The development of NEC and the gut-brain axis - more than gut feelings!

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4 th Special Interest Group NEC Meeting 2016 The development of NEC

Kramer, MD, PhD Neonatologist Director of Pediatric Research

Institute of Women s Health Maastricht University Medical Center,

1 4 th Special Interest Group NEC Meeting 2016 The development of NEC and the gut-brain axis - more than gut feelings! Boris W. Kramer, MD, PhD Neonatologist Director of Pediatric Research Professor of Neonatology Professor of Experimental Perinatology Institute of Women s Health Maastricht University Medical Center, Netherlands University College London, UK School of Oncology and Developmental Biology

3 Content - Basic idea(s) Gut-brain development - Animal data - Gut development, inflammation & immunmodulation and BEHAVIOUR - Clinical perspective: Follow-up data from preterm

4 Clinical scenario 24+2 week preterm baby, 5 days old, has not yet passed stools. Baby was born out clinical chorioamnionitis; Is fed with breast milk; Has been on antibiotics.

6 Organ injury - when, where, what effect? proinflammatory prenatal postnatal mechanical ventilation PDA sepsis chorioamnionitis resuscitation hyperoxia Hypoxia / Ischemia fetal gut 9 months 15 min - prematurity preterm gut weeks NEC antenatal steroids surfactant postnatal steroids Nutrition anti-inflammatory Gantert, Been, Garnier, Zimmermann, Kramer, J Perinatol Suppl:S21-30

7 Neonatology = where clinical care meets developmental biology Conception & In utero Infection Ventilation O 2 Organ Development Injury Repair Genetics Developmental Programming epigenetics Stem cell populations Preconditioning to modulate response to a stimulus Systemic immune modulation Postnatal drug effects Nutrition / Microbiome Normal Adverse Outcome

Paediatrics 1975;55:376-87 Risks of Neurodevelopment delay relating purely to the

8 Pathogenesis of NEC includes enteral feeding, gut ischaemia & bacterial infection Santulli et al. Paediatrics 1975;55: Risks of Neurodevelopment delay relating purely to the gut >90% of babies who develop NEC have been fed Genetic predisposition Luminal environment Intestinal immaturity Innate immunity Altered perfusion

9 2006 definition by International Society for Cellular Therapy (ISCT)

10 Gut feelings 100 million neurons in enteric nervous system More neural tissue in the gut than in spinal cord More than 30 neurotransmitters in gut and brain 95% body s serotonin is in the gut 90% traffic in vagus nerve is from gut to brain Over-complex just to move things out of colon

11 Brain development in Germ-free mice Reduced memory and reference memory Increased risk taking & exploratory behavior Chemistry changed: Increased turnover of dopamine and noradrenaline and 5-hydroxytryptamine Synaptophysin

12 In 1967, Abrams and Bishop showed that animals devoid of live microbes (germ-free) had decreased gut motility compared to animals harboring a conventional mouse microbiota (Abrams and Bishop, 1967).

14 Multiorgan disease of the fetus Control Chorioamnionitis Gantert, Been, Garnier, Zimmermann, Kramer, J Perinatol Suppl:S21-30

15 Innervation of the gut Control Chorioamnionitis Nikiforou et al., Science Rep., 2016

16 Microbiota and the gut brain axis Ingested nutrients induce secretion of gut peptides These peptides act by a paracrine or endocrine mechanism to signal the central nervous system Gut microbiota are known to be able to influence some of these pathway Appetite stimulation and suppression Mood behavior and anxiety Gut motility and motor function

17 Stiller et al., 2014

20 CRP impairs Blood-Brain-Barrier Figure 1. CRP disrupts the BBB in a time- and concentration-dependent manner. The effect of CRP on BBB integrity was examined using a coculture model of the BBB composed of either BBMVEC/rat astrocyte or ECV-304/C6. CRP induced a (A) time and (B) concentration (1 to 20 μg/ml) -dependent decrease of TEER values (initial value: 215.7±11.3 Ω cm 2 ), indicating a loss of barrier function. The arterial perfused isolated guinea pig brain (illustrated in a schematic drawing; C) was used to study the effects of CRP (10 μg/ml) in a complex model closer to the in vivo situation. Two-barrel micropipette in the entorhinal cortex (EC) used to record extracellular field potentials (EC FP) and extracellular potassium concentration (EC [K + ] 0 ). Traces in the lower panel show evoked potentials recorded in the EC of the in vitro-isolated guinea pig brain after stimulation of lateral olfactory tract (LOT) in control condition and after perfusion with CRP. D, Changes in [K + ] 0 induced by systemic perfusion of CRP (lower panel) or control vehicle (upper panel) are shown in the trace of a representative recording. Christoph R.W. Kuhlmann et al. Stroke. 2009;40:

21 CRP changes tight junctions CRP-induced rearrangement of ZO-1/occludin involves ROS and MLCK activation. The effect of CRP (20 μg/ml) on the distribution of the TJ molecules ZO-1/occludin was examined using ZO-1-specific immunostainings in cultured (A) BBMVEC, (B) ECV-304 and occludin-specific immunostainings in cultured (C) BBMVEC. TJ rearrangement was inhibited by apocynin (500 μmol/l) or ML-7 (10 μmol/l). The formation of paracellular gaps is marked by white arrows. Christoph R.W. Kuhlmann et al. Stroke. 2009;40:

22 CRP makes the Blood-Brain-Barrier permeable in vivo Cell Physiol Biochem. 2012;30(5):

23 Van Ganzewinkel, Acta Paed., 2016, in press

26 Van Ganzewinkel, submitted

28 Pain threshold Pain tolerance

31 Take home messages: - Low frequency of voiding of the gut may precede NEC - Innervation of the gut plus metabolites from the microbiome drive voiding - NEC survivors have a poor neurodevelopmental outcome pain?!

32 Thank you very much MUMC+ Prof. Dr. L.J.I. Zimmermann Dr. J. Been Dr. J. Collins Dr. R. Jellema Dr. Elke Kuypers Assoc. Prof. Dr. Tim Wolfs Drs. C. Ganzewinkel Würzburg Prof. Dr. C.P. Speer Prof. Dr. S. Kunzmann Funding NWO VENI School of Oncology and Developmental Biology School of Mental Health and Neuroscience NIH DFG Stichting Kindergeneeskunde Cincinnati Prof. Dr. A.H. Jobe Prof. Dr. S.G. Kallapur Thank you very much for Perth Prof. Dr. J. Newnham Dr. M. Kemp your attention!

Necrotizing Enterocolitis: The Role of the Immune System

Necrotizing Enterocolitis: The Role of the Immune System Patricia Denning, M.D. Associate Professor in Pediatrics Division of Neonatology Emory University School of Medicine What is NEC? What is NEC? Necrotizing