Favorite Posts of 2020

These are some of my favorite posts of the past year.

Humor:

GI:

Endoscopy:

Liver:

Nutrition

COVID-19:

Other:

From Picnic Island, Tampa Bay

Cochrane Review: Probiotics NOT Proven Effective for Acute Gastroenteritis

Collinson S, Deans A, Padua-Zamora A, Gregorio GV, Li C, Dans LF, Allen SJ. Link to website with PDF availability: Probiotics for treating acute infectious diarrhoea. Cochrane Database of Systematic Reviews 2020, Issue 12. Art. No.: CD003048. DOI: 10.1002/14651858.CD003048.pub4. Thanks to Kipp Ellsworth for this reference.

This review identified “82 studies in 12,127 people (included 11,526 children) with acute diarrhea.” Key findings:

  • The number of children with diarrhea longer than 48 hours was not different between those taking a probiotic and those taking a placebo
  • “It was unclear whether taking probiotics shortened the time spent in hospital compared with taking a placebo or no additional treatment .”

My take: Probiotics probably make little or no difference in the setting of acute gastroenteritis/diarrhea. This analysis is based on large trials with low risk of bias.

Related blog posts:

Why We Are Not Making Progress with Probiotics

A recent commentary A Khoruts et al. Gastroenterol 2020; 159: 409-413. Full text: Probiotics: Promise, Evidence, and Hope

Despite the fact that the probiotic industry has ample money which is projected to reach $70 billion yearly, there is very little high quality research.

Key points:

  • Probiotics are regulated by the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC). The FDA, unlike the FTC, regulates products by category (eg, foods, drugs, dietary supplements, medical devices, and cosmetics)…Foods and dietary supplements, unlike drugs, do not require FDA premarket approval. By law, probiotic foods and dietary supplements must be safe. However, food manufacturers are permitted to make a self-determination of whether their product meets the “generally recognized as safe” (GRAS) designation, typically based on history of prior use”
  • Probiotic food and dietary supplement manufacturers do not have to specify on their product labels the strains they use in probiotic products or specify the number of live microbes of each strain that the product delivers through the end of its shelf life; and, although they are required to have validation of label claims, they are not required to submit it to the FDA
  • Dietary supplements can make structure/function claims, even though they cannot claim to treat any specific disease. These claims can sound very promising and consumers may be hard pressed to distinguish between a statement that a product “improves digestion,” a structure/function claim that is so vague that it is literally untestable
  • Rational selection of donor microbiota should be possible based on microbiome-based diagnostics, as well as in vitro technologies that interrogate the functional potential of complex microbial communities. There are parallel, intensive efforts to develop defined microbial communities. A common theme among these different approaches is deployment of complex assemblages of microorganisms rather than single strains. Such complex consortia are likely to have more consistent and predictable effects.
  • The emergence of microbial therapeutics requires development of a new branch of pharmacology. The challenges of formulation, pharmacokinetics, and pharmacodynamics are very distinct from those of small molecule therapeutics or protein biologics.

My take: “These next-generation probiotics will need to be tested for safety and efficacy in well-designed and properly powered clinical trials.”  Probably the only way that will happen is to empower regulatory agencies to insist that these products are treated like medications.  Given the fact that probiotics are so profitable now with little evidence of efficacy for most strains, I am not optimistic about any changes in the near future.

Related blog posts:

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: