Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology

Abstract

The increase in obesity has been accompanied by a rise in the prevalence of painful peripheral neuropathy. Recently, studies have suggested a role for gut microbiome in the development of some peripheral pain, including chemotherapy- induced pain and fibromyalgia. In the present dissertation, we showed that modulation of gut microbiome in obese mice alleviated neuropathic indices, concurrent with changes in immune cell profile within the peripheral nerve system. We demonstrated that fecal transplantation from lean to obese mice decreased obesity-induced pain and restored nerve density in the skin. These improvements were accompanied by changes in peripheral nerve system gene expression, calcium signaling and inflammatory cells. Our results suggested that circulating butyrate, a metabolite secreted by gut microbiome upon fiber digestion, may be involved in pain improvement by acting directly on peripheral nerve system cells. We also observed that increasing circulating butyrate correlated with mechanical pain improvement and decreased inflammatory markers in the PNS of obese mice.Because obesity is a state of chronic low-grade inflammation, we hypothesized that butyrate could modulate inflammation levels to improve neuropathy in obese mice. Using a caspase-1 biosensor murine model to monitor inflammation, we observed caspase-1 activation in metabolic and neural tissues, including heart, brown adipose tissue and brain of lean, obese controls and obese mice subjected to butyrate treatment. Our data highlighted that butyrate acts on a tissue-specific manner and rescue some caspase 1-dependent inflammatory responses dysregulated in obesity settings.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Available for download on Friday, October 07, 2022

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