez-Manoff.  Also, he is the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases.”

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How Histamine-2 Receptor Blockers May Cause Problems for Preemies

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Previously, this blog has noted an association between ranitidine usage and necrotizing enterocolitis (NEC) (see below).  Now, another study provides insight into a potential mechanism (JPGN 2013; 56: 397-400).

This study examined the fecal microbiota in 76 premature infants who were enrolled in a case-controlled, cross-sectional study.  25 infants receiving H2-blockers were compared with 51 matched controls.

Results: microbial diversity was lower, relative abundance of Proteobacteria was increased, and Firmicutes was decreased in the stools of infants receiving H2-blockers.

While this study did not specifically examine the effect of H-2 blockers on NEC (no infants in this study had NEC), there are multiple reasons why the findings should be a cause for concern.

  • Gastric acidity acts as a natural defense against bacterial growth and H-2 blockers (as well as proton pump inhibitors) inhibit this defense
  • Previous studies have shown an association between NEC and with diminished microbial diversity/increased Proteobacteria.  Proteobacteria include well-known pathogens like Klebsiella, Shigella, Escherichia coli, and Citrobacter.

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Early antibiotic use and the development of inflammatory bowel disease

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Another study adds weight to the idea that early antibiotic use may increase the risk of developing inflammatory bowel disease (IBD) (J Pediatr 2013; 162: 510-4).

Using a nested case-control design, the authors matched 2377 controls to 294 children with IBD in a population-based database from Manitoba, Canada.  Specifically, the authors looked at the frequency of otitis media diagnosis and the likelihood of subsequent IBD.  By age 5 years, 89% of IBD cases had at least one diagnosis of otitis media, compared with 82% of the controls.  Despite the high frequency in both groups, the authors determined that individuals with a diagnosis of otitis media before age 5 years were 2.8-fold more likely to be an IBD case.

Some of the strengths of this study included the fact that it was a population-based analysis dating back to 1984 and likely captured almost all pediatric IBD cases (<19 years).  Nearly all physicians in Manitoba submit billing claims to a single publicly funded source.  Due to the nature of administrative data, this eliminates recall bias.

However, administrative data have several limitations as well.  Other confounding conditions may have been present and not identified; this could include family history and autoimmune diseases.

The authors “suspect” that the linkage between otitis media and IBD relates to the usage of antibiotics and subsequent alterations of the intestinal microflora.  Otitis media may serve as a “sensitive proxy measure” of antibiotic use.  Also, as boys are more frequently treated for otitis media, this may relate to the generally higher incidence of pediatric IBD in males.

For anyone interested in the association between antibiotic exposure and IBD, this study is useful and provides a number of references as well.

Related blog entries:

Colic Microbiome

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A new study identifies a potential microbiome signature that is associated with colic (Pediatrics 2013; 131: e550-58). Thanks to Mike Hart for this reference.

With new technology, the microbiome’s role in many gastrointestinal conditions is being unraveled.  For colic, there has been concern about that an abnormal microbiome has been contributing to the pathophysiology.  On a personal level, I have had an interest in this subject for quite a while:

In this current study, the authors serially followed the microbiome infants in a prospective longitudinal project.  Nine stool specimens were obtained from each infant. Four were obtained in the first month at day of life 2, 7, 14, and 28 days.  Five were obtained at 3 to 5 months.  All specimens were stored at -20°C until analyzed by the “Human Intestinal Tract Chip (HITChip).” The HITChip microarray was considered satisfactory if 2 independent hybridizations had >95% correlation.  These microarrays “showed a dynamic range of >10,000-fold and >200 independent microarray readouts were used.”

Of 160 healthy term infants, the authors identified colic in 25% who averaged >180 minutes of crying per day over a four-day period.  Then, the authors selected the 12 infants who cried the most and compared them to the 12 infants who cried the least.

Results:

  • In the infants who were highly similar, the “infants with colic showed a significantly reduced microbiota diversity at 14 and 28 days of life.”  Proteobacteria, including Enterobacter aerogenes, Escherichia coli, and Klebsiella pneumoniae, were increased with more than a doubled abundance.  Bifidobacteria and lactobacilli were decreased in colicy infants.
  • At about 3-4 months of age, the colic group had a similar microbiome as the non-colicy group.
  • The authors speculate that proteobacteria might cause inflammation and may displace helpful bacteria.  Certain butyrate-producing bacteria like Butyrivibrio crossotus and Coprococcus estates were more commonly present in the non-colicy group.  The authors note that butyrate reduces the pain sensation in adults.

Bottom-line:

These results could explain why administration of probiotics (and possibly antibiotics) can result in a decrease in colic symptoms.

Related blog entries:

Additional references:

  • -Pediatrics 2010; 126: e526.  Double-blind randomized placebo-controlled trial of Lactobacillus reuteri.
  • -J Pediatr 2009; 155:823. Increased calprotectin in colicy infants. n=36. editorial pg 772.
  • -J Pediatr 2009; 154: 514-20. Colic and reflux. (Orenstein et al), & 475 (editorial -Putnam). PPIs (lansoprazole) do not help colicy Sx in infants c GERD. n=162. Increased resp infections in pts on PPIs. 44% response in Rx & control group.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Pediatrics 2005; 116: e709. Low-allergen maternal diet was helpful.
  • -Arch Pediatr Adol Med 2002; 1183 &1172. lack of sequelae on maternal mental health.
  • -Arch Pediatr Adol Med 2002; 156: 1123-1128. colic 24% of infants, breastfeeding did not help.
  • -Pediatrics 2002; 109: 797-805. carbohydrate malabsorption with breath testing in colicy infants, n=30. 2 hour fasting period.
  • -Arch Dis Child 2001; 84: 138-41. Lack of benefit (vs placebo) of chiropractic manipulation for colic, n=100. 86 completed study. 70% improved vs 60% in placebo.
  • -JPGN 2001; 33:110-111. Lack of assoc c GER
  • -Pediatrics 2000; 106: 1349. Use of hydrolysate decreased crying by 63mins/day
  • -Pediatrics 2001; 108; 878-882. No assoc between colic and markers of atopy/asthma/allergy.

Microbiome in pediatric ulcerative colitis

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Alterations in the gastrointestinal tract microbiome may play an important role in many digestive conditions.  A recent article examines microbiome alterations in children with severe ulcerative colitis (UC) (Inflamm Bowel Dis 2012; 18: 1799-1808).

Stool samples from 26 healthy children and 27 children with severe UC were prospectively studied.  After DNA extraction, PCR amplification and microarray hybirdization were performed and analyzed.   None of the patients in the study had received antibiotics or probiotics in the preceding month.

Key findings:

  • There were substantial reductions in “richness,” diversity, and evenness of the gut microbiome in UC patients.  (Richness is a term used to reflect the number of detected phylospecies.)
  • There was a decrease in signal in almost all  phylospecies.
  • The number of phylospecies was reduced in UC (266 ± 69) vs controls (758 ± 3)
  • Steroid responders had even fewer phylospecies compared with responders (142 ± 49  vs. 338 ± 62)

It is not surprising that the stools from these children are much different.  The issues of causation and whether a snapshot of the microbiome diversity will have clinical relevance is not clear.  It is possible that antimicrobials may make an individual more susceptible to inflammatory bowel disease by altering the individual’s microbiome.

Related blog entries:

Eat your veggies…if you don’t want to get sick | gutsandgrowth

Why are we seeing so many more cases | gutsandgrowth

Eat your veggies…if you don’t want to get sick

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Maybe your mother was right –you should eat your vegetables!   For a long time, it has been known that dietary changes can be used to treat Crohn’s disease.  The specifics about what type of diet and the reasons for how diet promotes a healthy gastrointestinal tract are being unraveled.  A person’s diet affects their microbiome; and, a number of recent articles have highlighted the microbiome in both functional and nonfunctional disorders (see below).

An even more fascinating article is in last week’s New England Journal of Medicine (NEJM 2012; 366: 181).  This article discusses two publications which show how certain dietary components interact with intestinal immune receptors.

  • Kiss EA et al. Science 2011 October 27 (Epub ahead of print).
  • Li Y et al. Cell 2011; 147: 629-40.

This NEJM article implicates a typical ‘Western’ diet as a contributor to inflammatory bowel disease (IBD).  However, a diet high in vegetables may prevent or reduce inflammation.  One mechanism whereby vegetables affect the GI tract is through the AhR (aryl hydrocarbon) receptor.  Some vegetables, like broccoli, cabbage, and brussel sprouts, are natural ligands for this receptor.  A mouse model has shown that AhR deficiency “results in increased epithelial vulnerability, immune activation, and altered composition of the microbiota.”  In addition, AhR is down-regulated in the intestinal tissue of persons with IBD.  AhR ligands are associated with increased interleukin-22 which promotes intestinal integrity.

Additional work regarding the optimal diet are ongoing.  There has been an interest in a ‘carbohydrate specific diet.’  This year’s NASPGHAN meeting (abstract #48)  presented data on this diet from a retrospective study.  This poster described five patients on monotherapy (diet alone) and at 6 months –good results in four patients (80%).  A few prospective studies are underway; in fact, a prospective study with patients from our office will be presented at this year’s DDW.  Initial results look promising (personal communication from lead investigator, Stan Cohen).

Additional references:

  • -Gastroenterology 2010; 139: 1816, 1844.  Microbiome & affect on IBD vs mucosal homeostasis.
  • -J Pediatr 2010; 157: 240.  Microbiota in pediatric IBD -increased E coli and decreased F praunsitzil in IBD pts.
  • -Gastro 2011; 141: 28, 208.  GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -Scand J Gastro 2001; 36: 383-8.  Elemental & polymeric diets successful in maintaining remission in ~43% of adults with complete steroid withdrawal.
  • -Clin Gastro & Hepatology 2006; 4: 744.  10 weeks of exclusive modulen (along with clears) had 79% response rate (n=37).  Better histologic response than steroids.
  • -J Pediatr 2000; 136: 285. Nutritional treatment w polymeric diet is effective w/in 8 weeks in 32/37.
  • -JPGN 2000; 31: 3 & 8.  EN about as effective as steroids for primary Rx.
  • -Can J Gastroenterol 1998; 12(8):544-49. Patients, diets and preferences in
    a pediatric population with Crohn’s disease.
  • -Gastroenterology 1988; 94:603-610. Chronic intermittent elemental diet improves growth failure in  children with Crohn’s disease.
  • -JPGN 1989; 8:8-12. Nutritional support for pediatric patients with inflammatory bowel disease.
  • -J Pediatr 2000; 136: 285-91. The role of nutrition in treating pediatric Crohn’s disease in the new millennium.