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      α-Ketoglutarate for Preventing and Managing Intestinal Epithelial Dysfunction

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          Abstract

          The epithelium lining the intestinal tract serves a multifaceted role. It plays a crucial role in nutrient absorption and immune regulation and also acts as a protective barrier, separating underlying tissues from the gut lumen content. Disruptions in the delicate balance of the gut epithelium trigger inflammatory responses, aggravate conditions such as inflammatory bowel disease, and potentially lead to more severe complications such as colorectal cancer. Maintaining intestinal epithelial homeostasis is vital for overall health, and there is growing interest in identifying nutraceuticals that can strengthen the intestinal epithelium. α-Ketoglutarate, a metabolite of the tricarboxylic acid cycle, displays a variety of bioactive effects, including functioning as an antioxidant, a necessary cofactor for epigenetic modification, and exerting anti-inflammatory effects. This article presents a comprehensive overview of studies investigating the potential of α-ketoglutarate supplementation in preventing dysfunction of the intestinal epithelium.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)
          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies

            NaNa Keum, Edward Luciano Giovannucci (2019)
            Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death. Arising through three major pathways, including adenoma-carcinoma sequence, serrated pathway and inflammatory pathway, CRC represents an aetiologically heterogeneous disease according to subtyping by tumour anatomical location or global molecular alterations. Genetic factors such as germline MLH1 and APC mutations have an aetiologic role, predisposing individuals to CRC. Yet, the majority of CRC is sporadic and largely attributable to the constellation of modifiable environmental risk factors characterizing westernization (for example, obesity, physical inactivity, poor diets, alcohol drinking and smoking). As such, the burden of CRC is shifting towards low-income and middle-income countries as they become westernized. Furthermore, the rising incidence of CRC at younger ages (before age 50 years) is an emerging trend. This Review provides a comprehensive summary of CRC epidemiology, with emphasis on modifiable lifestyle and nutritional factors, chemoprevention and screening. Overall, the optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening.
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              Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.

              Lenny Dang, David W White, Stefan Gross … (2009)
              Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
              Article 0 comments Cited 594 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Mei-Jun Zhu
                Journal
                Journal ID (nlm-ta): Adv Nutr
                Journal ID (iso-abbrev): Adv Nutr
                Title: Advances in Nutrition
                Publisher: American Society for Nutrition
                ISSN (Print): 2161-8313
                ISSN (Electronic): 2156-5376
                Publication date PMC-release: 02 March 2024
                Publication date Collection: April 2024
                Publication date (Electronic): 02 March 2024
                Volume: 15
                Issue: 4
                Electronic Location Identifier: 100200
                Affiliations
                [1 ]School of Food Science, Washington State University, Pullman, WA, United States
                [2 ]Department of Animal Sciences, Washington State University, Pullman, WA, United States
                Author notes
                [* ]Corresponding author. meijun.zhu@ 123456wsu.edu
                Article
                Publisher Item ID: S2161-8313(24)00034-6 Publisher ID: 100200
                DOI: 10.1016/j.advnut.2024.100200
                PMC ID: 11016550
                SO-VID: 95f60824-23f5-4456-a9a9-b72ed4b4382b
                Copyright © © 2024 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 22 November 2023
                Date revision received : 16 February 2024
                Date accepted : 29 February 2024
                Categories
                Subject: Review

                Keywords: α-ketoglutarate,intestinal health,inflammatory bowel disease,colorectal cancer,gut microbiome
                Data availability:
                Keywords: α-ketoglutarate, intestinal health, inflammatory bowel disease, colorectal cancer, gut microbiome

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