This paper is part of the September 2016 Pediatrics Special Issue. Read the entire issue or download it.
August 31, 2016
IBS and Probiotic Treatment in Pediatric Patients
Effects of Lactobacillus rhamnosus GG on pain and function
Study finds Lactobacillus rhamnosus GG significantly reduces pain severity after one week and significantly improves functional ability after two weeks in children 4 to 18 years old.
Kianifar H, Jafari SA, Kiani M, et al. Probiotic for irritable bowel syndrome in pediatric patients: a randomized controlled clinical trial. Electron Physician. 2015;7(5):1255-1260.
Randomized, double-blind, placebo-controlled trial
Fifty-two children, 4-18 years old (25 female, 27 male) all had active abdominal pain for at least 2 weeks before entering the study. All participants were diagnosed by a pediatric gastroenterologist using Rome III Criteria for irritable bowel syndrome (IBS) with other differential diagnoses excluded by laboratory, abdominal ultrasound, radiographic imaging, endoscopy, and hydrogen breath test as required. Exclusion criteria included any medication use and any underlying diseases
Severity of pain; functional changes (eg, disruption of social activities, need to see a doctor, use of medications, days absent from school); and variables that could induce abdominal pain (eg, gastroenteritis, abdominal pathologies, life events) were primary outcomes. A validated scale (Likert scale) was used to specify severity of the pain from 0 to 5, with 5 being most severe. A 3-point Likert scale was used to assess function changes (1-decrease, 2-no change, 3-increase). Secondary outcomes were changes of the functional scale, stool patterns, and associated problems (eg, headache, limb pain, sleep problems).
Lactobacillus rhamnosus GG at 1x1010 CFU/mL or placebo of inulin (also in treatment capsule), 1 capsule twice daily for 4 weeks. Capsules were the same size, color, and taste.
There were 52 evaluable participants at the study conclusion. Of the 60 initial participants, none discontinued due to reaction to treatment or placebo. The mean age of the children evaluated was 7.1 years old. Their most common type of IBS was alternating constipation and diarrhea, experienced by 16 children in the placebo group and 15 in the treatment group. Of the remainder, 6 in the placebo group and 6 in the treatment group had mostly constipation, and 4 in the placebo group and 6 in the treatment group had mostly diarrhea.
Pain severity decreased significantly in the treatment group versus the placebo group after 1, 2, 3, and 4 weeks of treatment (P=0.01, 0.00, 0.00, 0.00, respectively). There was significant improvement in the functional scale after 2 weeks in the treatment group (P<0.00). There was no significant change in stool consistency or associated problems over the 4 weeks (P>0.1).
This study demonstrated that Lactobacillus GG 1x1010 CFU/mL twice daily can significantly reduce pain in pediatric IBS after 1 week and improve functional ability after 2 weeks, but the probiotic had no significant effect on stool consistency or associated health problems at the end of 4 weeks.
This was a well-designed study, but the lack of reporting all outcome measures as well as the statistical analysis weakened it considerably. The functional Liker scale was not presented, so that data is not available to evaluate. The significant P values reported as 0.00 are either errors, typos, or otherwise incorrect. The lack of significant change in stool habit is disappointing but not uncommon in IBS studies. The short length of this study may be a factor; in clinical, practice stool consistency changes can occur over the long-term.
Lactobacillus rhamnosus is naturally found in the gastrointestinal tract and the healthy female genitourinary tract. It also is used in yogurt and other fermented dairy, as well as semi-hard cheeses. Sherwood Gorbach and Barry Goldin isolated this species in 1983 from the intestinal tract of a healthy human. They sought a beneficial bacteria that would colonize, survive an acid environment, and out-compete pathogenic bacteria. On April 17, 1985, they filed for a patent of Lactobacillus acidophilus GG (from the first letter of their surnames) as ATCC 53103 (American Type Culture Collection). It was later reclassified as Lactobacillus rhamnosus GG (ATCC 53103). It is considered the world’s most studied probiotic bacteria.1 It can survive the acid and bile of the stomach and small intestine to colonize the digestive tract,2 stop peanut allergic reactions in most children,3 prevent rotavirus diarrhea in children,4 and reduce abdominal pain in children.5 It also has the potential to stop respiratory tract infections in children at daycare.6
Russian Nobel laureate Ilya Ilyich (Elie) Metchnikoff, professor at the Pasteur Institute in Paris, proposed in 1906 that one could modify the gut flora, replacing harmful bacteria with beneficial bacteria.7 He further proposed that the aging process resulted from the activity of putrefactive or proteolytic bacteria that produced toxins in the large bowel. The compound produced by this activity caused autointoxification and the physical changes associated with aging. His work sparked both controversy and research into the role of gut microbes and human health.
The controversy surrounding probiotics and their clinical effects is closely tied to the diverse species tested and the dosage used. A medium-size study (N=362) of encapsulated Bifidobacterium infantis 35624 compared 1x106, 1x108, 1x1010 CFU/mL in women with IBS over 4 weeks. The middle dose, 1x108, was significantly effective for abdominal pain, bloating, bowel dysfunction, incomplete evacuation, straining, and flatulence reduction.8 The other 2 doses were no better than placebo, and the largest dose had formulation issues. No adverse events were recorded. The authors concluded that the dose and dosage form were features of probiotic use that still needed clinical data and resolution.
A study of 141 children with IBS in 9 centers over 8 weeks used Lactobacillus rhamnosus GG or placebo for pain control. There was significant reduction in pain frequency (P<0.01) and pain intensity (P<0.01). These results were still significant at 12 weeks. When the trial began, 59% of the children had abnormal intestinal permeability. At the end of the trial the treatment group had a significant reduction (P<0.03) in intestinal permeability.5
A current review article argues that since up to 50% of orally ingested strains survive gastric passage, ingested bacteria can impact resident communities by trophic interactions such as competition for substrate; a direct alteration of fitness (eg, competitive exclusion, physical displacement, vitamin production); or an indirect alteration of fitness (eg, altered production of host-derived molecules, bile salt alteration).9 Alteration of bile salts determines the fitness of the bowel, the expression of some bacteria, and the risk for some diseases. Some studies show increased short-chain fatty acids that coincide with increased lactic acid bacteria and/or Bifidobacterium species. Supplementation with Bifidobacterium can directly stimulate butyrate producers that utilize acetate or lactate. Decreased butyrate production and the subsequent bloom of proteobacteria is associated with IBS, inflammatory bowel disease (IBD), and type 2 diabetes.9
There is a need for studies that that identify specific probiotic-induced changes in the gut. Giving Lactobacillus rhamnosus GG, and L Casei Shirota can increase Bifidobacterium populations.10 Administration of 1x109 CFU/mL Lactobacillus rhamnosus GG from birth to 6 month increased Lactobacillaceae and Bifidobacteriaceae. It also resulted in more community “evenness,” a greater diversity of species, and less risk of developing allergic disease. Starting with a healthier bowel may reduce the risk for IBS, IBD, and other microbial dysbiotic conditions.
Another study of pediatric IBS based on Rome III criteria in children 4 to 18 years old (66 boys, 137 girls) used Symbioflor® 2 (SF2). SF2 consists of both living and non-living Escherichia coli, 1.5-4.5x107 CFU/mL.11 The dose was 10 drops for those ages 4 to 11 and 30 drops for those ages 12 to 18 for 40 to 50 days (mean=43 days). Clinical benefits were significant improvements in abdominal pain, stool frequency, bloating, mucous, blood in stool, need for straining, and urge to defecate. The study lacked a control group, so a randomized, placebo-controlled trial is required to verify clinical effect. These results do suggest that there is more than one probiotic approach to treating IBS.
Lactobacillus rhamnosus GG has been shown in a randomized, double-blind, placebo-controlled clinical trial to lessen abdominal pain and improve functional ability in children 4 to 18 years old with Rome III–defined IBS. The dose was 1x1010 CFU/mL twice daily. The unknowns for clinicians are how the subjects’ gut microbes were altered to achieve this effect and how L rhamnosus GG compares to other probiotic species or species combinations. The unfortunate finding is the lack of change in stool consistency at the end of the 4-week trial. Given the risk/benefit analysis easily tips the scale in favor of the intervention, it may only be through time and trial that clinicians learn if this treatment warrants endorsement.
- Silva M, Jacobus NV, Deneke C, Gorbach SL. Antimicrobial substance from a human Lactobacillus strain. Antimicrob Agents Chemother.1987;31(8):1231-1233.
- Conway PL, Gorbach SL, Goldin BR. Survival of lactic acid bacteria in the human stomach and adhesion to intestinal cells. J Dairy Sci. 1987;70(1):1-12.
- Tang ML, Pnosonby AL, Orsini F, et al. Administration of a probiotic with peanut oral immunotherapy: a randomized trial. J Allergy Clin Immunol. 2015;135(3):737-744.
- Canaani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhea in children: a randomised trial of five different preparations. BMJ. 2007;335(7615):340.
- Francavilla R, Miniello V, Magista AM, et al. A randomized controlled trial of Lactobacillus GG in children with functional abdominal pain. Pediatrics. 2010;126(6):e1445-1452.
- Hojsak I, Snovak N, Abdovic S, Szajewska H, Misak Z, Kolacek S. Lactobacillus GG in the prevention of gastrointestinal and respiratory tract infections in children who attend day care centers: a randomized, double-blind, placebo controlled trial. Clin Nutr. 2010;29(3):312-316.
- Metchnikoff II. The Prolongation of Life: Optimistic Studies. 1906. English translation by PC Mitchell 1908. Putnam Books. New York.
- Whorwell PJ, Altringe L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101(7):1581-1590.
- Derrien M, van Hylckama Vlieg JET. Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends Microbiol. 2015;23(6):354-366.
- Sanders ME. Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroenterol. 2011;45(3):S115-S119.
- Martens U, Enck P, Zieseniss. Probiotic treatment of irritable bowel syndrome in children. Ger Med Sci. 2010;8:1-15.