Commensal Microbiota-Derived Indoles as Determinants of Inflammaging and Healthspan 公开
Powell, Domonica (Fall 2020)
Abstract
Aging is accompanied by an increase in baseline inflammation throughout the body and a decline in anti-inflammatory processes, a phenomenon known as inflammaging. Additionally, overall dysfunction of the immune system, known as immunosenescence, is observed with age. Inflammaging is associated with an increased risk of becoming frail with age and increased susceptibility to inflammatory age-related diseases. A proposed cause of inflammaging is a decline in intestinal barrier function with age, which allows continuous translocation of luminal antigens that can initiate a chronic inflammatory immune response. Moreover, dysbiosis associated with age-related diseases indicates a connection between the intestinal microbiota and inflammaging.
The intestinal epithelium is a highly dynamic structure that is continuously regenerating through intestinal stem cell proliferation and differentiation into absorptive and secretory cell types. Intestinal goblet cells are responsible for secreting mucus that protects the epithelium by limiting access of pathogens and lubricating the intestinal tract to prevent abrasion. Together, the mucus layers and intestinal epithelium form a highly integrated barrier system that limits contact of the intestinal microbiota with the host while still permitting access of small molecules produced by commensal bacteria.
This work demonstrates that geriatric mice lose goblet cells as they age, and small molecules related to indole, either provided through colonization with bacteria that secrete indole and its derivatives or administration of the indole derivative indole-3 aldehyde (ICA), can restore goblet cell numbers to those seen in young mice. Increased goblet cell differentiation in response to indoles was dependent on an aryl hydrocarbon receptor (Ahr)-mediated increase in expression of the immunoregulatory cytokine interleukin-10 (IL10). Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, when intestinal barrier function declines. Additionally, IL10 induced by commensal microbiota-derived indoles may function in organ systems outside of the intestine, such as skeletal muscle, to reduce the negative consequences of inflammaging.
Together, this work demonstrates that indoles may have utility as a therapeutic intervention to both limit the decline of barrier integrity by restoring goblet cell numbers and control systemic inflammation via the anti-inflammatory cytokine IL-10.
Table of Contents
CHAPTER I. Introduction............................................................................................................1
Overview..............................................................................................................................1
The Barrier System of the Colon..........................................................................................2
Interleukin-10 and Intestinal Homeostasis.........................................................................11
Consequences of Intestinal Inflammation..........................................................................13
Indoles as Therapeutics for Inflammaging.........................................................................21
Conclusions........................................................................................................................26
Figures................................................................................................................................28
CHAPTER II. Layered Defense: How Mucus And Tight Junctions Seal The Intestinal Barrier...........................................................................................................................................29
Abstract..............................................................................................................................30
Introduction........................................................................................................................30
Mucins Separate the Epithelia from the Intestinal Lumen.................................................32
TJs Form a Paracellular Seal..............................................................................................35
The Mucosal Barrier, Inflammation, and IBD....................................................................39
Summary and Future Directions.........................................................................................40
Figures................................................................................................................................42
CHAPTER III. Indoles from the Commensal Microbiota Act via AHR and IL10 to Tune the Cellular Composition of the Colonic Epithelium During Aging...............................................44
Abstract..............................................................................................................................45
Significance Statement.......................................................................................................45
Introduction........................................................................................................................46
Materials and Methods.......................................................................................................48
Results................................................................................................................................53
Discussion..........................................................................................................................58
Figures................................................................................................................................62
CHAPTER IV. Effects of Indoles Beyond the Intestine...........................................................70
Abstract..............................................................................................................................70
Introduction........................................................................................................................71
Materials and Methods.......................................................................................................72
Results................................................................................................................................74
Discussion..........................................................................................................................75
Figures................................................................................................................................79
CHAPTER V. Discussion............................................................................................................81
The Role of Goblet Cells in Health.....................................................................................82
Significance of Understanding Inflammaging...................................................................85
Future Directions................................................................................................................87
Conclusion.........................................................................................................................88
Figures................................................................................................................................89
REFERENCES.............................................................................................................................91
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