Crohn’s Disease: Potential Drugs for Modulation of Autophagy

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Abstract

Autophagy is an intracellular process whereby cytoplasmic constituents are degraded within lysosomes. Autophagy functions to eliminate unwanted or damaged materials such as proteins and organelles as their accumulation would be harmful to the cellular system. Autophagy also acts as a defense mechanism against invading pathogens and plays an important role in innate and adaptive immunity. In physiological processes, autophagy is involved in the regulation of tissue development, differentiation and remodeling, which are essential for maintaining cellular homeostasis. Recent studies have demonstrated that autophagy is linked to various diseases and involved in pathophysiological roles, such as adaptation during starvation, anti-aging, antigen presentation, tumor suppression and cell death. The modulation of autophagy has shown greatest promise in Crohn’s disease as most of autophagy drugs involved in these diseases are currently under clinical trials and some has been approved by Food and Drug Administration. This review article discusses autophagy and potential drugs that are currently available for its modulation in Crohn’s disease.

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Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health

David Ríos-Covián, Patricia Ruas-Madiedo, Abelardo Margolles … (2016)

The colon is inhabited by a dense population of microorganisms, the so-called “gut microbiota,” able to ferment carbohydrates and proteins that escape absorption in the small intestine during digestion. This microbiota produces a wide range of metabolites, including short chain fatty acids (SCFA). These compounds are absorbed in the large bowel and are defined as 1-6 carbon volatile fatty acids which can present straight or branched-chain conformation. Their production is influenced by the pattern of food intake and diet-mediated changes in the gut microbiota. SCFA have distinct physiological effects: they contribute to shaping the gut environment, influence the physiology of the colon, they can be used as energy sources by host cells and the intestinal microbiota and they also participate in different host-signaling mechanisms. We summarize the current knowledge about the production of SCFA, including bacterial cross-feedings interactions, and the biological properties of these metabolites with impact on the human health.

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The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

Dallas R Donohoe, Nikhil Garge, Xinxin Zhang … (2011)

The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. Copyright © 2011 Elsevier Inc. All rights reserved.

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ACG Clinical Guideline: Management of Crohn’s Disease in Adults

Bruce Sands, Edward V Loftus, Kim L Isaacs … (2018)

Crohn's disease is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. The incidence of Crohn's disease has steadily increased over the past several decades. The diagnosis and treatment of patients with Crohn's disease has evolved since the last practice guideline was published. These guidelines represent the official practice recommendations of the American College of Gastroenterology and were developed under the auspices of the Practice Parameters Committee for the management of adult patients with Crohn's disease. These guidelines are established for clinical practice with the intent of suggesting preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When exercising clinical judgment, health-care providers should incorporate this guideline along with patient's needs, desires, and their values in order to fully and appropriately care for patients with Crohn's disease. This guideline is intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. To evaluate the level of evidence and strength of recommendations, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time.

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Journal

Journal ID (nlm-ta): Medicina (Kaunas)

Journal ID (publisher-id): medicina

Title: Medicina

Publisher: MDPI

ISSN (Print): 1010-660X

ISSN (Electronic): 1648-9144

Publication date (Electronic): 29 May 2019

Publication date Collection: June 2019

Volume: 55

Issue: 6

Electronic Location Identifier: 224

Affiliations

Faculty of Pharmacy, Universiti Teknologi MARA, Cawangan Pulau Pinang Kampus Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia; nursyu437@ 123456ppinang.uitm.edu.my

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Nursyuhada Azzman https://orcid.org/0000-0001-6525-6603

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Publisher ID: medicina-55-00224

DOI: 10.3390/medicina55060224

PMC ID: 6630681

PubMed ID: 31146413

SO-VID: b82f369a-0831-4765-ac85-b9c574aa8359

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Crohn’s Disease: Potential Drugs for Modulation of Autophagy

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Karger: Gastroenterology

Most cited references 84

Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health

The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

ACG Clinical Guideline: Management of Crohn’s Disease in Adults

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