THE EFFECTS OF PROBIOTICS ON FEEDING TOLERANCE,BOWEL HABITS AND GASTROINTESTINAL MOTILITY IN PRETERM NEWBORNS FLAVIA INDRIO, MD Department of Pediatrics University of Bari, Italy LECTURE OUTLINES • Possible mechanisms for the effects of probiotics on intestinal motility. • Structure controlling intestinal motility • Study techniques • Our study on preterm newborns ACTIVITIES OF PROBIOTICS • Human origin • Non pathogenic • Resistance • Stability at different pH • Adhesion to epithelial receptors • Resistance in the intestine • Production of antimicrobial substances • IMMUNE MODULATION • METABOLIC EFFECTS BACKGROUND Why the probiotic should have effect on intestinal motility ? HOW DO BACTERIA COULD INTERACT WITH THE MECHANISM OF MOTILITY? RELATIONSHIP BETWEEN MICROFLORA AND GALT Development of Intestinal Angiogenesis With Microbes • Villi from (P14) versus (P28) conventionally raised mice. • Capillary networks are stained green (FITC). Stappenback, Hooper and Gordon, PNAS, 2002 Delayed Colonization: Development of Intestinal Angiogenesis With Microbes Stappenback, Hooper and Gordon, PNAS, 2002 INTESTINAL PUMP Mechanisms of interaction between the microflora and intestinal motility • RELEASE OF BACTERIAL METABOLITES (SCFA) • INTESTINAL NEUROENDOCRINE FACTORS • EFFECTS OF MEDIATORS RELEASED BY THE GASTROINTESTINAL IMMUNE SYSTEM SCFA Bacterial metabolites (SCFA) have metabolic effects on blood lipids and carbohydrates and seem to stimulate smooth muscle cellular calcium influx. The role might be to co-regulate the motility of the upper intestine. IMMUNE MODULATION AND MOTILITY DISORDERS ENTERIC NERVOUS SYSTEM “neuroimmune interaction” Cellular mechanism Humoral mechanism Antineuronal Antibody Receptors (the well known entities are intestinal pseudobstructive disorders, IBS, post operative ileus) IMMUNE MODULATION AND MOTILITY DISORDERS ENTERIC SMOOTH MUSCLE basically due to an inflammation of the GI mucosa rather than a inflammation of a muscle layer itself (mediated by TGF- beta and prostaglandin E2) IMMUNE MODULATION AND MOTILITY DISORDERS INTERSTITIAL CELLS OF CAJAL ganglioneuritis atrophy and vacuolar degeneration could be present METHODS OF STUDY MOTILITY Modification of gastric electric potential (EGG) Movement of the intestinal wall: ultrasound and radiology Modification of the pressure: manomety Movement of the content: GI transit EGG PARAMETERS mean frequency and dominant frequency(DF) instability coefficient the percentage of DF defined as normal, bradygastric and tachygastric power ratio Esempi di tracciati =Time x 64 s Normale Bradigastria Tachigastria ULTRASOUND PARAMETERS Gastric emptying time Gastric emptying rate Fasting antral area PILOT STUDY DOUBLE BLIND PLACEBO-CONTROLLED • L. reuteri for 30 days • evaluation of the symptoms after the treatment • Gastric emptying rate with ultrasound and EGG at time 0 and after 30 days of treatment • Daily diary with all gastrointestinal symptoms and tolerance CLINICAL PARAMETERS • regurgitation • vomiting • “stool frequency” • weight gain • anthropometric data • air colic (daily crying time) Demographic characteristics of the newborns Breast feed infant (BF) Formula feed infants +placebo Formula feed infants + (n° 10) (FP) (n° 10) Lact.Reuteri (FR) (n° 10) Mean gestational age 34 ± Mean gestational age 34 ± 1.06 Mean gestational age 34 ± 1.13 1.26 Birth weight (g) 1920 ± 491.2 Birth weight (g) 1850 ± 342.2 Birth weight (g) 1890 ± 432.1 Apgar score 8.76 ± 0.78 Apgar score 8.82 ± 0.78 Apgar score 8.92 ± 0.29 Male/Female 8/2 Male/Female 7/13 Male/Female 14/6 Vaginal/cesarian delivery 3/7 Vaginal/cesarian delivery 4/6 Vaginal/cesarian delivery 5/5 Values are given as mean and SD. P=NS Mean of daily weight gain 45 40 35 30 Weigth gain/day ( gr) 25 20 15 10 5 0 Breast feed infant (BF) Formula feed infants +placebo (FP) Formula feed infants Lactobacillus Reuterii (FR) p=NS Number of feeds /day 7 6 5 Number of feed/day 4 3 2 1 N.A. 0 Breast feed infant (BF) Formula feed infants Formula feed infants +placebo (FP) Lactobacillus Reuterii (FR) Mean daily episodes of regurgitation 6 5 4 REGURGITATION 3 2 1 0 Breast feed infant (BF) Formula feed infants Formula feed infants +placebo (FP) Lactobacillus Reuterii (FR) P<0.01 Mean daily number of evacuation 6 5 NUMBER EVACUATIONS 4 3 2 1 0 Breast feed infant (BF) Formula feed infants Formula feed infants +placebo (FP) Lactobacillus Reuterii (FR) P<0.01 Mean of daily crying time 120 100 Crying time (min/day) 80 60 40 20 0 Breast feed infant (BF) Formula feed infants Formula feed infants +placebo (FP) Lactobacillus Reuterii (FR) P<0.01 Mean daily episodes of vomiting 3 2,5 2 VOMITING 1,5 1 0,5 0 Breast feed infant (BF) Formula feed infants Formula feed infants +placebo (FP) Lactobacillus Reuterii (FR) p<0.01 EGG values in preterm newborns fed formula with placebo , formula with Lactobacillus reuteri, and breast feeding after 30 days of administration Breast fed infant (BF) Formula fed infants Formula fed infants +placebo (FP) Lactobacillus reuteri (FR) Preprandial EGG Dominant frequency 2.9[2,7-2,9] 3.0[2.5-3.2] 3.1[2.6-5.8] Instability coefficient 41.2[34-47] 35[34-54] 43.8[39-50] % Bradygastria 25.8[22-36] 22.5[11-22] 29.0[19-32] % normal slow waves 57.1[47-70] 64.5[40-74] 54.8[51-61] % Tachygastria 9.6[5.9-15.6] 12.9[3.2-32] 14.5[6.4-16.1] Postprandial EGG Dominant frequency 2.9[2.5-3.2] 2.9[2.7-3.1] 3[2.7-3.3] Instability coefficient 35.5[33.9-43.2] 51.1[20.9-81.3] 39.3[35.1-45.2] % Bradygastria 24[12-38] 26.2[12.5-49] 20.9[16.1-32.2] % normal slow waves 64[47.5-77.2] 66.1[44.7-87.5] 67.7[54.8-70.9] % Tachygastria 12.9[5.8-15.7] 6.4[0-12.9] 12.9[9.6-16.1] Power ratio 1.5[0.9-1.7] 1.3[1.3-1.3] 1[0.6-1.8] Fasting antral area recorded from the three groups of newborns after 30 days of intervention diet. 1 .7 5 Fasting antral area (cm ) 2 1 .5 0 1 .2 5 1 .0 0 0 .7 5 0 .5 0 0 .2 5 0 .0 0 o LR ilk b tm ce a+ la ul as p rm re a+ Fo B ul rm Fo Gastric emptying rates recorded from the three groups of newborns after 30 days of intervention diet. 100 75 % GE rate 50 25 0 LR i lk o eb m a+ ac t ul as pl rm re a+ Fo B ul mr Fo Fo Fasting antral area (cm2) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 rm ul a+ LR B re as tm Fo ilk rm ul a+ Fasting antral area pl ac eb o % GE rate Fo 0 25 50 75 100 rm ul a+ LR B re as tm Fo ilk rm ul a+ pl ac eb Gastric emptying rate o CONCLUSIONS Clinical effects • reduction of the daily number of regurgitation • reduction of the daily crying time (air colic) • increased number of evacuations CONCLUSIONS EFFECTS ON MOTILITY • faster gastric emptying rate • smaller fasting antral area • reduction of gastric residual • improved colonic motility CONCLUSIONS No side effects Safety and tolerance in preterm The Effects of Probiotics on Feeding Tolerance, Bowel Habits, and Gastrointestinal Motility in Preterm Newborns FLAVIA INDRIO, MD, GIUSEPPE RIEZZO, MD, FRANCESCO RAIMONDI, MD, MASSIMO BISCEGLIA, MD, LUCIANO CAVALLO, PROF, AND RUGGIERO FRANCAVILLA, MD, PHD Probiotic supplements for preterm infants There are now a number of trials demonstrating that live bacteria, similar to those found in human milk (probiotics), may decrease the incidence of necrotizing enterocolitis when fed to very preterm infants. There are no studies of the physiologic effects of these organisms on gut function. In this issue of The Journal, Indrio et al report their measurements of clinical symptoms and gastric electrical activity and emptying in infants at about 34 weeks gestation. These results suggest physiologic differences in GI function with lactobacillus supplementation. Ultimately, any routine clinical use must await information about which probiotic organisms should be given, at which dose, and for how long. –Alan H. Jobe, MD, PhD Summary • Intestinal microbes have major roles in various aspects of intestinal development and motor function during infancy. • Manipulation of the microbes may have unforeseen long term effects that may be beneficial. • In the the probiotics could act as a surrogate to promote the intestinal colonization • We still have a lot to learn about intestinal microbes and their interactions with the developing host to manipulate them safely, especially in select groups, e.g. premature infants .