The enthusiasm for probiotics is generally greater than expected based on the data available to support their use for many indications. This has been discussed several times on this blog (see below). The reasons why probiotics are sometimes not effective can be related to being poorly regulated/lack rigorous production standards; even in conditions in which there is some effectiveness (eg. antibiotic-associated diarrhea [AAD]), the number of persons needed to treat for one person to benefit is fairly high. Furthermore, as a recent study (A Olek et al. J Pediatr 2017; 186: 82-6) shows, even in conditions like AAD in which probiotics have proven efficacy, the effects may be strain-specific and/or dose-related.
Olek et al showed that Lactobacillus planatarum DSM9843 (LP299V) was NOT beneficial compared to placebo in reducing the incidence of loose/watery stools or mean number of stools among 438 children receiving outpatient antibiotic therapy.
Specifics: This was a prospective, double-blind, randomized, placebo-controlled parallel-group study. The treatment group received LP299V during antibiotic therapy and for 1 week afterwards. In addition to monitoring the number of stools, the authors determined the frequency of AAD which they defined according to WHO guidelines (>3 loose/watery stools/24 hours after initiation of antibiotics). In this study, AAD was confined to study duration rather than over 2 months.
- Overall, 44.5% of children developed loose/watery stools among placebo group and 39% among probiotic group
- 4.1% developed AAD among placebo group and 2.8% among LP299V
- LP299V showed no significant beneficial effects in reducing AAD or loose/watery stools
The authors note that LP299V has been effective in studies involving adult hospitalized patients. They question whether healthy children, therefore, may be less likely to benefit from probiotics and whether a higher dose could have been more effective.
My take: “Data from clinical studies on probiotics are conflicting” for many conditions, including antibiotic-associated diarrhea.
Lovers Leap, near Ashville (Appalachian Trail)
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In a recent study (O Jadresin et al. JPGN 2017; 64: 925-9), 55 children with functional abdominal pain or irritable bowel syndrome were randomized (prospective, double-blind, placebo-controlled study) to either L reuteri DSM or placebo.
- The intervention group had more days without pain: median 89.5 days vs. 51 days (P=.029)
- Abdominal pain was less severe in the intervention group at some time points (second month, and fourth month)
- The two groups did not differ with regard to duration of abdominal pain, stool type, or absence from school
Limitation: Small number of patients -the estimated samples size was not reached
My take: This study suggests that probiotics may help some pediatric patients with irritable bowel syndrome. Trying to identify which patients should receive a probiotic and which probiotic should be selected remains unclear.
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Pierre Renoir’s portrait of Claude Monet, Musee d’Orsay
Families are often surprised to learn my opinion about probiotics. The “truth” about probiotics is that they are poorly regulated/lack rigorous production standards and are mostly ineffective for many of the conditions for which they have been promoted. Even in conditions in which there is some effectiveness (eg. antibiotic-associated diarrhea), the number of persons needed to treat for one person to benefit is fairly high.
In addition, when someone says that they are taking a probiotic, many families do not understand the idea of “strain” specific effects. I tell families that if they see a “dog in yard” sign that they do not know if that is a poodle of a pit bull. With probiotics, similarly you often do not know if you are getting a pit bull or a poodle.
As a consequence, I think negative studies like a recent report (K Wojtyniak et al. J Pediatr 2017; 184: 101-05) are helpful. In this study, the authors examined the effectiveness of Lactobacillus casei rhamnosus Lcr35 (Lcr35) in the management of constipation.
This randomized, double-blind, placebo-controlled trial was conducted in 94 children <5 years of age. Dose: 8 x10 to the 8th CFU twice daily x 4 weeks.
- “Lcr35 as a sole treatment was not more effective than placebo in the management of functional constipation.” In fact, the placebo group had a greater increase in bowel movement frequency than the treatment group.
- Both groups had improvement -more than half in each group (total 52 of 81 who completed study) had reached endpoint of 3 or more BMs/week without soiling.
My take: Probiotics often are ineffective. This study showed that Lcr35 was NOT helpful for pediatric constipation.
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Claude Monet, La Rue Montorgueil
Probiotics and alterations in the microbiome are being examined for a range of ailments. However, as noted in previous blog posts, the current evidence shows only a limited number of disorders where probiotics have been proven effective. There is more evidence, now, that probiotics may be beneficial for nonalcoholic fatty liver disease (NAFLD).
- Am J Clin Nutr 2014; 99: 425-6. editorial
- Am J Clin Nutr 2014; 99: 535-42.
The referenced article examined 52 nondiabetic patients with fatty liver disease in a double-blind, randomized, placebo-controlled trial. Patients were considered to have NAFLD on the basis of an ultrasonography and an alanine aminotransferase value >60 U/L. Those who received a probiotic were compared with a placebo group and followed for 28 weeks.
In this study, rather than a probiotic, technically, the treatment group received a synbiotic because it contained fructooligosaccharides (FOS) which are non digestible oligosaccharides in addition to a probiotic mixture. FOS can stimulate the growth of intestinal bacteria. The probiotic mixture included Lactobacillus case, Lactobacillus rhamnosus, Streptococcus thermopiles, Bificobacterium breve, Lactobacillus, acidophilus, B. longum, and Lactobacillus bulgaricus.
- There were improvements in ALT values and in baseline mild fibrosis (estimated by Fibroscan).
- There were decreased levels of circulating TNF-α and decreased nuclear transcription factor κβ in circulating mononuclear leukocytes –both consistent with decreased systemic inflammation
- Study did not include liver histology (biopsy). In addition, in nearly all subjects, the fibroscans were near normal, both before and after the intervention. Thus, the reduction in liver stiffness is not clear cut.
- Small number of participants.
- Short study period.
Bottomline: This study along with several others points towards a potential role for modulating the microbiome to improve NAFLD along with metabolic syndrome more broadly.
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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.
- 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.
These results could explain why administration of probiotics (and possibly antibiotics) can result in a decrease in colic symptoms.
Related blog entries:
- -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.
Recent developments in necrotizing enterocolitis (NEC) have focused on the potential role of new biomarkers and preventive strategies (JPEN 2012; 36: 30S-35S). In this report, the clinical/diagnostic features of NEC are reviewed:
- classic form develops between 29-32 weeks corrected gestational age
- features include feeding intolerance, abdominal distention, bloody stools
- imaging features: pneumotosis intestinalis, portal venous gas, paucity of gas, fixed bowel loops
- full term or late NEC usually occurs in the setting of risk factors like congenital heart disease, exchange transfusions, gastroschisis, and neural tube defects
- spontaneous intestinal perforation due to glucocorticoids or indomethacin may be confused with NEC. It usually occurs earlier than NEC
This review describes the potential for new biomarkers, including urinary I-FABP & fecal calprotectin. These assays would need to be available with very short turn-around time given the often rapid development of NEC.
Finally, this articles discusses the evidence for preventive measures. Human milk has been shown to decrease NEC and gradual introduction of feedings remains important. With regard to microbial colonization, NEC does not occur until at least 8-10 days postpartum coincident with anerobic bacterial colonization of intestinal tract.
This has led to attempts to alter the colonization to decrease NEC incidence. 16 randomized controlled trials with 14 different probiotics have been completed. Most are underpowered. “The available trials do not permit a decision to be made with respect to optimum strain, dosing, or protocol.” In a cautionary note, a preterm pig model demonstrated an increase NEC incidence with the use of a specific probiotic (Pediatr Res 2011; 69: 10-16). Furthermore, probiotics are plagued by a lack of adequate quality control.
- -Ann Surg 2010; 251: 1174-80. Non-invasive biomarkers for NEC.
- -J Peds 2011; 158: 672-74. Caution advised with probiotics for NEC.
- -J Peds 2011; 159: 392. n=124 cases (248 controls). retrospective study suggested that abx exposure is a risk factor for NEC (3-fold risk). Abx -marker for illness or true predisposing factor?
- -NEJM 2011; 364: 255-64. NEC review.
- -Cochrane Database Syst Rev 2011; 3: CD005496. Probiotics for NEC.
- -NEJM 2011; 364: 1877. Probiotics likely helpful in preemies with birth wt >1000gm.
- -NEJM 2010; 364: 255.
- -Pediatrics 2010; 125: 921-30. Meta-analysis of probiotics for NEC.
- -JPS 2009; 44: 1072-76. Mortalitiy of NEC expressed by birth weight.
- –Pediatrics 2008; 122: 693-700. Multicenter trial of probiotics in VLBW for NEC prevention.
- -J Pediatr 2008; 153: 339. Cluster of NEC due to norovirus.
- -Pediatrics 2007; 119; e164. Rate of 0.4% among large cohort of infants w/o indocin, steroids & w slow delayed feedings.
- -Pediatrics 2006; 117: e137. H2-blockers associated with increased NEC (?causal)
- -Pediatrics 2005; 116: 1064. CRP helpful. If CRP was persistently normal, antibiotics were aborted and enteral feeds restarted safely.
- -Pediatrics 2005; 115: 1-4 & 171 editorial. Probiotics decreased NEC in this study.
- -J Pediatr 2003; 143: 543. Images of pneumotosis.