Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is a devastating condition of multi-factorial origin that affects the intestine of premature infants and results in high morbidity and mortality. Infants that survive contend with several long-term sequelae including neurodevelopmental impairment (NDI)—which encompasses cognitive and psychosocial deficits as well as motor, vision, and hearing impairment. Alterations in the gut-brain axis (GBA) homeostasis have been implicated in the pathogenesis of NEC and the development of NDI. The crosstalk along the GBA suggests that microbial dysbiosis and subsequent bowel injury can initiate systemic inflammation which is followed by pathogenic signaling cascades with multiple pathways that ultimately lead to the brain. These signals reach the brain and activate an inflammatory cascade in the brain resulting in white matter injury, impaired myelination, delayed head growth, and eventual downstream NDI. The purpose of this review is to summarize the NDI seen in NEC, discuss what is known about the GBA, explore the relationship between the GBA and perinatal brain injury in the setting of NEC, and finally, highlight the existing research into possible therapies to help prevent these deleterious outcomes.

Microbiome and its impact on fetal and neonatal brain development: current opinion in pediatrics

“…SCFAs, such as butyrate, propionate, and acetate, result from anaerobic microbial fermentation of indigestible polysaccharides in the colon [ 10 ]. SCFAs contribute to the maintenance and modulation of both gut and blood—brain barrier (BBB) integrity [ 11 , 12 ▪▪ ]. They can directly affect the brain compromising the BBB, binding to local receptors, inducing epigenetic modifications, contributing to brain homeostasis, and modulating neuro inflammation [ 13 ].…”

“…They can directly affect the brain compromising the BBB, binding to local receptors, inducing epigenetic modifications, contributing to brain homeostasis, and modulating neuro inflammation [ 13 ]. For instance, butyrate can possess direct anti-inflammatory effects on oligodendrocytes which are crucial for early brain development [ 11 , 14 ]. SCFAs can enhance regulatory T cell (Treg) function, vital for immune tolerance, and activate the sympathetic nervous system and vagal nerve [ 11 , 15 ].…”

“…For instance, butyrate can possess direct anti-inflammatory effects on oligodendrocytes which are crucial for early brain development [ 11 , 14 ]. SCFAs can enhance regulatory T cell (Treg) function, vital for immune tolerance, and activate the sympathetic nervous system and vagal nerve [ 11 , 15 ]. Indole, a tryptophan derivative, exhibits beneficial effects on neuro inflammation, nerve signal transduction, and gut and BBB integrity [ 9 , 16 ].…”

“…For example, Lactobacilli , Bifidobacteriae , and Bacteroidetes are capable of producing GABA [ 8 , 15 ], while Escherichia coli ( E. coli ) and specific strains of Lactobacillus can contribute to serotonin production. These neurotransmitters can exert local effects by stimulating the vagal nerve or gut peristalsis [ 8 ], but can also traverse the SCFA weakened gut and BBB, exerting a more direct impact on the brain [ 11 ].…”

“…Furthermore, lipopolysaccharide (LPS) containing bacteria can induce an inflammatory cascade by TLR 4 signaling, with NF-kB induced release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. These can directly affect the brain, by the weakening of the BBB, or via pathogenic signaling through the vagal nerve [ 11 ]. The resulting inflammatory processes damage the oligodendrocytes, pivotal for early brain development.…”