Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Cheng, Chia-Wei; Biton, Moshe; Haber, Adam L.; Gündüz, Nuray; Eng, George; Gaynor, Liam T.; Tripathi, Saurabh; Calibasi-Kocal, Gizem; Rickelt, Steffen; Butty, Vincent; Moreno-Serrano, Marta; Iqbal, Ameena M.; Bauer-Rowe, Khristian E.; Imada, Shinya; Ulutaş, Mehmet Sefa; Mylonas, Constantine; Whary, Mark T.; Levine, Stuart S.; Başbınar, Yasemin; Hynes, Richard O.; Mino‐Kenudson, Mari; Deshpande, Vikram; Boyer, Laurie A.; Fox, James G.; Terranova, Christopher; Rai, Kunal; Piwnica‐Worms, Helen; Mihaylova, Maria M.; Regev, Aviv; Yılmaz, Ömer H.

doi:10.1016/j.cell.2019.07.048

Cited by 268 publications

(264 citation statements)

References 89 publications

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“…One of these diseases is ulcerative colitis, an inflammatory bowel disease. Ketogenic diets may dampen inflammation within the gastrointestinal tract by inhibiting the activity of the NLRP3 inflammasome (8), promoting intestinal stem cell regeneration and gut healing (9), and stimulating the release of bile acids that facilitate intestinal immune system homeostasis (10,11).…”

Section: Introductionmentioning

confidence: 99%

A Standard Lipid Panel Is Insufficient for the Care of a Patient on a High-Fat, Low-Carbohydrate Ketogenic Diet

Norwitz

Loh

2020

Front. Med.

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High-fat, low-carbohydrate ketogenic diets have recently become popular for weight loss and the treatment of numerous chronic diseases; however, the general medical community still expresses concern regarding the impact of high-fat diets on serum lipids and cardiovascular risk. Herein, we report on a young man who adopted a ketogenic diet to treat his inflammatory bowel disease. Incidentally, changes in his serum lipids that would be considered adverse by current standards were noted. A more critical analysis of his lipid profile suggests that the changes he experienced may not be dangerous and may, at least with regard to several parameters, represent improvements. This case study demonstrates how the manner in which lipid panels are often reported and reviewed can lead to misleading conclusions and highlights that, at least in the care of those on a ketogenic diet, more nuanced analyses of lipid subfractionations should be conducted in order for physicians to provide optimal care and clinical recommendations.

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Section: Introductionmentioning

confidence: 99%

A Standard Lipid Panel Is Insufficient for the Care of a Patient on a High-Fat, Low-Carbohydrate Ketogenic Diet

Norwitz

Loh

2020

Front. Med.

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“…A ketogenic diet also restored oligodendrocyte integrity and increased CNS myelination in a murine Pelizaeus-Merzbacher disease model 19 . Furthermore, exogenous β-HB improved stem cell homeostasis and intestinal stem cell function through activation of Notch signaling, which is a key signaling axis for tissue regeneration 20 . Thus, β-HB and ketogenic diets can be considered important mediators with regenerative potential that also have the capacity to retard agingassociated phenotypes.…”

Section: Agingmentioning

confidence: 99%

β-hydroxybutyrate and its metabolic effects on age-associated pathology

2020

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Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments.

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“…(growth inhibitor), and Atf3 (regulates stress response in ISCs) (Cheng et al, 2019;Draheim et al, 2010;Jadhav and Zhang, 2017;Zhou et al, 2017). Genes down-regulated by KPT-330 treatment appear related to proliferation and cell cycle, including the marker Mki67.…”

Section: Slc16a6 (Principal Transporter Of Ketone Bodies; Instructionmentioning

confidence: 99%

High-throughput organoid screening enables engineering of intestinal epithelial composition

Mead

Hattori

Levy

et al. 2020

Preprint

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Barrier tissue epithelia play an essential role in maintaining organismal homeostasis, and changes in their cellular composition have been observed in multiple human diseases.Within the small intestinal epithelium, adult stem cells integrate diverse signals to regulate regeneration and differentiation, thereby establishing overall cellularity. Accordingly, directing stem cell differentiation could provide a tractable approach to alter the abundance or quality of specialized cells of the small intestinal epithelium, including the secretory Paneth, goblet, and enteroendocrine populations. Yet, to date, there has been a lack of suitable tools and rigorous approaches to identify biological targets and pharmacological agents that can modify epithelial composition to enable causal testing of disease-associated changes with novel therapeutic candidates. To empower the search for epithelia-modifying agents, we establish a first-of-its-kind high-throughput phenotypic organoid screen. We demonstrate the ability to screen thousands of samples and uncover biological targets and associated small molecule inhibitors which translate to in vivo. This approach is enabled by employing a functional, cell-type specific, scalable assay on an organoid model designed to represent the physiological cues of in vivo Paneth cell differentiation from adult intestinal stem cells. Further, we miniaturize and adapt the organoid culture system to enable automated plating and screening, thereby providing the ability to test thousands of samples. Strikingly, in our screen we identify inhibitors of the nuclear exporter Xpo1 modulate stem cell fate commitment by inducing a panepithelial stress response combined with an interruption of mitogen signaling in cycling intestinal progenitors, thereby significantly increasing the abundance of Paneth cells independent of known WNT and Notch differentiation cues. We extend our observation in vivo, demonstrating that oral administration of Xpo1 inhibitor KPT-330 at doses 1,000fold lower than conventionally used in hematologic malignancies increases Paneth cell abundance. In total, we provide a framework to identify novel biological cues and therapeutic leads to rebalance intestinal stem cell differentiation and modulate epithelial tissue composition via high-throughput phenotypic screening in rationally-designed organoid model of differentiation.

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Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Cited by 268 publications

References 89 publications

A Standard Lipid Panel Is Insufficient for the Care of a Patient on a High-Fat, Low-Carbohydrate Ketogenic Diet

A Standard Lipid Panel Is Insufficient for the Care of a Patient on a High-Fat, Low-Carbohydrate Ketogenic Diet

β-hydroxybutyrate and its metabolic effects on age-associated pathology

High-throughput organoid screening enables engineering of intestinal epithelial composition

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