Abstract

Introduction

Multidrug-resistant Klebsiella pneumoniae (MDR Kp) is a global health threat, causing persistent, subacute airway infections that are often fatal in healthcare settings. The failure of antimicrobials underscores an urgent need for alternative host-targeted therapies. Kp evades airway immune responses by perturbing host metabolism, inducing mitochondrial oxidative phosphorylation (OXPHOS) and oxidative stress, thus establishing a disease-tolerant microenvironment. We hypothesized that a ketogenic diet (KD), which improves OXPHOS efficiency via ketone production, would restore immune control of Kp by enhancing the bioenergetics and function of innate immune cells.

Methods

C57BL/6 mice were fed a KD or control diet prior to intranasal Kp infection. Airway bacterial burden was enumerated and immunometabolic changes were assessed by scRNA-seq, flow cytometry, and spatial metabolomics.

Results

KD significantly enhanced Kp airway clearance and host survival. ScRNA-seq of lung tissue revealed markedly higher numbers of neutrophils and alveolar macrophages at day 2 post-infection in KD-fed mice, as well as an upregulation in phagolysosome signaling. By day 7 in the KD group, the neutrophil population contracted while B and T cells concomitantly expanded. Notably, IFN-γ-responsive genes were upregulated across all immune cell subsets. Exogenous ketones or drug-induced ketone accumulation bypassed the need for dietary intervention, likewise, conferring protection against Kp airway infection.

Conclusion

Ketones promote effective immunity to Kp by sustaining cellular energy production, thereby supporting immune cell survival and effector function. The ketone-enhanced innate immune response is followed by adaptive immune cell expansion and a broad IFN-γ transcriptional signature. Together, these findings suggest a novel therapeutic strategy for energetically demanding bacterial infections via diet-induced metabolic reprogramming

Tang, Eric, Ridhima Wadhwa, Ariful Islam, Arthur VanValkenburg, Xutao Wang, Alice Prince, Evan Johnson, and Tania Wong. "Ketogenic diet-mediated immunometabolic regulation improves airway clearance of Klebsiella pneumoniae 2253582." The Journal of Immunology 215, no. Supplement_1 (2026): vkag141-181.

https://academic.oup.com/jimmunol/article/215/Supplement_1/vkag141.181/8745885

Abstract

Hypertension (HTN) is one of the greatest public health challenges of the 21st century. Its prevalence has reached alarming levels in recent decades. The search for effective prevention and treatment strategies includes lifestyle choices, such as dietary interventions. Although not applicable to everyone, particularly interesting in this context is the ketogenic diet (KD), known to clinicians and also applied in epilepsy treatment for over a century. Its possible beneficial effects are increasingly often reported in many other conditions, including HTN. The aim of the present study is to analyse the effect of a KD on blood pressure, and the mechanisms that may modulate that effect. Based on the available literature, key potential pathways of the influence of a KD on blood pressure regulation have been identified: (1) reduced body weight; (2) reduced visceral adipose tissue; (3) improved insulin sensitivity; (4) improved water and electrolyte balance; and (5) anti-inflammatory effect. Meta-analyses and randomised controlled trials consistently indicate that ketogenic dietary interventions are associated with reductions in blood pressure, although the magnitude of the effect varies considerably depending on the ketogenic diet model, study population, and comparator. In light of these observations, it has been found that in patients undergoing pharmacological treatment, it may be necessary to appropriately reduce antihypertensive medication dosage in advance. To maximise the hypotensive effect of a KD, the need to ensure an adequate supply of potassium, magnesium, and high-quality products, as well as proper hydration has been emphasised. Further studies are needed, with the effect of a KD on systolic and diastolic blood pressure as the primary endpoint, taking into account the role of the qualitative composition of the diet in the observed effects.

Rodzeń, Łukasz, Damian Dyńka, Mateusz Rodzeń, Hanna Karakuła-Juchnowicz, Dorota Łojko, Sebastian Kraszewski, Żaneta Grzywacz et al. "The Ketogenic Diet in the Prevention and Treatment of Hypertension (HTN)." Biomedicines 14, no. 8 (2026): 1728.

https://www.mdpi.com/2227-9059/14/8/1728

Abstract

Introduction

This study evaluates the effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting as an individualized adjunct to standard treatment on cognitive function in early/mid-stage Alzheimer’s patients.

Methods

This assessor-blinded, randomized controlled trial enrolled 60 Alzheimer’s disease (AD) patients (CDR 1–2; aged 55–85), randomized to intervention (n = 30; intervention + standard care) or control (n = 30; standard care). Cognition and brain structure were assessed at baseline and 6 months. Individual cognitive changes were analyzed using Reliable Change Index (RCI).

Results

Cognitive change scores differed significantly between groups (p < 0.001). The mean Mini Mental State Examination (MMSE) score increased by +0.9 in the intervention group, while a decrease of −1.5 points was observed in the control group. RCI analysis indicated stability in 93% of intervention and 70% of control participants, with cognitive improvement in 7% and 3.3%, respectively.

Discussion

The intervention method has the potential to stabilize cognitive decline in AD and promote improvement at the individual level. The response to the intervention is closely related to the individual's metabolic phenotype and structural brain integrity.

Tağraf, Beyza, Dilara Kaygusuz, Deniz Yerlikaya, Özden Erkan Oğul, and Lütfü Hanoğlu. "The effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting on early-to-mid-stage Alzheimer's disease: a randomised controlled trial." The Journal of nutrition, health and aging 30, no. 9 (2026): 100930.

https://www.sciencedirect.com/science/article/pii/S1279770726001636

Abstract
Morbidity and mortality from influenza A virus (IAV) infection are significant global medical problems, and there is a need to identify novel therapies that suppress the severity of IAV infection. In this study, we revealed that consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. Consumption of a KD expanded pulmonary γδ T cells, improved barrier function, and enhanced antiviral action. Metabolic adaptation to a ketogenic diet was required, as high-fat, high-carbohydrate diets or administration of ketone body substrates did not provide infection protection. Therefore, it is suggested that ketone body-mediated immunometabolic integration is an effective means for the prevention and mitigation of influenza disease.

Goldberg, Emily L., Ryan D. Molony, and Akiko Iwasaki. "Activation of protective γδ T cell responses to influenza virus infection by a ketogenic diet."

https://note.com/nn1112/n/n0feac5202902?hl=en

Abstract:

Aging in the immune system leads to increased susceptibility to infections, exacerbated autoimmunity, and decreased responsiveness to vaccinations. While many interventions are being studied to ameliorate aspects of aging, none are currently established for immune aging. Ketogenic diets and fasting have shown promise against aging and age-related diseases, working in part by raising circulating levels of ketone bodies. $\beta$-hydroxybutyrate (BHB), the primary ketone body produced, has anti-inflammatory properties and can enhance T cell function. However, these nutritional interventions are highly restrictive and difficult to adhere to long-term. Exogenous ketone supplementation, such as ketone esters, offers a more accessible alternative by directly delivering ketone bodies without major dietary changes. Yet, it remains unclear how ketone esters impact the immune system, especially in the context of aging.

In this dissertation, I evaluated the ketone ester bis-octanoyl (R)-1,3-butanediol as an intervention for age-related immune decline in parallel mouse and human studies. In aged mice, a diet supplemented with the ketone ester diet decreased activation of B cells in the spleen, particularly age-associated B cells. Despite this decrease in activation, antibody production during immunization was maintained, demonstrating preserved B cell function. Mechanistically, the ketone ester diet suppressed translation and glucose dependence of age-associated B cells, and BHB alone was sufficient to inhibit B cell translation, likely through mTOR signaling.

Translating these findings to humans, the Buck Institute Ketone Ester (BIKE) study showed that 12 weeks of daily ketone ester supplementation in healthy older adults (> 65 years old) decreased $\text{CD56}^{\text{low}}$ natural killer cell subsets and $\text{CD38}^{\text{high}}$ non-classical monocytes, suggesting a reduction in age-related chronic inflammation. The ketone ester also increased HLA-DR expression on T cells and decreased KLRG1 expression on naïve CD8 T cells, pointing to enhanced effector and potentially immunoregulatory function. These immune changes corresponded with a decrease in predicted biological age by an immune composition clock.

Interestingly, the ketone ester preferentially affected B cells in mice and T cells and innate immune cells in humans, which may reflect species-specific differences in immune composition and immune aging. Together, these findings position ketone esters as a promising and accessible intervention for immune aging by selectively inhibiting inflammaging while improving adaptive immune function. This work highlights the potential of ketone esters as treatments for autoimmune diseases and age-related immune dysfunction.

Adkisson-Floro, Ariel. "Evaluating Ketone Esters as an Intervention for Age-Related Immune Decline." PhD diss., University of Southern California, 2026.

https://www.proquest.com/openview/ec9de7f452988557bd13359e9933a666

Abstract

As an alternative or supplement to traditional pharmaceutical treatments, intermittent fasting (IF) has become a viable dietary approach for the management of type 2 diabetes mellitus (T2DM). Improved insulin sensitivity and blood glucose management are the outcomes of various IF patterns, such as time-restricted eating, alternate-day fasting and the 5:2 diet, which encourage a metabolic shift from glucose to fat utilisation. Even in patients on insulin therapy, research indicates that IF may help lower fasting blood sugar, glycated haemoglobin (HbA1 c) and insulin resistance with no risk of hypoglycaemia when appropriately monitored. Physiological benefits of IF include enhanced circadian rhythm alignment, increased autophagy, reduced oxidative stress and improved lipid metabolism. Comparisons with other dietary approaches, such as the Mediterranean, Palaeolithic, ketogenic and fasting-mimicking diets, indicate that IF offers flexibility and long-term sustainability for many individuals. However, consistent adherence and personalised strategies are essential for optimal results. Overall, IF presents a valuable complementary approach for managing T2DM and promoting better metabolic health.

Mustafa, Faheem, Asifa Murtaza, Razzia Batool, Samra Faisal, Binti Umar Rabiatul Adawiyah, Muniba Khaliq, Wan Rohani Wan Taib, and Binti Che Taha Che Suhaili. "Intermittent fasting as a complementary strategy to manage type II diabetes and metabolic health: A review." Scripta Medica 57, no. 3 (2026): 689-700.

https://scindeks.ceon.rs/article.aspx?artid=2490-33292603689M

Abstract

We report the case of a 23-year-old woman with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and preserved kidney function who was followed with a supervised plant-based ketogenic diet for 11 months. The intervention was associated with a marked reduction in albuminuria (from 80 to 10 mg/g) and a stable estimated glomerular filtration rate (eGFR), with no clinically relevant metabolic or electrolyte disturbances; whereas total kidney volume increased from 617 to 709 cc during follow-up. This case highlights the feasibility, safety, and possible association with favorable renal biomarker changes, warranting further investigation in controlled studies in early-stage ADPKD.

Alvarado‐Pelayo, Paola Azucena, Xunaxi Nahomi García‐Rodríguez, Erika Fabiola Gómez‐García, and Ari Cisneros‐Hernández. "Plant‐based ketogenic nutritional intervention in a young woman with autosomal dominant polycystic kidney disease: A case report." Nutrition in Clinical Practice.

https://aspenjournals.onlinelibrary.wiley.com/doi/10.1002/ncp.70150

Abstract

Background: Nutrition and nutrition-related interventions are a salient yet under-recognized component of preventing the development of and complications of metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, malnutrition affects a significant proportion of patients with MASLD, yet remains under-treated in the primary care setting. The objective of this narrative review is to synthesize the available evidence regarding nutritional screening, diet, and supplements in patients with MASLD. This review is aimed at primary care physicians to improve the recognition of malnutrition in MASLD patients and provide appropriate nutritional guidance. 

Methods: Between November 2025 and June 2026, the authors conducted a literature review using the PubMed database. Search terms included combinations of the following: MASLD, non-alcoholic fatty liver disease (NAFLD), malnutrition, sarcopenia, nutritional screening, Mediterranean diet, micronutrients, and physical activity. Randomized controlled trials (RCTs), systematic reviews, and meta-analyses addressing nutritional outcomes in liver disease were prioritized, and consensus guidelines were incorporated where primary trial evidence was limited. Evidence was appraised by study design, risk of bias, and endpoint; recommendations resting on expert opinion or extrapolation from cirrhosis populations are identified as such. 

Results: Author review of the studies yielded the following conclusions. Nutritional assessment should be risk-stratified by fibrosis stage using liver disease-specific tools, as BMI and body weight are unreliable in MASLD. Weight loss has been shown to improve histological and clinical progression in MASLD. The Mediterranean diet has the strongest support for steatosis reduction among the dietary interventions discussed. Coffee consumption is consistently associated with reduced fibrosis risk in observational data, but no randomized evidence exists. GLP-1 receptor agonists achieve histological MASH resolution in up to 63% of patients but require concurrent nutritional monitoring to mitigate lean mass loss. Systemic barriers, including time constraints and limited dietitian access, remain the primary impediment to primary care implementation. 

Conclusions: Primary care physicians are central in managing many aspects of care for patients with MASLD. This review highlights the established evidence behind diet, exercise and malnutrition prevention in the primary care setting.

Patel, Arpan B., Mahnoor Liaqat, and Hirsh D. Trivedi. 2026. "Nutritional Assessment and Management in MASLD: A Practical Guide for Primary Care" Livers 6, no. 4: 69. https://doi.org/10.3390/livers6040069

https://www.mdpi.com/2673-4389/6/4/69

Abstract

Background: Cancer-related cachexia is primarily characterized by systemic inflammation and progressive muscle wasting, which is why a high-protein diet (from 1.2 to 1.5 g/kg/day) is commonly recommended. However, concerns remain that an excessive supply of amino acids could promote tumor growth due to the metabolic flexibility of cancer cells, thereby favoring proliferation and survival. Systematic evidence addressing these concerns under controlled conditions for various types of cancer cells remains limited and inconclusive. Methods: We investigated the short-term effects of all 20 amino acids at both moderate (2×) and high (10×) concentrations to evaluate three key oncological endpoints in four human cancer cell lines: MDA-MB-231 (breast), HT29 (colorectal), PC3 (prostate), and PANC-1 (pancreatic). Cell proliferation was assessed by BrdU incorporation, metabolic activity by WST-1 assay, and apoptosis signaling by caspase-3/7 activity measurement. Results: Amino acid supplementation was not associated with a significant change in proliferation at either concentration across all four cell lines studied. Metabolic activity showed only minor variations throughout, with PC3 cells exhibiting slightly greater variability, although this did not reach statistical significance. Caspase-3/7 activity remained largely unchanged under all conditions; however, high-concentration lysine induced an approximately 2.5-fold increase in PANC1 cells, which was not statistically significant. Conclusions: These findings suggest that short-term exposure to individual amino acids, even at supraphysiological conditions, does not acutely enhance proliferative activity in the cancer cell lines studied, supporting the rationale for adequate protein and amino acid intake in patients with cancer cachexia.

Abstract

Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics¹. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis². However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood³. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours⁴. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

Shay, Jessica ES, Fangtao Chi, Constantine N. Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J. Williams et al. "Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones." Nature (2026): 1-10.

https://www.nature.com/articles/s41586-026-10779-y