Environmental cues shape mucosal enteric glia networks independent of lamina propria innervation

Mucosal enteric glia are implicated in different aspects of gut function but the determinants of their occupancy of the lamina propria remain obscure. Analyzing mucosal enteric glia during intestinal inflammation and in mouse models differing for diet and gut microbiota, we found that colitis drastically impacts glial network organization, and that diet modulates mucosal glia cyto-architecture, with microbiota inducing intestinal region-specific variations. Restored by conventionalization, germ-free mice exhibit reduced mucosal glia numbers throughout the intestine.

Vagotomy affects mucosal enteric glia maintenance in a diet-dependent fashion but does not influence lamina propria colonization. Also, differences in nerve fiber density fail to account for the variations in mucosal enteric glia networks. Providing insight into their interaction with neuronal components and the luminal milieu, our results emphasize the profound plasticity of enteric glia, and suggest that their presence in the mucosa is not merely configured by lamina propria innervation.

We thank the Advanced Optical Microscopy Centre at UHasselt, especially the help provided by Sam Duwé, for support with microscopy experiments, which were made possible by FWO (I001222N) and Methusalem UHasselt. Sincere thanks to the UHasselt animal facility for animal husbandry. We also thank Truus van der Have for her help with the experiments, Laura Dusaer for her excellent technical assistance, and the other members of the Enteric Neurobiology Lab for their support and insightful comments on the manuscript.

A special thanks to the members of the Enomoto Laboratory, in particular Salsabila Luthfi Sesotyosari, Akimasa Orii and Mukhamad Sunardi for their help with genotyping, preparation of histological samples and microscopy at Kobe University. We would also like to thank Lisa Mayrginther and the other members of the Melotte Lab, for their help with H&E stainings and all the precious suggestions. The schematic images were created in BioRender (Sanchini, G. full license).

This work was supported by the Research Foundation Flanders (FWO: G036320N, W001620N, W004025, K256423N and I001222N) and the Dutch Research Council (NWO VIDI: 016.196.367). A.C. was supported by a fellowship from FWO (11L8322N). W.B. acknowledges additional funding from the Francqui Foundation.

S.P.R. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through the Emmy Noether Programme RO 6247/1-1 (446316360), DFG SFB 1160 IMPATH (256073931), DFG SFB 1755 CASCAID (550296805), TRR 359 PILOT (491676693), and TRR 417 (540805631). M.K. was supported by the FWO (G080121N) and by a BOF and iBOF project (21GP17BOF, 23IU04KLEM) through Hasselt University. H.E. was supported by the Japan Science and Technology Agency CREST (JPMJCR2021).