Delta-Valerobetaine is a Microbe-Generated Metabolite that Alters Gut Epithelial Integrity and Mitochondrial Biogenesis Restricted; Files Only
Askew, Lauren (Spring 2025)
Abstract
The human microbiome produces bioactive metabolites and small molecules that can impact health and disease. The most discriminatory metabolite generated by the microbiome is δ-valerobetaine. Here, we show new evidence that δ-valerobetaine modulates gut epithelium integrity in the colon. We detected that δ-valerobetaine decreased gut barrier permeability in vitro and in vivo and induced differential expression of Claudin proteins that function in orchestrating barrier function. When mice treated with δ-valerobetaine were challenged with experimental colitis, mice supplemented with δ-valerobetaine exhibited attenuated colitis severity compared to vehicle-treated control mice. In addition, we investigated the role of δ-valerobetaine in mitochondrial biogenesis and regulation in the small intestine and colon. We determined that δ-valerobetaine is capable of inducing transcription of genes required for mitochondrial biogenesis, fission, fusion, and mitophagy in the colon. Furthermore, δ-valerobetaine administration to healthy mice elevated transcription of the SIRT1 and SIRT3 proteins that play crucial roles in metabolism and cellular health. Altogether, we show that δ-valerobetaine is a potent activator of barrier function and mitochondrial turnover in the colon. We hypothesize that δ-valerobetaine regulates SIRT1 and SIRT3 translation or acetylation activity to drive mitochondrial turnover and provide the necessary energy to enhance barrier function.
Table of Contents
Distribution Agreement
Abstract
Acknowledgements
Chapter 1: Introduction…………………………………………………………………(1-40)
1.1 Microbiome Development………………………………………………………….1
1.2 Microbe-Generated Metabolites………………………………………………..…2
1.3 δ-Valerobetaine……………………………………………………………………..6
1.4 Stem Cell Niche and Epithelial Cell Types……………………………………...10
1.5 Gut Epithelial Barrier and Claudins……………………………………………...15
1.6 Mitochondrial Maintenance………………………………………………………22
1.7 Inflammatory Bowel Disease…………………………………………………….27
1.8 Literature Cited………………………………………………………….…………30
Chapter 2: The microbial metabolite delta-valerobetaine
strengthens the gut epithelial barrier……………………………………………….(41-84)
2.1 Introduction………………………………………….………………….………….43
2.2 Methods……………………………………………………….……………...……45
2.3 Results……………………………………………………….………………….....54
2.4 Discussion……………………………………………………….…………….......76
2.5 Literature Cited………………………………………………………….………...81
Chapter 3: The microbial metabolite delta-valerobetaine induces
mitochondrial biogenesis through the SIRT family……………………….…......(85-99)
3.1 Introduction………………………………………………………….………….....85
3.2 Methods………………………………………………………….……………...…87
3.3 Results………………………………………………………….……………...…..89
3.4 Discussion……………………………………………………….………………...96
3.5 Literature Cited………………………………………………………….…………99
Chapter 4: General Discussion.……….…………………….………….………...(100-108)
4.1 Microbiome-generated metabolites and the epithelial barrier….……...……100
4.2 Microbiome-generated metabolites and mitochondria……………...….……103
4.3 Literature Cited………………………………………………………….……….107
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File download under embargo until 22 May 2026 | 2025-04-21 19:28:15 -0400 | File download under embargo until 22 May 2026 |
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