1 The irritable infant The irritable infant J. Marc Rhoads, M.D. J. Marc Rhoads, M.D. I have the following financial relationships to disclose: BioGaia, Inc.* $15,000 unrestricted gift for basic science research * Products or services produced by this company are relevant to my presentation. Agenda 1. What makes babies irritable? 2. What is colic? Etiology: Theories 3. Current treatment 4. Potential role of probiotics Causes of crying Causes of crying Cow milk protein Cow milk protein allergy allergy Esophageal reflux Esophageal reflux Dysphagia Dysphagia Dysphagia Dysphagia Dyschezia Dyschezia Normal infant Normal infant behavior behavior 2. What is colic? Wessel, “The Rule of Threes” Wessel, “The Rule of Threes” Pediatrics 1954 Pediatrics 1954 • > 3 hours/day > 3 hours/day • >3 days/week >3 days/week >3 days/week >3 days/week • >3 weeks >3 weeks • Gone during 3rd month of age Gone during 3rd month of age
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1
The irritable infantThe irritable infant
J. Marc Rhoads, M.D.J. Marc Rhoads, M.D.
I have the following financial relationships to disclose:
BioGaia, Inc.*$15,000 unrestricted gift for basic science research
* Products or services produced by this company are relevant to my presentation.
Agenda
1. What makes babies irritable?
2. What is colic? Etiology: Theories
3. Current treatment
4. Potential role of probiotics
Causes of cryingCauses of crying
Cow milk protein Cow milk protein allergyallergy
Esophageal refluxEsophageal reflux
DysphagiaDysphagia DysphagiaDysphagia
DyscheziaDyschezia
Normal infant Normal infant behaviorbehavior
2. What is colic?Wessel, “The Rule of Threes” Wessel, “The Rule of Threes”
•• Immaturity of nerves, muscles in GI tractImmaturity of nerves, muscles in GI tract
•• Allergy to dietary proteinAllergy to dietary protein
P ti b l i tP ti b l i t•• Poor parenting by overly anxious parentsPoor parenting by overly anxious parents
•• Wastebasket term that's used when we can't Wastebasket term that's used when we can't explain what's going on inside a babyexplain what's going on inside a baby
Increased macromolecular permeability in babies with colic
Lothe L et al. Acta Paediatr Scand 1990; 79: 417-21
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3. Current Treatment
Behavioral interventions.
Controlled trials of counseling and a car-ride simulation device: these interventions are nosimulation device: these interventions are no better than reassurance alone
• Parkin PC, Schwartz CJ and Manuel BA. Pediatrics 92: 197-201, 1993.
World’s Happiest Baby: H. Karp, MD• 5 S’s
QuizQuiz
•• Which medical treatment(s) have been Which medical treatment(s) have been shown to be beneficial in a randomized, shown to be beneficial in a randomized, controlled trial for babies with colic?controlled trial for babies with colic?
•• Which treatment(s) have been shown to be beneficial Which treatment(s) have been shown to be beneficial in a randomized, controlled trial for babies with colic?in a randomized, controlled trial for babies with colic?
Is Is L. reuteriL. reuteri an effective treatment an effective treatment for infant colic?for infant colic?
•• 90 breast90 breast--fed infants with colic fed infants with colic Age: 11Age: 11--80 days80 days
•• L. reuteri L. reuteri (10(1088 cfu/day) in sunflower oilcfu/day) in sunflower oil versus simethicone placeboversus simethicone placebo
•• L. reuteri L. reuteri decreased crying time decreased crying time 156 to 51 min./day156 to 51 min./day
Savino et al, Pediatrics 2007
Effectiveness of L reuteri versus placebo Study #2
Savino F et al. Pediatrics 2010;126:e526-e533
Evidence that microbiota may contribute to colic
Babies with colic have elevated fasting breath H2 values
Culture techniques identified increased Enterobacteriaceae and reduced Lactobacilli in infants with colic
Therapeutic administration of L. reuteri improved colic symptoms
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ALTERED FECAL MICROFLORA AND ALTERED FECAL MICROFLORA AND INTESTINAL INFLAMMATION IN BABIES INTESTINAL INFLAMMATION IN BABIES
WITH COLICWITH COLIC
Nicole Y Fatheree, BBA1, Michael J Ferris, PhD2, Johana Norori, MS2, Yuying Liu, PhD1, Joseph F Lucke, PhD1, Jon E Tyson, MD1 and Jon Marc Rhoads, MD1
1Pediatrics, University of Texas Health Sciences Ctr., Houston, Texas, United States and 2Pediatric Research Institute, Children's Hospital, New Orleans, LA, United States.
HypothesesHypothesesIn Babies with ColicIn Babies with Colic
•• Molecular analysis will show specific bacteria Molecular analysis will show specific bacteria
associated with colic and elevated breath Hassociated with colic and elevated breath H22
•• Fecal Fecal calprotectincalprotectin will show intestinal will show intestinal
Akkermansia muciniphila 100-99 X X X XBacteroides vulgatus 99-97 X X* X X*Bacteroides thetaiotaomicron 98 X XBifidobacterium adolescentis 99 XBifidobacterium bifidum 99 XBifidobacterium breve 100-99 X XBifidobacterium longum 96-99 X X X X X XBifidobacterium scardovii 100 XClostridium butyricum 97 XClostridium nexile 99 XClostridium ramosum 100 XClostidium clostridiiformis 96 XClostridium paraputrificum 100 XClostridium orbiscindens 96 XCl t idi f i X
Denaturing Gradient Gel Electrophoresis Analysis
Clostridium perfringens 100 XCoprobacillus catenaformis 99 X
Escherichia/Shigella/Enterobacter 100-99 X X X X X* X X* X X X X X X XEnterobacter sp. 100 XEnterobacter/Pantoea 99-98 X X X X* X X X X
Enterococcus faecalis 97 X X
Enterococcus sp. 98 X X* X X
Lactobacilli gasserii 100-98 X X
Lachnospiraceae sp. 95 X
Klebsiella sp. 99 X X*
Klebsiella pneumoniae 100-98 X X X X X X X
Proteus mirabilis 100 XStreptococcus salivarius 100-99 X X X X X XStreptococcus thermophilus 100 XTM7 phylum bacterium 99 X
Akkermansia muciniphila 100-99 X X X XBacteroides vulgatus 99-97 X X* X X*Bacteroides thetaiotaomicron 98 X XBifidobacterium adolescentis 99 XBifidobacterium bifidum 99 XBifidobacterium breve 100-99 X XBifidobacterium longum 96-99 X X X X X XBifidobacterium scardovii 100 XClostridium butyricum 97 XClostridium nexile 99 XClostridium ramosum 100 XClostidium clostridiiformis 96 XClostridium paraputrificum 100 XClostridium orbiscindens 96 XCl t idi f i 100 X
Denaturing Gradient Gel Electrophoresis Analysis
Clostridium perfringens 100 XCoprobacillus catenaformis 99 X
Escherichia/Shigella/Enterobacter 100-99 X X X X X* X X* X X X X X X XEnterobacter sp. 100 X
Enterobacter/Pantoea 99-98 X X X X* X X X X
Enterococcus faecalis 97 X X
Enterococcus sp. 98 X X* X X
Lactobacilli gasserii 100-98 X X
Lachnospiraceae sp. 95 X
Klebsiella sp. 99 X X*
Klebsiella pneumoniae 100-98 X X X X X X X
Proteus mirabilis 100 XStreptococcus salivarius 100-99 X X X X X XStreptococcus thermophilus 100 XTM7 phylum bacterium 99 X
Veillonella ratti 99 X X*
Fecal Calprotectin
•• Fecal calprotectin, a neutrophil product, is a Fecal calprotectin, a neutrophil product, is a
marker for gastrointestinal inflammation marker for gastrointestinal inflammation
•• Developed Developed v. v. developingdeveloping countriescountries•• Country Country v. v. citycity•• Birth at home Birth at home v. v. inin--hospitalhospital•• Premature Premature v. v. termterm•• Antibiotics Antibiotics v. v. nonenone•• Diarrheal illnessDiarrheal illness
Reduced bacterial diversity
Crohn’s disease
Celiac disease
Obesity
Subsequent development of eczema
Klebsiella
Pneumonia in the elderly alcoholic
Neonatal sepsis
Infant diarrhea
Ecchymotic colitis
Klebsiella
Rashid T and Ebringer A. Clin Rheumatol 2007;26:858-864
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Molecular identification of coliform bacteria from colicky breastfed
infants (Turin, Italy)
Savino F et al. Acta Paediatrica 2009; 98:1582-8
Phase II: Infant Colic StudyPhase II: Infant Colic Study
L reuteriflora
Lactobacilli
Klebsiella
? Other
Happy baby
↑
↓
L. reuteri Colonic
L. reuteri
PlaceboLactobacilli
Klebsiella
? Other
Infant with colic:•Flatulence•Abdominal distension•Insatiable appetite•Borborygmi•Poor sleep
↑
→
Placebo
• Lactobacillus reuteri▫ Biogaia as drops in sunflower oil▫ Orally qd for 8 weeks▫ Dose▫ Dose 0.2 ml, 1 x 108 c.f.u.
Placebo: sunflower oil
Potential mechanisms of probiotics?Potential mechanisms of probiotics?
• Competition with endogenous microbiota
• Bacterial products:• Reuterin
• Immune system “modulation”
• Barrier function• Mucin
• Tight junctions
• Improved gastric motility
Indrio F, J. Pediatr 2008;152:801-6
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Blood studiesToll-like receptors 2 and 4
Regulatory T-cells (Tregs)
In vitro stimulation of cytokine production in isolated peripheral blood mononuclear cells PBMC stimulation in vitro: via phorbol myristate PBMC stimulation in vitro: via phorbol myristate