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MICROBIOTA AND DEVELOPMENT OF GI FUNCTION AND INFLAMMATION
Università degli Studi di Bari “Aldo Moro”
U.O. Gastroenterologia Pediatrica Policlinico di Bari – Giovanni XXIII
FLAVIA INDRIO
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The Versatile Intestine: The intestine is not only a digestive-absorptive organ
Largest immune
organ of the body.
Harbors a huge
microbial
ecosystem.
Harbors the enteric
nervous system
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Intestinal Surface Area
The intestinal
surface area is the
largest of the body
and approximates
that of a tennis
court (250 m2).
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Digestion and absorption of nutrients. Maintenance of hydroelectric
homeostasis Regulation of peristalsis Modulation of immune response Production of neuroendocrinal signals Microbiota
INTESTINAL FUNCTIONS
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Growth in Length
• Human fetal intestine elongates
1000 fold from 5-40 weeks.
• Length doubles in last 15 weeks of
gestation.
• Mean length at birth (term) is 275
cm. (small intestine is about
200cm).
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Capability for Digestion,
Absorption and Assimilation
• Digestion-occurs in lumen.
• Absorption-occurs at the enterocyte interface
(microvillus membrane).
• Assimilation-occurs in the enterocyte and
beyond.
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Digestion, absorption and motility in relation to fetal and neonatal development
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The Intestinal Microbiome
Neish, A. Gastroenterology vol. 136,No. 1, 2009
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Brandtzaeg, Immunological Investigations 2010
F
F
FAE
Gut-Associated Lymphoid Tissue structures are strategically situated in relation to the greatest concentration of microbiota
• Peyer’s patches: distal ileum (nos. 100-250) • Isolated lymphoid follicles (ILFs): large bowel (nos.
~ 30 000)
GUT ASSOCIATED LYNPHOID TISSUE
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Jasarevic Endocrinology 2015
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Human Milk Formula
Increased Bifidobacteria Increased Folate
Increased DNA Methylation
Increased Firmicutes
Increased Histone Deacetylation
Decreased Gene Transcription
Increased Gene Transcription
Epigenetically Induced Metabolic Changes
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INTESTINAL MOTILITY
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Migration of neural crest precursor cells (NCC) into gut
Proliferation of NCC within the gut to ultimately form millions of ENS cells
Assembly of NCC into groups (myenteric ganglia, submucosal ganglia)
Differentiation of NCC into a range of enteric neuronal types and glial cells
Formation of the functional circuitry necessary for controlled gut activity
Post-natal modifications to adapt to a changing gut environment
Key steps in ENS development
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Development of smooth muscle and ENS in human gut
GREEN - SMA
RED – p75 (NCC)
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10 16 22 28 34 40
Weeks Gestation
Nerves / Muscles / ICCs present
Intestinal motor
activity
Swallow
Sucking
Organised activity
Courtesy of Prof. Peter Milla
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Dietary modifications - effects on proportions of neurons
and gut motility
Stress/inflammation – changes in ENS in e.g. maternal
separation model
ENS damage/injury – chemical ablation of myenteric plexus
POSTNATAL MODIFICATION OF ENS
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SHORT-CHAIN FATTY ACIDS REGULATE ENTERIC NEURONS AND
CONTROL GI MOTILITY
SCFAs are generated in the large intestine as a result of bacterial fermentation of dietary fiber and resistant starch. Butyrate increased the proportion of ChAT-immunoreactive (IR) myenteric neurons in vivo. Butyrate also increased colonic transit and neuronally mediated contractile response in the colon.
From: Soret et al., 2010. Gastroenterology 138:1772–1782
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NEUROIMMUNE INTERACTION
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Close apposition between
mast cells and PGP9.5
fibres – similar to that seen
in IBS
Barreau F et al. Gut 2008;57:582-590
LONG-TERM ALTERATIONS OF COLONIC NERVE–MAST CELL
INTERACTIONS INDUCED BY NEONATAL MATERNAL DEPRIVATION
IN RATS
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Commensal microbes affect the neural network responsible for controlling stress responsiveness
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Extrinsic Neural Regulation of Antroduodenal Motor Activity in Preterm Infants Youhanna Al-Tawil, George Klee and Carol Lynn Berseth
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Horm Metab Res 2004; 36(11/12): 735-741
A Centenary of Gastrointestinal Endocrinology J. F. Rehfeld
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THE INTESTINE THE NEGLECTED ORGAN….
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ILEAL EXPRESSION OF TYROSINE HYDROXILASE AND VASOACTIVE INTESTINAL PEPTIDE ( neuronal density) AFFECTED BY DIET ( prebiotic
composition)
Berding et al JPGN 2016
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GUT BRAIN COMUNICATION
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MARCH 2015
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INTESTINAL PERMEABILITY
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DNA methylation in genetically identical C57 wild-type mice under either conventional (CNV) or germ-free (GF) conditions. Different methylation happen in the whole colon
Yu et al 2015
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Plos ONE May 2015
INTERAZIONE TRA DIETA MICROBIOTA E MOTILITA’
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Kraiczyet al 2015
Different DNA methylation and Protein expression in Fetal and Pediatric intestinal epithelium
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Relation between intestinal function and microbiota
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60 preterm (GA 28-32wks) were enrolled in the study and double-blind assigned to receive either L. reuteri at dose of 1x108 CFU a day or placebo for 30 days.
Was recorded:
- Days on parenteral nutrition,
- Days of hospital stay
- Number of days of antibiotics
- Gastric emptying rate at 1 month of life
- Fecal cytokines and fecal calprotectin at 1 month of life
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RESULTS ON MOTILITY
Gastric emptying rate was significantly increased and fasting antral area riduced in the newborns receiving supplemention with L. reuteri.
Submitted
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Results on fecal cytokine
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CLINICAL FEATURES
SUBMITTED
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Take Home Messages
• The Developing GI tract is complex and is much
more than an organ of digestion and absorption.
• The premature intestine is capable of significant
but limited digestion and absorption. Motility is
be limiting but all of these functions are
stimulated with enteral feeding.
• The role of microbiota is crucial and driving the
changes in the intestinal colonization could
improve intestinal maturation .
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