Who's talking to whom: microbiome-enteric nervous system interactions in early life

Abstract

The enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal tract (GI) and regulates important GI functions, including motility, nutrient uptake, and immune response. The development of the ENS begins during early organogenesis and continues to develop once feeding begins, with ongoing plasticity into adulthood. There has been increasing recognition that the intestinal microbiota and ENS interact during critical periods, with implications for normal development and potential disease pathogenesis. In this review, we focus on insights from mouse and zebrafish model systems to compare and contrast how each model can serve in elucidating the bidirectional communication between the ENS and the microbiome. At the end of this review, we further outline implications for human disease and highlight research innovations that can lead the field forward.

Keywords: ENS neuropathies; enteric glia; enteric neuron; microbiota; zebrafish.

Graphical abstract

Figure 1.

Schematic timeline of enteric nervous system (ENS) development in mice and zebrafish. Developmental stages in mice and zebrafish can be described by periods of early development and early feeding, at which point the gastrointestinal (GI) tract has greater opportunities to be colonized by microbiota. In both mice and zebrafish, the development of the ENS can be conceptualized into three stages: migration of progenitor cells and colonization within the gut wall, proliferation, and differentiation. Created with BioRender.com. hpf, hours postfertilization.

Figure 2.

The myenteric plexus is hypoplastic in early postnatal GF mice. Myenteric nerves were visualized by immunolabeling with antibodies to PGP9.5 (red). A–C: myenteric plexus in the SPF duodenum, jejunum, and ileum is organized in a lattice-like network, with even spacing between ganglia and uniform thickness of connective nerve fibers. D: myenteric plexus in the GF duodenum resembles that of SPF duodenum. E and F: in GF mice, the myenteric plexus of the jejunum and ileum appears unorganized, with fewer ganglia and thinner connecting nerve fibers. G–I: In ASF colonized mice, the structure appears similar to that observed in SPF-colonized animals. Bar = 120 μm [from Collins et al. (71) with permission]. SPF: specific pathogen-free; GF: germ-free; ASF: Altered Shaedler Flora.

Figure 3.

Summary of components of the intestine and enteric nervous system (ENS) functions. ENS neurons (green) and ENS glial cells (blue) interact with different intestinal cell types and control important intestinal functions (boxes). ICC: interstitial cells of Cajal. Modified from Ganz et al. (72) with permission.

Figure 4.

Examples of enteric nervous system (ENS)-regulated intestinal functions—luminal pH and intestinal motility—that impact the colonization and composition of the intestinal microbiota. A: luminal pH is lower in zebrafish sox10 mutants (bottom) compared with wild types (top). B: in zebrafish wild type (wt), the ENS (top) regulates the chemical environment of the intestinal lumen and thereby maintains a healthy microbiota and neutrophil population. In zebrafish sox10 mutants (bottom), the absence of ENS leads to a reduced luminal pH thereby increasing the abundance of proinflammatory Vibrio and neutrophils which results in an inflammatory response. C: example of competition between Vibrio (blue) and Aeromonas (magenta) in the zebrafish intestine over time using live imaging on a light-sheet microscope. D: intestinal contractions in the wild-type zebrafish host (top) promote the collapse of Aeromonas population when challenged by Vibrio. Lack of intestinal contractions in zebrafish ret mutants (bottom) prevents Aeromonas from being outcompeted by Vibrio. A: based on Fig. 4 from Hamilton et al. (74), which is licensed under CC BY 4.0; C: based on Fig. 3A from Wiles et al. (106), which is licensed under CC BY 4.0.