Weak Support For Probiotics in Acute Gastroenteritis

Two recent well-controlled studies (D Schnadower et al.N Engl J Med 2018; 379:2002-2014, SB Freedman et al. N Engl J Med 2018; 379:2015-2026) showed that probiotic-treated children with acute gastroenteritis (AGE) did not have better outcomes than placebo-treated children. In addition, a recent AGA practice guideline recommended against the use of probiotics for most GI conditions, including in AGE.

However, a new report (H Szajewska et al. JPGN 2020; 71; 261-69) from an ESPGHAN  working group recommends that probiotics should have a role for AGE.  Several points about this report:

  1. Their recommendations are very qualified: “weak recommendation” with “low to very low certainty of evidence” for the following in descending order: S boulardiii, L rhamnosis GG, L reuteri DSM 17938, and L rhamnosus 19070 & L reuteri DSM 12246
  2. It is noted that this report has a disclaimer from ESPGHAN: “it does not represent ESPGHAN policy and is not endorsed by ESPGHAN”
  3. The authors have extensive disclosures
  4. The report notes that “despite large number of identified trials, we could not identify 2 randomized controlled trials of high quality for any strain that provided benefit when used for treating acute gastroenteritis”

Of note, the associated editorial (pg 146-47) also favors probiotics in the setting of AGE.  “These recommendations…have clarified that there is a role for probiotics in treating” AGE.

Related article (just published): F Mourney et al. The Pediatric Infectious Disease JournalAugust 7, 2020 – Volume Online First – Issue –doi: 10.1097/INF.0000000000002849 A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Saccharomyces boulardii in Infants and Children With Acute Diarrhea (n=100) Key findings: The time of recovery from diarrhea was significantly shorter in the probiotic group compared with the placebo group (65.8 ± 12 hours vs. 95.3 ± 17.6 hours, P = 0.0001).

My take: Overall, probiotic effectiveness is overstated; though, some strains may be helpful for AGE.  Still, there are concerns about variation in production and quality standards even in these strains.

Related blog posts:

IBD Update -August 2020

S Jansson et al JPGN 2020; 71: 40-5. This retrospective study (1998-2008) showed that pediatric patients with extraintestinal manifestations (EIM) had more severe IBD course than patients with IBD without an EIM.  EIM often had a temporal relationship with a relapse of IBD as well. Of 333 patients, 14 had an EIM at diagnosis and 47 had an EIM develop during followup.

PA Olivera, JS Lasa et al. Gastroenterol 2020; 158: 1554-73. This systematic review and meta-analysis ultimately included 82 studies with 66,159 patients (including those with IBD and other immune-mediated diseases) exposed to a JAK inhibitor; two-thirds of studies were randomized controlled trials.  Key findings:

  • Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81, 2.67, 0.89, and 0.48 per 100 person year respectively. After meta-analysis, the authors conclude that there is an increased risk of herpes zoster (RR 1.57), but all other adverse events were not increased among patients treated with JAK inhibitors
  • Mortality was not increased in those receiving JAK inhibitors compared to placebo

Loebenstein, JD Schulberg. Gastroenterol 2020; 158: 2069-71.  This case report describes a successful alternative anti-TNF rechallenge after infliximab induced Lupus in Crohn’s disease.  The authors note that in a previous study, 14 of 20 IBD patents with drug-induced lupus secondary to an anti-TNF agent were rechallenged with an alternative anti-TNF agent and 13/14 tolerated rechallenge without recurrent lupus (Inflamm Bowel Dise 2013; 19: 2778-86).

These images show active disease prior to intervention. The article provides f/u images showing endoscopic remission after re-starting a different anti-TNF agent.

Probiotics in Preemies: Lifesaving Therapy

Lots of studies have indicated that probiotics may be beneficial in premature newborns; the problem is that there are currently no FDA-approved probiotics for preterm infants. The use of probiotics as a non-regulated FDA product leads to the potential risk of contamination due to inconsistent quality control as well as variability in the strains and concentrations.  The risks are not inconsequential as there has been a report of 29-week infant who died from mucormycosis due to probiotic contamination with mold.

Despite the potential problems with probiotics in this population, their usage is increasing as described in a recent multicenter retrospective cohort study (KD Gray et al. J Pediatr 2020; 222: 59-64) which took place between 1997-2016 with 78,076 infants (23-29 weeks gestational age) in 289 NICUs.

Key findings

  • 3626 (4.6%) received probiotics
  • Probiotic use increased over the study period (>10% in 2015 & 2016)
  • By matching 2178 infants who received probiotics with 33,807 without probiotics, the authors determined that those received probiotics had a decrease likelihood of necrotizing enterocolitis (OR 0.62) and death (OR 0.52).  The authors observed an increase in Candida infection (OR 2.23); though, this is an infrequent infection and the absolute difference in risk was <1%
  • Limitations: “similar to many previous studies, there was great variation in probiotic products and organisms, as well as a lack of dosing information, which made it unclear which product, organism, or dose might be most effective.”  Also, other contributing factors like consumption of breastmilk and antibiotic exposure are not detailed in this report.

My take: Probiotics could be life-saving for premature infants. It would be nice if we could find out which strains work and which ones do not as well as to assure safe manufacturing processes.

Related blog posts:

AGA Practice Guidelines: Probiotics NOT Helpful for Most GI Conditions

Here is a link to the EPUB draft of AGA clinical report (G Su et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.059): AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders

Here is a link to the pre-draft technical review by GA Preidis et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.060 AGA Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders

  • The report recommends NOT using probiotics outside of clinical trials for irritable bowel syndrome, Clostridium difficile infection treatment, Crohn’s disease, and gastroenteritis.
  • It recommends a specific probiotic for pouchitis and for prevention of necrotizing enterocolitis in preterm infants <37 weeks and 3 probiotics for patients who are receiving antibiotics (to prevent Clostridium difficile infection)

CNN summary: Probiotics don’t do much for most people’s gut health despite the hype, review finds

“While our guideline does highlight a few use cases for probiotics, it more importantly underscores that the public’s assumptions about the benefits of probiotics are not well-founded,” said Dr. Grace L. Su, a professor of medicine and chief of gastroenterology at the University of Michigan, Ann Arbor, in a news statement. She was the chair of the panel that issued the new guidance….

“The industry is largely unregulated and marketing of product is often geared directly at consumers without providing direct and consistent proof of effectiveness,” said the new guidelines. “This has led to widespread use of probiotics with confusing evidence for clinical efficacy,” it said…

“Not all probiotics are created equal. Some probiotic strains and mixtures are very effective for some types of diseases and should not be overlooked due to studies that lump all probiotics together as one”

My take: Probiotics are overhyped and underperform for most conditions. This report suggests that most people should NOT be taking probiotics.

Related blog posts:

Those Probiotics May Actually Be Hurting Your ‘Gut Health’

A very readable article in the Wall Street Journal: Those Probiotics May Actually Be Your ‘Gut Health’ –may be behind a paywall. (Thanks to Ben Enav for sharing)

This study makes the following key points:

  • “In a landmark paper by my colleague Dr. Jennifer Wargo at the University of Texas MD Anderson Cancer Center that was published in Science last year, melanoma patients with the healthiest gut microbiomes—that is, the greatest diversity of microorganisms—showed enhanced systemic and antitumor immunity as well as significantly increased odds of responding to immunotherapy.”
  • “The preliminary results [from an MD Anderson Study] showed that patients who reported taking an over-the-counter probiotic supplement had a lower probability of responding to immunotherapy as well as lower microbiome biodiversity. But those eating a high-fiber diet were about five times more likely to respond to immunotherapy and had high gut bacteria diversity, including bacteria previously linked to a strong immunotherapy response.”
  • “The cheapest and safest way to improve our microbiome and gut health is to make simple dietary changes to feed the development of good bacteria and crowd out the bad. There is no pill, special food, unique diet or quick fix for what ails our health and diet. The key is simply to focus on eating a diverse, whole-food, plant-centered, high-fiber diet.”

More information on studies alluded to above:

Related blog posts:

Probiotics -Lack of Efficacy for Acute Gastroenteritis (Part 2)

This blog post highlights a second study showing a lack of efficacy of probiotics for acute gastroenteritis.  Link to 2 minute Summary: Quick Take on Probiotics for AGE

My take: While some probiotic strains have been shown to be helpful in some conditions (eg. antibiotic associated diarrhea), this study indicates that probiotics are likely ineffective in altering the course of acute gastroenteritis.

SB Freedman et al. N Engl J Med 2018; 379:2015-2026 Link to abstract: Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis

Related blog posts:

One for the Probiotic Skeptics: Lack of Efficacy in Acute Gastroenteritis (Part 1)

My opinion has been that probiotics are generally over-hyped and are likely ineffective for many conditions in which they are commonly used (see related blog posts below).

A recent study (D Schnadower et al.N Engl J Med 2018; 379:2002-2014) provided more data to support this skeptical view when probiotics are utilized for acute gastroenteritis.  Another study in the same issue will be highlighted tomorrow and reaches a similar conclusion.

Link to Abstract: Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children

METHODS: We conducted a prospective, randomized, double-blind trial involving children 3 months to 4 years of age with acute gastroenteritis who presented to one of 10 U.S. pediatric emergency departments. Participants received a 5-day course of Lactobacillus rhamnosus GG … twice daily or matching placebo…

RESULTS Among the 971 participants, 943 (97.1%) completed the trial…There were no significant differences between the L. rhamnosus GG group and the placebo group in the duration of diarrhea (median, 49.7 hours in the L. rhamnosus GG group and 50.9 hours in the placebo group; P=0.26), duration of vomiting (median, 0 hours in both groups; P=0.17), or day-care absenteeism (median, 2 days in both groups; P=0.67) or in the rate of household transmission (10.6% and 14.1% in the two groups, respectively; P=0.16).

CONCLUSIONS Among preschool children with acute gastroenteritis, those who received a 5-day course of L. rhamnosus GG did not have better outcomes than those who received placebo

My take: While some probiotic strains have been shown to be helpful in some conditions (eg. antibiotic-associated diarrhea), this study indicates that probiotics are likely ineffective in altering the course of acute gastroenteritis.

Related blog posts:

 

Probiotics Lower Risk of Sepsis in Newborns

Summary of recent study from NPR: Probiotic Bacteria Can Protect Newborns from Deadly Infections

Previous studies have shown that probiotics lower the risk of necrotizing enterocolitis in premature infants.  Now, a study (full text link below) from India examines whether probiotics could lower other infections.

An excerpt:

Feeding babies the microbes dramatically reduces the risk newborns will develop sepsis, scientists report Wednesday in the journal Nature.

Sepsis is a top killer of newborns worldwide. Each year more than 600,000 babies die of the blood infections, which can strike very quickly…

Babies who ate the microbes [Lactobacillus plantarum] for a week — along with some sugars to feed the microbes — had a dramatic reduction in their risk of death and sepsis. They dropped by 40 percent, from 9 percent to 5.4 percent.

But that’s not all. The probiotic also warded off several other types of infections, including those in the lungs. Respiratory infections dropped by about 30 percent…

The only significant side effect seen in the study was abdominal distension, which occurred in six babies. But there were more cases reported in the placebo group than in the group that got the probiotic.

Full text link (thanks to Kipp Ellsworth’s twitter feed for this link): A randomized synbiotic trial to prevent sepsis in newborns in rural India. P Panigrahi et al.

My take: Whether probiotics would be useful broadly in full-term infants in developed countries is uncertain –more studies are needed.

Related blog posts:

 

Balanced Summary of Probiotics & Microbiome Effects on the Brain

A good updated summary on probiotics from 538 GutScienceWeek:

Do probiotics work? Are they good for me?

This link reviews a good deal of science and has a nice table explaining costs.

Take home message: Probiotics which vary greatly by strain and often lack rigorous production standards may be beneficial for specific conditions like preventing antibiotic-induced diarrhea but probably are not beneficial on an ongoing basis.

The final post in the series looks at How the Gut Affects Your Mood.

While the author explains that there is likely a microbiome effect on the central nervous system as well as some intriguing animal studies, it is too early to know that manipulation of the microbiome will have beneficial effects on neurological/developmental concerns.

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

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)?