ABSTRACT

Emerging evidence suggests dietary interventions regulate inflammatory signaling through gut microbiome modulation, yet their therapeutic potential in radiation-induced intestinal injury (RIII)remains underexplored. This study demonstrates that the ketogenic diet (KD), a high-fat and low-carbohydrate dietary regimen, exerts protective effects against RIII through dual mechanisms involving microbial regulation and inflammatory pathway inhibition. Using high-salt diet (HSD) as a dietary control,KD significantly attenuated intestinal inflammation by downregulating pro-inflammatory cytokines while enhancing barrier integrity through tight junction protein upregulation in a radiation-exposed murine model.16S rDNA sequencing showed KD enriched Akkermansia and reduced Enterobacteriaceae, whereas HSD exhibited inverse patterns. Mechanistically, RNA sequencing revealed that KD uniquely suppressed theJAK2/STAT3 pathway in RIII mice. In vitro studies demonstrated that β-hydroxybutyrate, a key ketone metabolite, effectively suppressed RORγt expression and subsequent downregulation of IL-17A gene transcription via the inhibition of JAK2/STAT3 pathway, thus mitigate inflammatory damage. Fecal microbiota transplantation validated that KD-modified microbiome directly inhibited JAK2/STAT3signaling activation, as well as the downregulation of RORγt and IL-17A. These findings establish KD as a promising dietary strategy mitigate acute RIII through synergistic modulation of gut microbiota and inflammatory signaling, providing novel insights into nutritional approaches targeting microbial-hostcrosstalk in radiation injury.

Yang, Jingjing, Zhi Ling, Ming Zhou, Mingyang Tao, Jingxian Mao, Huaijuan Guo, Jiaxin Wang et al. "Ketogenic diet alleviates acute radiation-induced intestinal injury through JAK2/STAT3/RORγt/IL-17A signaling pathway via gut microbiome." Communications Biology (2026).

https://www.nature.com/articles/s42003-026-10546-9_reference.pdf

ABSTRACT

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms that significantly impair patients' quality of life. While pharmacological therapies provide symptomatic relief, no disease-modifying treatments have been conclusively established. In recent years, there has been increasing interest in non-pharmacological interventions, including dietary strategies, for their potential role in symptom management and disease modification. This literature review aims to examine the emerging role of the ketogenic diet (KD) in the management of PD, exploring its potential to alleviate symptoms and impact disease progression. Preliminary evidence suggests that KD may offer symptomatic benefits in PD through mechanisms such as mitochondrial support, anti-inflammatory effects, neuroinflammation, and impacting gut dysbiosis. Studies have shown promising results, particularly for non-motor symptoms such as urinary function, fatigue and cognition, however consistent improvement in motor outcomes has yet to be demonstrated. It should be noted that existing clinical data are derived from small pilot trials (generally n<20) with heterogenous dietary protocols and variable ketone targets, limiting definitive conclusions. While the mechanistic rational and early clinical signals are encouraging, larger and longer duration randomized controlled trials with standardized ketogenic protocols are needed to fully characterize KD’s potential in PD management.

Hitawala, Gazala, and Lisa M. Shulman. "A Fat Chance at Neuroprotection: Ketogenic Diet and Parkinson’s Disease." Clinical Nutrition ESPEN (2026): 103430. https://doi.org/10.1016/j.clnesp.2026.103430

https://www.sciencedirect.com/science/article/abs/pii/S2405457726005279

Abstract

Cancer cells frequently reside in a glucose-deprived microenvironment due to rapid tumor proliferation and insufficient angiogenesis. However, the mechanisms by which colorectal cancer cells (CRC) adapt to glucose starvation to sustain proliferation remain unclear. Succinylation, a novel post-translational modification, has been implicated in regulating tumor cell proliferation and survival under nutrient stress. Our study reveals that fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, is downregulated in CRC and acts as a tumor suppressor. Under glucose starvation mimicked in vitro, FH protein expression is reduced, leading to abnormal accumulation of its upstream metabolites fumarate and succinate, which correlates with advanced clinical stage and poor prognosis in CRC patients. Mechanistically, accumulated fumarate specifically binds to and stabilizes the NRF2 protein, upregulating the expression of GPX4 and FTH1 to inhibit ferroptosis, thereby sustaining CRC cell proliferation. Meanwhile, glucose starvation induces CPT1A-mediated succinylation of FH at residues K66/K80, reducing FH protein stability and promoting its degradation via the autophagy-lysosome pathway. Our findings reveal the critical role of FH and its succinylation in CRC cell adaptation to glucose starvation, inhibiting ferroptosis, and maintaining cancer cell proliferation, providing novel potential targets and a theoretical basis for the clinical treatment of CRC.

Abstract

Proposed mechanism of the ketogenic diet-microbiota-MMA-immune axis in CRC. (Part 1) A ketogenic diet remodels gut microbiota homeostasis by depleting MMA-producing bacteria, thereby reducing the accumulation of the oncometabolite (MMA). (Part 2) At the molecular level, MMA acts as a ligand that binds to Rap1, activating the downstream MAPK/ERK signalling cascade. This signalling event drives the transcriptional reprogramming of TAMs towards the pro-tumorigenic M2 phenotype. (Part 3) Clinically, elevated serum MMA in CRC patients correlates with increased M2 macrophage infiltration in the tumour microenvironment and poor prognosis.

Lu, Yang, Bo Shi, Jinmiao Chen, Huihui Yao, Xiuwei Mi, Minke Shao, Yiyuan Zhao et al. "Ketogenic Diet Alleviates Colorectal Cancer by Attenuating Macrophage M2 Polarisation Triggered by Oncometabolite MMA Derived From the Gut Microbiota." Cell proliferation: e70247.

https://onlinelibrary.wiley.com/doi/10.1111/cpr.70247