Necrotizing Enterocolitis, Gut Microbiota, and Brain Development: Role of the Brain-Gut Axis

Abstract

Necrotizing enterocolitis (NEC) is a relatively common disease in very-low-birth-weight infants and is associated with high mortality and morbidity. In survivors, neurodevelopmental impairment is frequently seen. The exact etiology remains largely to be elucidated, but microbiota are considered to play a major role in the development of NEC. Furthermore, emerging evidence exists that the microbiota is also of importance in brain function and development. Therefore, microbiota characterization has not only potential as a diagnostic or even preventive tool to predict NEC, but may also serve as a biomarker to monitor and possibly even as a target to manipulate brain development. Analysis of fecal volatile organic compounds, which shape the volatile metabolome and reflect microbiota function and host interaction, has been shown to be of interest in the diagnosis of NEC and late-onset sepsis. In this review, we discuss evidence of the role of the complex interplay between microbiota, NEC, and brain development, including the brain-gut axis in preterm infants.

Keywords: Brain development; Brain-gut axis; Necrotizing enterocolitis; Preterm infants.

Fig. 1

Schematic overview of the role of microbiota in brain development and functioning and in NEC, and summary of the effects of the gut microbiota on brain, gut motility and inflammation. The gut microbiota are highly metabolically active. Bacterial metabolites have multiple effects on the gut and brain development, and function by different pathways, including the circulation and vagal nerve (top panel). In NEC, LPS-containing microbes can inflame the brain by TLR4-induced cytokine release. SCFAs, produced by microbial processes, are of importance in maintaining gut barrier functioning, and may have a direct effect on brain functioning. Recently, it was recognized that the gut microbiota produced metabolites that signal to colonic enterochromaffin cells (ECs). ECs increase serotonin (5-HT) biosynthesis, resulting in the secretion of 5-HT into the lumen and basolaterally (lower left panel). This increases the stimulation of myenteric neurons, resulting in gut motility. Besides, microbes can play a direct role in the production different neurotransmitters, such as GABA and 5-HT. In a symbiotic condition, the gut microbiota is mainly comprised of obligate anaerobic bacteria. The gut microbiota regulate hemostasis of the intestinal epithelial cells (lower right hand panels). In a normal, symbiotic situation the intestinal lumen is kept hypoxic by beta-oxidation, maintaining the growth of anaerobic bacteria partially by the activity of nitric oxide synthase (NOS) 2. The SCFA butyrate is a key microbial metabolite since it is detected by the intracellular peroxisome proliferator-activated receptor-γ (PPAR-γ), which activates beta-oxidation in macrophages. After treatment with antibiotics or other environmental factors which may provoke the dominance of pathogenic bacteria (dysbiosis), the metabolism changes to glycolysis, which favors proliferation of pathogenic bacteria. The gut immune system is in balance/not activated in a symbiotic situation. However, dysbiosis (upper and lower panels) results in a systemic inflammatory response that can be overwhelming, resulting in NEC.