Ketogenic diets in healthy dogs induce gut and serum metabolome changes suggestive of anti‐tumourigenic effects: A model for human ketotherapy trials

Allenspach, Karin; Borcherding, Dana C.; Iennarella-Servantez, Chelsea A.; Mosichuk, Allison P; Atherly, Todd; Sahoo, Dipak Kumar; Kathrani, Aarti; Suchodolski, Jan S.; Bourgois-Mochel, Agnes; Serao, Mariana Rossoni; Serão, Nick V. L.; Willette, Auriel A.; Perez, Beatriz Agulla; Gabriel, Vojtěch; Mao, Sichao; Kilburn, Logan; Dang, Viet Anh; Borts, David J.; Almada, Luciana L.; Fernández-Zapico, Martín E.; Phillips, Gregory J.; Jergens, Albert E.; Mochel, Jonathan P.

doi:10.1002/ctm2.1047

Cited by 3 publications

(13 citation statements)

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“…This aligns with earlier in vivo and in vitro investigations involving mice and dogs, as evidenced by previous studies [7,34]. Consequently, we opted to employ 30 µM PA for subsequent experiments.…”

Section: Resultssupporting

confidence: 69%

“…The congruence between our observations in canine colonoids and the ndings from in vivo human [15,40] and dog studies [34,35] bolsters the translational signi cance of our research. The consistent outcomes observed across diverse models emphasize the potential relevance of our ndings to human health, aligning with the principles of the One Health initiative.…”

Section: Discussionsupporting

confidence: 72%

“…In parallel, canine investigations have revealed a similar trend where PA exposure is linked to an ampli cation of stemness in intestinal cells [34]. Notably, studies employing canine enteroids have disclosed that PA exposure elicits an elevation in the expression of stem cell markers such as LGR5, concurrent with heightened expression of peroxisome proliferator-activated receptor-γ, a pivotal nuclear receptor transcription factor [34]. The noticeable surge in proliferative activity within colonoids further accentuates the potential in uence of PA on tissue regeneration processes.…”

Section: Discussionmentioning

confidence: 84%

“…This may have implications for tissue repair and regeneration but could also contribute to hyperproliferative disorders if dysregulated. In parallel, canine investigations have revealed a similar trend where PA exposure is linked to an ampli cation of stemness in intestinal cells [34]. Notably, studies employing canine enteroids have disclosed that PA exposure elicits an elevation in the expression of stem cell markers such as LGR5, concurrent with heightened expression of peroxisome proliferator-activated receptor-γ, a pivotal nuclear receptor transcription factor [34].…”

Section: Discussionmentioning

confidence: 93%

“…In canines subjected to a HFD, biopsies revealed a notable augmentation in stem cell characteristics [34]. Intriguingly, employing PA as a surrogate for mimicking the effects of a HFD yielded similar results, with elevated stemness characteristics coinciding with heightened expression of the peroxisome proliferatoractivated receptor-γ, a pivotal nuclear receptor transcription factor [34].…”

mentioning

confidence: 80%

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High-Fat Diet Enhances Stemness and Compromises Intestinal Permeability in A Translational Canine Intestinal Organoid Model

Nagao,

Ambrosini

2023

Preprint

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Background: Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5+ intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between lipotoxicity, stemness, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction. Results: Canine colonoids were subjected to palmitic acid (PA) exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of stemness characteristics. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group. Conclusions: By employing canine intestinal organoid systems, we provide compelling insights into the impact of lipotoxicity on intestinal physiology. These findings underscore the importance of considering both stemness and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.

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Section: Resultssupporting

confidence: 69%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 80%

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High-Fat Diet Enhances Stemness and Compromises Intestinal Permeability in A Translational Canine Intestinal Organoid Model

Nagao,

Ambrosini

2023

Preprint

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Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus

Dang

2023

Cold Spring Harb Perspect Med

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A century ago, Otto Warburg's work sparked the field of cancer metabolism, which has since taken a tortuous path. As evidence accumulated over the decades, consensus views of causes of cancer emerged, whereby genetic and epigenetic oncogenic drivers promoted immune evasion and induced new blood vessels and neoplastic metabolism to support tumor growth. Neoplastic cells abandon social cues of intercellular cooperation, escape tissue confinement, metastasize, and ultimately kill the host. Herein, key milestones in the study of cancer metabolism are chronicled with an emphasis on carbohydrate metabolism. The field began with a cancer cell-autonomous view that has been refined by a richer understanding of solid cancers as growing, immune-suppressive, complex organs comprising different cell types that are nourished by a variety of nutrients and variable amounts of oxygen through abnormal neovasculatures. Based on foundational historical studies, our current understanding of cancer metabolism offers a hopeful outlook for targeting metabolism to enhance cancer therapy.

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High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model

Nagao,

Ambrosini

2024

BMC Mol and Cell Biol

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Background Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5 + intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between palmitic acid (PA), cell proliferation, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction. Results Canine colonoids were subjected to PA exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of cell proliferative activity. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group. Conclusions By employing canine intestinal organoid systems, we provide compelling insights into the impact of PA on intestinal physiology. These findings underscore the importance of considering both cell proliferative activity and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.

show abstract

Ketogenic diets in healthy dogs induce gut and serum metabolome changes suggestive of anti‐tumourigenic effects: A model for human ketotherapy trials

Cited by 3 publications

References 10 publications

High-Fat Diet Enhances Stemness and Compromises Intestinal Permeability in A Translational Canine Intestinal Organoid Model

High-Fat Diet Enhances Stemness and Compromises Intestinal Permeability in A Translational Canine Intestinal Organoid Model

Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus

High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model

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