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Review
. 2015 Sep;149(3):553-62.
doi: 10.1053/j.gastro.2015.06.046. Epub 2015 Jul 11.

Role of Autophagy in the Maintenance of Intestinal Homeostasis

Leigh A Baxt  1 , Ramnik J Xavier  2
Affiliations
Review

Role of Autophagy in the Maintenance of Intestinal Homeostasis

Leigh A Baxt et al. Gastroenterology. 2015 Sep.

Abstract

Genome-wide association studies of inflammatory bowel disease have identified several risk loci in genes that regulate autophagy, and studies have provided insight into the functional effects of these polymorphisms. We review the mechanisms by which autophagy contributes to intestinal homeostasis, focusing on its cell type-specific roles in regulating gut ecology, restricting pathogenic bacteria, and controlling inflammation. Based on this information, we are beginning to understand how alterations in autophagy can contribute to intestinal inflammation.

Keywords: Cell Biology; Genetics; IBD; Pathogenesis.

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Figures

Figure 1
Figure 1. Challenges to understanding pathogen-induced autophagy
(A) When studying autophagy triggered by pathogen infection, a number of variables must be considered, with cell type, host species, and pathogen biology of primary importance (top). Differences in cell type will determine which E3 ligases function in ubiquitination of autophagy substrates (e.g., LRSAM1 in epithelial cells, SMURF1 in macrophages). Species context is important to consider, as several autophagy proteins are not conserved between mice and humans (e.g., IRGM, NDP52). Lastly, pathogen biology is relevant as different pathogens (e.g., virus, bacteria, parasites) have different intracellular lifestyles that impact different cellular pathways. In assessing the impact of pathogen-related autophagy factors (bottom), one must take into account both population-level dynamics well as cellular metabolic responses. As only a small percentage of pathogens are targeted for autophagy, a strong phenotype may translate to a subtle effect at the population level. Hallmarks of infection will induce cellular metabolic recalibration, so the amount of time an infection is allowed to proceed must also be considered. In the context of these complex dynamics, phenotypic readouts of both host and pathogen effects may be subtle. (B) To understand how perturbations to a single factor may lead to disease, one may consider “multiple hits” models. In the first model, a single factor has a function that impacts multiple cellular pathways (e.g,. autophagy and ER stress). In the second model, a single factor plays a role in multiple cell types (e.g., Paneth cells and macrophages).
Figure 2
Figure 2. Defective intestinal homeostasis associated with perturbations in the autophagy system
Perturbations to the autophagy system result in breakdown of multiple aspects of innate and adaptive immunity that support the maintenance of intestinal homeostasis. This schematic illustrates the state of the intestinal epithelium in the context of perturbations to the autophagy system. Changes include a defective mucus layer, decreased AMP production, increased paracellular permeability resulting in increased bacterial translocation, expansion of the microbiota, defective antigen presentation and adaptive immune cell priming, and decreased IgA production. Crosstalk between autophagy and immune cells supports intestinal homeostasis, and breakdowns in this communication are associated with defective intestinal barrier function. References included in the right panel list primary literature further detailing specific changes in crosstalk associated with changes in autophagy.
Figure 3
Figure 3. Framework for building a gut-autophagy interactome
To understand the multiple pathways involved in maintenance of gut homeostasis, one must consider a number of pathways that converge to determine healthy or disease states in this organ system. Multiple cellular, nutrient, and pathogenic stressors induce autophagy. At the same time, transcriptional regulation affects expression of multiple factors involved in these pathways. Stressors and transcription converge on the selective autophagy pathway. This pathway is modulated by the actions of well-studied core autophagy genes. Additional factors, many of which have yet to be identified, include trigger-specific regulators and effectors of autophagy, selective autophagy factors, and components that function in multiple pathways that can be co-opted by invading pathogens. Together the actions of these proteins have profound effects on the cellular turnover, microbial ecology, stem cell niche, and inflammatory state in physiology and disease states that determine the homeostatic properties of the gut.
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References

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