Human resident gut microbe Bacteroides thetaiotaomicron regulates colonic neuronal innervation and neurogenic function

ABSTRACT

Background and aims

As the importance of gut–brain interactions increases, understanding how specific gut microbes interact with the enteric nervous system (ENS), which is the first point of neuronal exposure becomes critical. Our aim was to understand how the dominant human gut bacterium Bacteroides thetaiotaomicron (Bt) regulates anatomical and functional characteristics of the ENS.

Methods

Neuronal cell populations, as well as enteroendocrine cells, were assessed in proximal colonic sections using fluorescent immunohistochemistry in specific pathogen-free (SPF), germ-free (GF) and Bt conventionalized-germ-free mice (Bt-CONV). RNA expression of tight junction proteins and toll-like receptors (TLR) were measured using qPCR. Colonic motility was analyzed using in vitro colonic manometry.

Results

Decreased neuronal and vagal afferent innervation observed in GF mice was normalized by Bt-CONV with increased neuronal staining in mucosa and myenteric plexus. Bt-CONV also restored expression of nitric oxide synthase expressing inhibitory neurons and of choline acetyltransferase and substance P expressing excitatory motor neurons comparable to those of SPF mice. Neurite outgrowth and glial cells were upregulated by Bt-CONV. RNA expression of tight junction protein claudin 3 was downregulated while TLR2 was upregulated by Bt-CONV. The enteroendocrine cell subtypes L-cells and enterochromaffin cells were reduced in GF mice, with Bt-CONV restoring L-cell numbers. Motility as measured by colonic migrating motor complexes (CMMCs) increased in GF and Bt-CONV.

Conclusion

Bt, common gut bacteria, is critical in regulating enteric neuronal and enteroendocrine cell populations, and neurogenic colonic activity. This highlights the potential use of this resident gut bacteria for maintaining healthy gut function.

KEYWORDS:

• Bacteroides thetaiotaomicron
• gut microbiome
• enteric nervous system
• neuronal plasticity
• colonic motility

Author contribution

All authors had access to the study data and reviewed and approved the final manuscript. Study concept and design – MP, RA & LAB; Acquisition of data – MP, RA, NP, LB; Analysis and interpretation of data – MP, RA, NP, SC and LAB; Drafting of the manuscript – MP & RA; Critical revision of the manuscript for important intellectual content – all authors; Statistical analysis – RA & MP; Obtained funding – LAB & SC; Administrative, technical or material support – RS, AP, AG, & AB; Study supervision – MP, SC & LAB.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

The author(s) gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project (BBS/E/F/000PR10355).