Gut-Brain Axis in the Early Postnatal Years of Life: A Developmental Perspective

Abstract

Emerging evidence suggests that alterations in the development of the gastrointestinal (GI) tract during the early postnatal period can influence brain development and vice-versa. It is increasingly recognized that communication between the GI tract and brain is mainly driven by neural, endocrine, immune, and metabolic mediators, collectively called the gut-brain axis (GBA). Changes in the GBA mediators occur in response to the developmental changes in the body during this period. This review provides an overview of major developmental events in the GI tract and brain in the early postnatal period and their parallel developmental trajectories under physiological conditions. Current knowledge of GBA mediators in context to brain function and behavioral outcomes and their synthesis and metabolism (site, timing, etc.) is discussed. This review also presents hypotheses on the role of the GBA mediators in response to the parallel development of the GI tract and brain in infants.

Keywords: brain; cognition; gastrointestinal tract; gut-brain axis; metabolites; microbiota; postnatal development.

FIGURE 1

Parallel development of the GI tract and the brain in first 3 years of life. In the GI tract, increase in microbial abundance and diversity, enterocyte maturation (change in crypt and villi structure) and ENS maturation (change in nerve density, type of neurons) occurs rapidly in the first 3 years of life. Meanwhile, brain also develops rapidly, with the change in its volume (peak in the first year), synaptogenesis, myelination, synaptic refinement, and establishment of cognitive abilities like auditory and visual processing, perception, and memory. The darkness of the color represents the intensity/peak of the developmental event. GI, gastrointestinal; ENS, enteric nervous system. Note: The developmental timing of the cellular events may vary across different regions of the brain.

FIGURE 2

Mechanism of communication between the GI tract and the brain. A myriad of mediators is involved in the complex communication between the GI tract and the brain. These include neural (vagus nerve), endocrine (hormones; PYY, GLP-1, CCK, and ghrelin), immune [cytokines (IL-1β and TNF-α), microglia, microbial antigenic component (LPS, peptidoglycan), and metabolic (TRP metabolites (kynurenines, 5-HT, and indole), SCFA, neurotransmitters (GABA, dopamine, NE, and histamine)] mediators. The mode of action of these mediators is by: activating the vagus nerve or crossing the BBB to communicate with the brain directly. SCFA regulates other mediators (EEC to produce hormones, microglia maturation, AHR activation; an essential receptor for TRP metabolites (produced both by the host and microbiota). GI, gastrointestinal; GLP-1, glucagon-like peptide-1; PYY, peptide YY; CCK, cholecystokinin; TNF-α, tumor necrosis factor-α; IL-β, interleukin-β; GABA, gamma-aminobutyric acid; NE, norepinephrine; SCFA, short-chain fatty acids; EEC, enteroendocrine cells; TRP, tryptophan; LPS, lipopolysaccharides; BBB, blood–brain barrier; AHR, aryl hydrocarbon receptor; EC, enterochromaffin cell; 5-HT, serotonin. Note: Kynurenines include kynurenine and downstream metabolites of the kynurenine pathway and not necessarily all the kynurenines can cross the blood–brain barrier.

FIGURE 3

Tryptophan metabolism along different pathways. Key metabolites (serotonin, melatonin, kynurenine, and indole) are in red. Rate-limiting enzymes shown are Trpytophan-2,3-dioxygenase (TDO), indoleamine-2,3-dioxygenase (IDO), tryptophan hydroxylase (TPH), Aromatic L-amino acid decarboxylase (AADC), N-acetyl transferase (NAT), hydroxyindole-O-methyl transferase (HIOMT), tryptophanase (tnaA). *All the downstream metabolites and enzymes of the kynurenine pathway have not been shown for simplicity.