How Ketosis Impacts Brain Health and Cognitive Performance

Dr Oliver Finlay

KEY POINTS

·      Ketogenic diets shift metabolism to fat burning, producing ketones (ketosis) and positively impact the gut microbiota.

·      Originally developed for the management of epilepsy, ketogenic diets show potential cognitive benefits like memory and attention.

·      Ketones serve as an alternative, efficient brain energy source, bypassing impaired glucose use.

·      Early research suggests ketones can improve mental clarity and slow cognitive decline.

·      Ketosis may offer neuroprotection by reducing oxidative stress and inflammation.

Introduction

The Ketogenic Diet

The ketogenic diet (KD) is a nutritional approach characterised by high fat, moderate protein, and very low carbohydrate intake. This composition shifts the body's metabolism from relying primarily on glucose to utilising fat as its main energy source, leading to the production of ketone bodies—a state known as ketosis. Originally developed in the 1920s to manage epilepsy, the KD has garnered attention for its potential benefits on cognitive function and as a therapeutic strategy for neurodegenerative diseases.

Impact of Ketosis on Cognitive Performance

Emerging research suggests that the KD may enhance various aspects of cognitive function, including memory, attention, and processing speed, thanks to the ability of ketone bodies to cross the blood brain barrier. A systematic review encompassing both animal and human studies reported that over 80% of the human studies observed favourable effects of KD interventions on cognition, with none indicating detrimental outcomes (Chinna-Meyyappan et al, 2023). However, the authors noted that definitive conclusions are limited by small sample sizes and methodological inconsistencies across studies.

The proposed mechanisms behind these cognitive improvements include:

1. Alternative Energy Source: Ketone bodies, such as β-hydroxybutyrate (BHB), serve as an efficient energy substrate for the brain, especially when glucose metabolism is impaired in neurodegenerative disease states. The early research suggests that the ketones can bypass the impaired glucose metabolism pathways and provide a constant and reliable source of energy directly to the neurons (Yang et al, 2019). As a result, where those affected by impaired glucose metabolism experience chronic mental fogginess, poor memory and cognitive decline, ketosis can help stabilise cognitive function, improve clarity and slow the neurodegenerative decline.

How Ketones Provide an Alternative Energy Source for the Brain

2. Neuroprotection: Ketosis may reduce oxidative stress and inflammation, both of which are implicated in cognitive decline.

Regarding oxidative stress, ketosis may promote an enhanced endogenous antioxidant capacity. Cells are like tiny engines and when they work to produce energy, they also create some waste products called free radicals. These are unstable molecules that can damage other important parts of your cells, like DNA and proteins. This damage is called oxidative stress. Over time, too much oxidative stress can contribute to aging and various diseases. Ketosis might help your body produce more of its own antioxidants, with some research suggesting that ketones can activate pathways that tell your body to make more of these protective molecules (Chen et al, 2024). Furthermore, the reduced reliance on glucose metabolism in ketosis may mitigate pathways associated with increased free radical production (Wan et al, 2023; Maalouf et al, 2007). Since KD keeps blood sugar levels low, it might reduce some of the processes that normally lead to the creation of those damaging free radicals in the first place. High blood sugar can sometimes cause more "waste" to be produced in your cells.

In the context of inflammation, ketosis, and specifically BHB, has demonstrated potential anti-inflammatory properties. Studies have shown that BHB can inhibit the activation of the pathway that centrally regulates pro-inflammatory cytokine expression (Youm et al, 2015). Additionally, BHB has been observed to suppress the activity of the multiprotein complex involved in the processing and release of pro-inflammatory cytokines (Kim et al, 2019).

The altered metabolic environment of ketosis may also influence the function of immune cells, potentially favouring less pro-inflammatory cell types (Polito et al, 2023). Consequently, a reduction in the circulating levels of pro-inflammatory cytokines has been reported in some studies examining ketogenic interventions (Guerreiro et al, 2024; Rondanelli et al, 2024).

It is important to acknowledge that the precise mechanisms and the extent to which ketosis impacts oxidative stress and inflammation are still under investigation. Findings may vary depending on the specific context, including the duration and strictness of the KD, the physiological state of the individual, and the specific disease or condition under study. Nevertheless, the current body of evidence suggests plausible biological pathways through which ketosis may exert protective effects against oxidative damage and inflammatory processes.

Further rigorous research, particularly in human populations, is warranted to fully characterise these relationships and their clinical implications.

How Ketosis Contributes to Neuroprotection and Neuromodulation

3. Enhanced Mitochondrial Function: With the indication that ketone bodies may serve as an alternative, “cleaner” mitochondrial fuel source, mitochondrial efficiency may be enhanced and the generation of reactive oxygen species as a byproduct of ATP synthesis reduced (Yang et al, 2019). Thus, improved mitochondrial efficiency and energy production in neurons may support better cognitive performance.

How Ketosis Enhances Mitochondrial Function

4. Positive Effect on Gut Microbiota: The gut microbiota plays a crucial role in overall health, including immune function, metabolism, and brain health. A balanced gut microbiota is necessary for maintaining the integrity of the blood-brain barrier (BBB) and regulating inflammation. Dysbiosis, or an imbalance in the gut microbiota, has been associated with several neurological disorders, including Alzheimer's and Parkinson's (Sampson et al., 2016).

Recent research suggests that a ketogenic diet may have a positive effect on gut microbiota composition (Jiang et al, 2025). For instance, studies have shown that a KD can increase the abundance of beneficial bacteria like Bifidobacterium and Akkermansia muciniphila, which are known to support gut barrier function and reduce inflammation (Zhao et al., 2024). A healthier gut microbiota can, in turn, reduce systemic inflammation - a key factor in the progression of neurodegenerative diseases.

In Alzheimer’s disease, chronic inflammation and oxidative stress play significant roles in the degradation of neurons. The ketogenic diet has been shown to reduce inflammation and improve mitochondrial function, which are critical for neuron survival. The reduction in neuroinflammation could be partly mediated by changes in the gut microbiota, as a healthier microbiota can reduce levels of pro-inflammatory molecules in the body (Yang et al., 2019).

Similarly, in Parkinson’s disease, neurodegeneration is also linked to systemic inflammation. Evidence suggests that the ketogenic diet may reduce this inflammation and even protect dopaminergic neurons from oxidative damage, potentially slowing the progression of Parkinson’s disease (Jiang et al., 2020). Again, alterations in the gut microbiota may play a role in modulating these beneficial effects. For example, Akkermansia muciniphila has been shown to modulate the immune response and improve metabolic health, which could be beneficial in reducing Parkinson’s-related neuroinflammation (Zhao et al, 2024).

Therapeutic Ketosis in Neurodegenerative Disorders

Therapeutic Ketosis in Neurodegenerative Disease Management

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterised by progressive loss of neuronal function. The KD has been investigated as a potential therapeutic approach for these conditions (Chinna-Meyyappan et al, 2023; Dewsbury et al, 2021; Jiang et al, 2022; Pavón et al, 2021; Rong et al, 2024).

Alzheimer's Disease: A systematic review and meta-analysis of randomised controlled trials found that KD interventions significantly improved cognitive function in individuals with AD. The study reported enhancements in mental state assessments and cognitive scales, suggesting that KD can positively influence cognitive outcomes in AD patients (Grammatikopoulou, 2020; Rong et al, 2024). However, whilst the research suggests that KD may improve cognitive function in people with mild cognitive impairment and in those with mild-to-moderate AD who do not carry the apolipoprotein ε4 allele (APOε4-), the evidence is less clear for individuals with the APOε4+ variant (Bohnen, Albin and Bohnen, 2023).

Parkinson's Disease: Research into KD's effects on PD is still in early stages. Some studies indicate that ketosis may improve motor function and potentially alleviate non-motor symptoms, although more rigorous clinical trials are needed to confirm these findings.

Mechanisms Underlying Therapeutic Effects

Mechanisms Underlying the Therapeutic Effects of Ketosis

The beneficial effects of KD in neurodegenerative diseases are thought to arise from several interconnected mechanisms (Jiang et al, 2022):

- Energy Metabolism: Ketone bodies provide an alternative energy source for neurons, which may be particularly beneficial in disease states where glucose metabolism is compromised (Yang et al, 2019).

- Anti-Inflammatory Effects: KD has been shown to modulate neuroinflammation, a key contributor to neurodegeneration. By reducing inflammatory markers, KD may help protect neuronal integrity (Jiang et al, 2022; Rondanelli et al, 2024; Rong, 2024)

- Oxidative Stress Reduction: Ketosis may enhance antioxidant defences, thereby reducing oxidative damage to neurons (Rong et al, 2024).

- Neurotransmitter Elevation: KD may increase levels of GABA (gamma-aminobutyric acid), which is a neurotransmitter integral in stabilising mood, reducing anxiety and enhancing emotional resilience (Rong et al, 2024).

- Promotion of Autophagy: Ketones function as a signalling molecule can support the brain’s natural process of removing dysfunctional cells.

Considerations and Future Directions

While the KD shows promise, it's important to consider potential side effects, such as nutrient deficiencies and gastrointestinal discomfort. Long-term adherence can also be challenging (Dewsbury et al, 2021). Future research should focus on large-scale, well-controlled studies to better understand the efficacy, safety, and applicability of KD in various populations.

Conclusion

The KD offers a compelling avenue for enhancing cognitive performance and managing neurodegenerative diseases. While preliminary findings are encouraging, further research is essential to establish standardised protocols and fully elucidate the therapeutic potential of KD in cognitive health.

References & Scientific Power Evaluation

Astrup, A. and Hjorth, M.F., 2017. Improvement in age-related cognitive functions and life expectancy by ketogenic diets. Nature Reviews Endocrinology, 13(12), pp.695-696.

Overview: The article discusses findings from rodent studies indicating that low-carbohydrate, ketogenic diets may prevent age-related cognitive decline and extend lifespan by increasing circulating levels of ketone bodies. The authors propose that ketone bodies might improve central nervous system insulin resistance, suggesting potential benefits for preventing cognitive decline and dementia, particularly in patients with type 2 diabetes mellitus.

Strengths: The article highlights compelling preclinical evidence supporting the role of ketogenic diets in enhancing cognitive function and longevity. By focusing on the potential mechanisms, such as improved insulin sensitivity in the central nervous system, the authors provide a plausible explanation for the observed benefits. This perspective encourages further exploration into dietary interventions as preventive strategies against neurodegenerative conditions.​

Limitations: A significant limitation of the article is its reliance on animal studies, which may not directly translate to human outcomes. The authors acknowledge the preliminary nature of the findings and the need for clinical trials to validate the efficacy and safety of ketogenic diets in humans. Additionally, the article does not address potential risks or challenges associated with long-term adherence to such diets.​

Conclusion: The authors provide an insightful commentary on the potential cognitive and longevity benefits of ketogenic diets, grounded in preclinical research. While the findings are promising, they underscore the necessity for human studies to confirm these effects and to develop practical dietary recommendations.​

Scientific Power: LOW to MODERATE - While the proposed mechanisms are biologically plausible, the foundation in animal studies without direct human data means that the absence of clinical evidence limits the strength of the conclusions. Future research involving human participants is essential to substantiate these preliminary observations.​

Bohnen, J.L., Albin, R.L. and Bohnen, N.I., 2023. Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal. Frontiers in Neurology, 14, p.1123290.

Overview: The systematic review examines the effectiveness of ketogenic interventions—diets that are high in fats and low in carbohydrates—on individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD). The authors analysed clinical trials from 2005 onward, assessing the quality of evidence using the American Academy of Neurology's criteria. Their findings suggest that ketogenic diets may improve cognitive function in people with MCI and in those with mild-to-moderate AD who do not carry the apolipoprotein ε4 allele (APOε4-). However, the evidence is less clear for individuals with the APOε4+ variant and for those with PD.​

Strengths: The review's comprehensive nature is a significant strength, as it consolidates data from multiple studies to provide a clearer understanding of how ketogenic interventions might affect neurodegenerative conditions. By employing standardised criteria to evaluate the quality of evidence, the authors ensure a rigorous and objective analysis. Additionally, the review highlights the potential of ketogenic diets to enhance brain function in specific patient groups, offering a foundation for future research.​

Limitations: Despite its thoroughness, the review faces certain limitations. The studies included vary in design, sample size, and the specific ketogenic interventions used, which can lead to inconsistent findings. Moreover, many studies have small participant groups and short durations, making it difficult to draw long-term conclusions. The review also notes a lack of research on more potent ketogenic treatments, like exogenous ketone esters, and calls for larger, more detailed studies to better understand the effects of these diets across diverse populations.​

Conclusion: The review provides valuable insights into the potential benefits of ketogenic diets for individuals with MCI and certain cases of AD. While the preliminary findings are promising, especially for APOε4- individuals, further large-scale studies are necessary to confirm these effects and to explore the impact on other groups, including those with PD and APOε4+ individuals.​

Scientific Power: MODERATE - The comprehensive analysis and use of standardised evaluation criteria lend credibility to the findings. However, the variability among included studies and the limited scope of some research reduce the overall strength of the conclusions. Further well-designed, large-scale clinical trials are needed to provide more definitive evidence on the efficacy of ketogenic interventions for neurodegenerative diseases.​

Chen, Y., You, Y., Wang, X., Jin, Y., Zeng, Y., Pan, Z., Li, D. and Ling, W., 2024. β-Hydroxybutyrate Alleviates Atherosclerotic Calcification by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis via AMPK/Nrf2 Pathway. Nutrients, 17(1), p.111.

Overview: The study investigates the effects of β-hydroxybutyrate (BHB) on atherosclerotic calcification (AC), a condition where arteries harden due to calcium deposits. Using ApoE^−/− mice fed a Western diet, the researchers supplemented the mice's diet with BHB for 24 weeks. They observed a reduction in calcified areas, calcium content, and alkaline phosphatase activity in the aortas, indicating that BHB alleviated AC. Further analysis suggested that BHB inhibited endoplasmic reticulum stress (ERS)-mediated apoptosis (cell death) in vascular smooth muscle cells (VSMCs) through the activation of the AMPK/Nrf2 signalling pathway.

Strengths: The study's strengths include its comprehensive approach, combining both in vivo (within living organisms) and in vitro (outside of a living organism) experiments to explore BHB's potential therapeutic effects on AC. The 24-week supplementation period allows for the observation of long-term effects, providing valuable insights into the chronic impact of BHB. Additionally, the identification of the AMPK/Nrf2 pathway as a mediator offers a plausible mechanism for BHB's protective role, contributing to the understanding of its biological effects.​

Limitations: Despite its strengths, the study has limitations. The use of ApoE^−/− mice, while common in atherosclerosis research, may not fully replicate human disease conditions, potentially limiting the applicability of the findings to human health. Furthermore, the study focuses on rat VSMCs for in vitro experiments; incorporating human VSMCs could enhance the relevance of the results. The exact dosage and safety profile of BHB supplementation in humans remain undetermined, necessitating caution before considering clinical applications.​

Conclusion: The research suggests that BHB supplementation may mitigate atherosclerotic calcification by inhibiting ERS-mediated apoptosis in VSMCs via the AMPK/Nrf2 pathway. These findings provide a foundation for future studies exploring BHB as a potential therapeutic agent for cardiovascular diseases. However, further research, particularly clinical trials involving human participants, is essential to confirm these results and assess the safety and efficacy of BHB supplementation in humans.​

Scientific Power: MODERATE - The well-structured experimental design and the integration of both in vivo and in vitro analyses strengthen the validity of the findings. However, the reliance on animal models and non-human cells, along with the absence of human clinical data, limits the direct applicability of the results to human health. Further studies involving human subjects are necessary to substantiate these findings and determine their clinical relevance.​

Chinna-Meyyappan, A., Gomes, F.A., Koning, E., Fabe, J., Breda, V. and Brietzke, E., 2023. Effects of the ketogenic diet on cognition: a systematic review. Nutritional Neuroscience, 26(12), pp.1258-1278.

Overview: The systematic review examines the impact of the ketogenic diet (KD) on cognitive function. Analysing 49 studies, 22 of which involved animal models and 27 focused on humans—the authors explore KD's effects across various conditions, including epilepsy, neurodegenerative diseases, cognitive impairment, and in healthy individuals. The review suggests that KD may enhance cognitive domains such as working memory, reference memory, and attention. Notably, over 80% of the human studies reported positive cognitive outcomes, with none indicating adverse effects. ​

Strengths: The review's comprehensive scope is a significant strength, encompassing a wide range of studies that provide a holistic view of KD's potential cognitive benefits. The adherence to PRISMA 2020 guidelines ensures a systematic and transparent approach to data collection and analysis. Additionally, the inclusion of both animal and human studies allows for a comparative perspective, enhancing the understanding of KD's effects across different contexts.​

Limitations: Despite its thoroughness, the review faces several limitations. Many included studies have small sample sizes, which can limit the generalisability of the findings. The absence of control groups and randomisation in some studies raises concerns about potential biases. Furthermore, the lack of standardised, objective measures for assessing cognitive function makes it challenging to draw definitive conclusions. The variability in study designs, participant populations, and KD protocols also complicates the ability to compare results directly.

Conclusion: The review indicates that the ketogenic diet holds promise for enhancing cognitive function across various populations. However, the preliminary nature of the evidence underscores the need for more rigorous, large-scale studies with standardised methodologies to confirm these findings and elucidate the underlying mechanisms.​

Scientific Power: LOW to MODERATE - While the systematic approach and breadth of studies provide valuable insights, the limitations inherent in the included studies—such as small sample sizes, lack of controls, and methodological inconsistencies—diminish the strength of the conclusions. Future research with more robust designs is essential to substantiate the cognitive benefits of the ketogenic diet.​

Dewsbury, L.S., Lim, C.K. and Steiner, G.Z., 2021. The efficacy of ketogenic therapies in the clinical management of people with neurodegenerative disease: a systematic review. Advances in Nutrition, 12(4), pp.1571-1593.

Overview: The systematic review examines the effectiveness of ketogenic therapies—diets high in fats and low in carbohydrates—in managing neurodegenerative diseases such as Alzheimer's and Parkinson's. The authors analysed multiple studies to determine how these diets impact cognitive and motor functions in affected individuals. Their findings suggest that ketogenic diets may offer benefits, including improved energy metabolism and reduced disease progression.​

Strengths: The review's comprehensive nature is a significant strength, as it consolidates existing research on ketogenic therapies for neurodegenerative diseases. By evaluating various studies, the authors provide a broad perspective on potential benefits, such as enhanced brain energy utilisation and symptom alleviation. This synthesis offers valuable insights for future research directions and clinical applications.​

Limitations: The studies included vary in design, sample size, and methodologies, which can lead to inconsistent findings. Many studies have small participant groups and short durations, making it difficult to draw long-term conclusions. Additionally, adherence to ketogenic diets can be challenging for patients, potentially affecting the feasibility of this therapy in real-world settings.​

Conclusion: The review provides an insightful analysis of ketogenic therapies in the context of neurodegenerative diseases. While preliminary findings indicate potential benefits, the authors emphasise the need for more rigorous, large-scale clinical trials to confirm these effects and to address practical considerations related to diet adherence and long-term safety.​

Scientific Power: MODERATE - The comprehensive analysis and inclusion of multiple studies lend credibility to the findings. However, the variability among included studies, small sample sizes, and short durations limit the strength of the conclusions. Further well-designed, large-scale clinical trials are necessary to provide more definitive evidence on the efficacy of ketogenic therapies for neurodegenerative diseases.​ 

Grabowska, K., Grabowski, M., Przybyła, M., Pondel, N., Barski, J.J., Nowacka-Chmielewska, M. and Liśkiewicz, D., 2024. Ketogenic diet and behavior: Insights from experimental studies. Frontiers in Nutrition, 11, p.1322509.

Overview: The review explores how the ketogenic diet (KD)—a high-fat, low-carbohydrate dietary regimen—affects various behaviours in animal models. The authors systematically analyse existing experimental studies to assess KD's impact on cognition, anxiety, depression, social interactions, and nutritional behaviours. Their synthesis reveals that KD generally enhances cognitive functions, such as memory and learning. However, its effects on anxiety and depression-related behaviours are inconsistent, with studies reporting reductions, no changes, or even increases in such behaviours. Notably, the review highlights a gap in research concerning KD's influence on social and nutritional behaviours, indicating areas for future investigation. ​

Strengths: This review's comprehensive approach is a significant strength, as it consolidates findings from various studies to provide a holistic understanding of KD's behavioural effects. By focusing on animal models, the authors offer insights into potential mechanisms underlying observed behavioural changes, which can inform future clinical research. The systematic analysis of diverse behavioural domains—cognition, mood-related behaviours, social interactions, and nutritional aspects—allows for a nuanced perspective on KD's multifaceted impact.​

Limitations: Despite its thoroughness, the review faces certain limitations. The reliance on animal studies presents challenges in directly translating findings to humans, as species-specific differences may influence outcomes. Additionally, variations in study designs, such as differences in KD formulations, durations, and behavioural assessments, complicate direct comparisons and synthesis of results. The review also notes a scarcity of research on KD's effects on social and nutritional behaviours, underscoring the need for more targeted studies in these areas.​

Conclusion: The review suggests that the ketogenic diet may positively influence cognitive functions in animal models, while its effects on anxiety and depression-related behaviours remain inconclusive. The identified research gaps, particularly concerning social and nutritional behaviours, highlight opportunities for future studies to explore these under-investigated domains. Overall, the review provides a foundational understanding of KD's behavioural effects, serving as a valuable resource for guiding subsequent research endeavours.​

Scientific Power: LOW to MODERATE - While the comprehensive analysis of existing animal studies offers valuable insights, the reliance on preclinical models limits the direct applicability to human populations. Furthermore, inconsistencies in study methodologies and outcomes reduce the overall strength of the conclusions. To enhance scientific power, future research should aim for standardised protocols and include clinical trials to validate findings in human subjects.​

Grammatikopoulou, M.G., Goulis, D.G., Gkiouras, K., Theodoridis, X., Gkouskou, K.K., Evangeliou, A., Dardiotis, E. and Bogdanos, D.P., 2020. To keto or not to keto? A systematic review of randomized controlled trials assessing the effects of ketogenic therapy on Alzheimer disease. Advances in Nutrition, 11(6), pp.1583-1602.

Overview: The systematic review examines randomised controlled trials (RCTs) to assess the effects of ketogenic therapy on individuals with Alzheimer's disease (AD) or mild cognitive impairment (MCI). The review included 10 RCTs with interventions ranging from 45 to 180 days, utilising various ketogenic approaches such as ketogenic diets, medium-chain triglyceride (MCT) supplements, and ketogenic formulas. The findings suggest that ketogenic therapy may improve general cognition, as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) and enhance episodic and secondary memory in long-term interventions. However, no significant improvements were observed in psychological health, executive function, or attention. The study also noted that individuals carrying the APOE ε4 allele exhibited a delayed response to the therapy compared to non-carriers. ​

Strengths: The review's comprehensive analysis of multiple RCTs provides a robust evaluation of ketogenic therapy's potential benefits for AD and MCI patients. By focusing exclusively on RCTs, the authors ensured a high standard of evidence, minimizing biases associated with observational studies. The inclusion of various forms of ketogenic interventions enhances the applicability of the findings across different therapeutic approaches. ​

Limitations: Despite its strengths, the review faces certain limitations. The heterogeneity among the included studies, such as differences in intervention types, durations, and outcome measures, complicates the synthesis of results and may affect the overall conclusions. Additionally, the relatively small sample sizes and short durations of some studies limit the generalisability and long-term applicability of the findings. The variability in adherence to ketogenic protocols among participants could also influence the outcomes. ​

Conclusion: The systematic review indicates that ketogenic therapy holds promise in enhancing certain cognitive functions in individuals with AD or MCI, particularly in improving general cognition and memory. However, the evidence is still preliminary, and further large-scale, long-term RCTs with standardised interventions and outcome measures are necessary to confirm these findings and establish clinical guidelines.

Scientific Power: MODERATE - While the focus on RCTs and the systematic approach strengthen the reliability of the findings, the heterogeneity among studies and limitations in sample sizes and durations reduce the overall strength of the conclusions. Future research with more uniform methodologies and larger participant groups is essential to enhance the evidence base for ketogenic therapy in AD and MCI management.

Guerreiro, D., Almeida, A. and Ramalho, R., 2024. Ketogenic Diet and Neuroinflammation: Implications for Neuroimmunometabolism and Therapeutic Approaches to Refractory Epilepsy. Nutrients, 16(23), p.3994.

Overview: The review article explores the relationship between the ketogenic diet (KD) and neuroinflammation, focusing on how this high-fat, low-carbohydrate diet may influence immune system metabolism and its potential as a therapeutic approach for refractory epilepsy—seizures that do not respond to standard treatments. The authors discuss the role of neuroinflammation in epilepsy and propose that the KD might help modulate the immune response, potentially reducing seizure frequency and severity. ​

Strengths: This review offers a comprehensive examination of current research linking the KD to neuroinflammation and epilepsy. By integrating findings from various studies, the authors provide a clear overview of how metabolic changes induced by the KD might affect immune cell function and inflammatory pathways in the brain. This synthesis is valuable for understanding the broader implications of dietary interventions in neurological disorders.​

Limitations: Despite its thorough analysis, the review has certain limitations. Much of the evidence discussed comes from preclinical studies or small clinical trials, which may not fully represent the broader patient population. Additionally, the exact mechanisms by which the KD influences neuroinflammation remain not entirely understood, indicating a need for further research. The review would benefit from more discussion on potential side effects or challenges associated with implementing the KD in clinical settings.​

Conclusion: The review suggests that the ketogenic diet holds promise as a therapeutic strategy for managing refractory epilepsy, potentially through its effects on neuroinflammation and immune system metabolism. However, they emphasise the necessity for more extensive, well-designed clinical studies to confirm these findings and to better understand the underlying mechanisms.​

Scientific Power: MODERATE - While the authors provide a detailed and insightful synthesis of existing research, the reliance on preclinical data and limited clinical studies reduces the strength of the conclusions. Further large-scale clinical trials are essential to substantiate the proposed benefits of the ketogenic diet in managing refractory epilepsy.​

Hernandez, A.R., Hernandez, C.M., Campos, K., Truckenbrod, L., Federico, Q., Moon, B., McQuail, J.A., Maurer, A.P., Bizon, J.L. and Burke, S.N., 2018. A ketogenic diet improves cognition and has biochemical effects in prefrontal cortex that are dissociable from hippocampus. Frontiers in Aging Neuroscience, 10, p.391.

Overview: The study investigates how a ketogenic diet (KD)—a high-fat, low-carbohydrate diet—affects cognitive function and brain chemistry in aged rats. Over 12 weeks, they compared rats on a KD to those on a standard diet, assessing cognitive performance through behavioural tests and analysing biochemical changes in the prefrontal cortex (PFC) and hippocampus, two brain regions crucial for cognition. The results showed that the KD improved cognitive performance and led to distinct biochemical changes in the PFC, differing from those observed in the hippocampus. 

Strengths: A notable strength of this study is its focus on aged rats, providing insights into potential dietary interventions for age-related cognitive decline. The combination of behavioural assessments with biochemical analyses offers a comprehensive understanding of how the KD influences both cognitive function and underlying brain chemistry. Additionally, the study's design allows for the observation of region-specific effects of the KD, highlighting that the PFC and hippocampus respond differently to the diet. ​

Limitations: Despite its strengths, the study has certain limitations. The use of animal models means the findings may not directly translate to humans, necessitating caution when applying these results to human dietary recommendations. The sample size was relatively small, which could limit the generalisability of the findings. Furthermore, the study primarily focused on male rats, leaving it unclear whether similar effects would be observed in females. ​

Conclusion: The research suggests that a ketogenic diet can enhance cognitive function in aged rats, with distinct biochemical effects in the prefrontal cortex compared to the hippocampus. These findings contribute to the understanding of dietary interventions in age-related cognitive decline, though further research, particularly in human subjects, is necessary to confirm these effects and explore their potential therapeutic applications. ​

Scientific Power: MODERATE - The well-structured design and comprehensive analysis of behavioural and biochemical data strengthen the findings. However, limitations such as the use of animal models, small sample size, and focus on a single sex reduce the generalisability and applicability of the results to humans. Further studies, including larger and more diverse samples and human trials, are needed to build upon these findings.

Jiang, Z., Yin, X., Wang, M., Chen, T., Wang, Y., Gao, Z. and Wang, Z., 2022. Effects of ketogenic diet on neuroinflammation in neurodegenerative diseases. Aging and Disease, 13(4), p.1146.

Overview: The review article examines how the ketogenic diet (KD)—a high-fat, low-carbohydrate diet—affects neuroinflammation in neurodegenerative diseases such as Alzheimer's and Parkinson's. The authors discuss the potential mechanisms by which the KD may reduce inflammation in the nervous system, including the modulation of energy metabolism and the influence on various biochemical pathways.​

Strengths: This review provides a comprehensive analysis of existing research on the relationship between the KD and neuroinflammation. By integrating findings from various studies, the authors offer a clear overview of how metabolic changes induced by the KD might influence inflammatory processes in the brain. This synthesis is valuable for understanding the broader implications of dietary interventions in neurodegenerative diseases.​

Limitations: Despite its thorough analysis, the review has certain limitations. Much of the evidence discussed comes from preclinical studies or small clinical trials, which may not fully represent the broader patient population. Additionally, the exact mechanisms by which the KD influences neuroinflammation remain not entirely understood, indicating a need for further research. The review would benefit from more discussion on potential side effects or challenges associated with implementing the KD in clinical settings.​

Conclusion: The review suggests that the ketogenic diet holds promise as a therapeutic strategy for managing neurodegenerative diseases, potentially through its effects on neuroinflammation. However, it emphasises the necessity for more extensive, well-designed clinical studies to confirm these findings and to better understand the underlying mechanisms.​

Scientific Power: MODERATE - While the authors provide a detailed and insightful synthesis of existing research, the reliance on preclinical data and limited clinical studies reduces the strength of the conclusions. Further large-scale clinical trials are essential to substantiate the proposed benefits of the ketogenic diet in managing neurodegenerative diseases.​

Jiang, Y., Chen, Y., Chen, Y., Gong, X.;,Chen, Z., Zhang, X., 2025. Ketogenic Diet and Gut Microbiota: Exploring New Perspectives on Cognition and Mood. Foods, 14, p.1215.

Overview: The article investigates the intricate relationship between the ketogenic diet (KD), the gut microbiota, and their combined influence on cognition and mood. The review synthesises existing preclinical and clinical studies, exploring how the KD-induced metabolic shift and subsequent alterations in gut microbial composition might contribute to neurological and psychological outcomes. The authors highlight the potential of the gut-brain axis as a key mediator in the KD's effects on cognitive functions like memory and attention, as well as emotional states.

Strengths: This review offers a timely and relevant synthesis of a rapidly evolving research area. It effectively connects two distinct fields – nutritional neuroscience and microbiome research – to provide a more holistic understanding of the KD's impact. The article clearly outlines potential mechanisms through which KD-driven changes in gut bacteria, such as the production of short-chain fatty acids (SCFAs), could influence brain health via reduced inflammation and direct neuronal signalling. The inclusion of both animal and human studies provides a broader perspective on the current evidence.

Limitations: While comprehensive, the review acknowledges the inherent limitations within the reviewed literature. These include variability in KD protocols (e.g., macronutrient ratios, duration), small sample sizes in many human studies, and methodological inconsistencies across investigations. The precise causal relationships between specific microbial changes induced by the KD and specific cognitive or mood outcomes remain to be fully elucidated. The review also notes the need for more longitudinal studies to understand the long-term effects of the KD on the gut-brain axis and its clinical significance.

Conclusion: The review provides a valuable overview of the emerging evidence linking the ketogenic diet, gut microbiota modulation, and improvements in cognition and mood. It underscores the potential of the gut-brain axis as a critical pathway mediating the KD's neurological and psychological effects. However, the authors emphasise the need for more rigorous and standardised research to solidify these findings and translate them into effective therapeutic strategies.

Scientific Power: MODERATE - The review synthesises a body of literature that includes both preclinical studies (often with strong experimental control) and human studies (which are more directly relevant but often have methodological limitations). While the proposed mechanisms are biologically plausible and supported by some consistent findings, the heterogeneity of human studies and the need for more definitive causal links lower the overall scientific power to moderate. Future well-designed, large-scale clinical trials with detailed microbiome analysis will be crucial to strengthen the evidence in this field.

Kim, D.H., Park, M.H., Ha, S., Bang, E.J., Lee, Y., Lee, A.K., Lee, J., Yu, B.P. and Chung, H.Y., 2019. Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction. Aging (Albany NY), 11(4), p.1283.

Overview: The study investigates how β-hydroxybutyrate (β-HB), a ketone body produced during fasting or low-carbohydrate diets, affects inflammation in aged rats. The authors discovered that β-HB reduces inflammation by influencing two key proteins: PGC-1α and FoxO1. These proteins play significant roles in energy metabolism and stress responses. The study suggests that β-HB's anti-inflammatory effects are like those observed with calorie restriction, a known method for extending lifespan and improving health.​

Strengths: A major strength of this research is its focus on the molecular mechanisms through which β-HB exerts its effects. By identifying the roles of PGC-1α and FoxO1, the study provides a clearer understanding of how β-HB may mimic the benefits of calorie restriction. Additionally, the use of aged animal models is particularly relevant for studying interventions aimed at age-related inflammation and diseases.​

Limitations: The research was conducted on animal models, so the findings may not directly translate to humans. Moreover, the study primarily focuses on specific molecular pathways, and other mechanisms might also contribute to β-HB's anti-inflammatory effects. Further research is needed to explore these additional pathways and to confirm the findings in human subjects.​

Conclusion: The study suggests that β-hydroxybutyrate can reduce inflammation in aged rats by modulating PGC-1α and FoxO1, mechanisms similar to those activated by calorie restriction. These findings contribute to our understanding of how dietary interventions might combat age-related inflammation and associated diseases. However, further studies, particularly in humans, are necessary to fully grasp the therapeutic potential of β-HB.​

Scientific Power: MODERATE - While it offers significant insights into the molecular mechanisms of β-HB's anti-inflammatory effects, the reliance on animal models limits the direct applicability of the results to humans. Future research involving human participants is essential to validate these findings and assess their clinical relevance.

Li, C., Ma, Y., Chai, X., Feng, X., Feng, W., Zhao, Y., Cui, C., Wang, J., Zhao, S. and Zhu, X., 2024. Ketogenic diet attenuates cognitive dysfunctions induced by hypoglycemia via inhibiting endoplasmic reticulum stress-dependent pathways. Food & Function, 15(3), pp.1294-1309.

Overview: The study explores how a ketogenic diet (KD)—a high-fat, low-carbohydrate diet—affects cognitive impairments caused by hypoglycaemia (low blood sugar) in mice. Over two weeks, one-month-old mice were fed a KD, and changes in their gut microbiota were analysed using 16S rRNA gene sequencing. To induce hypoglycaemia, insulin was administered, after which cognitive functions were assessed. The researchers found that the KD alleviated anxiety-like behaviours and improved cognitive performance. They attributed these benefits to modifications in gut microbiota composition and the inhibition of endoplasmic reticulum (ER) stress-dependent pathways, which are associated with cell stress responses. ​

Strengths: A notable strength of this study is its comprehensive approach, combining dietary intervention with behavioural assessments and molecular analyses. By examining both gut microbiota changes and ER stress pathways, the researchers provided a multifaceted understanding of how the KD may protect against hypoglycaemia-induced cognitive dysfunction. Additionally, the use of well-established techniques, such as 16S rRNA sequencing and various staining methods, enhances the reliability of their findings. ​

Limitations: The research was conducted exclusively on young mice, which may not fully represent other age groups or translate directly to humans. Furthermore, the study primarily focused on specific molecular pathways, potentially overlooking other mechanisms through which the KD might exert its effects. The short duration of the dietary intervention also raises questions about the long-term applicability of the findings.​

Conclusion: The research suggests that a ketogenic diet may mitigate cognitive impairments induced by hypoglycaemia in mice, potentially through alterations in gut microbiota and the suppression of ER stress-dependent pathways. These findings contribute to the growing body of evidence supporting the neuroprotective effects of the KD. However, further studies, particularly involving human participants and longer intervention periods, are necessary to validate these results and explore their clinical relevance.​

Scientific Power: MODERATE - While the research design is robust and the findings are insightful, the reliance on animal models and the short duration of the intervention limit the generalisability of the results. Future research involving diverse populations and extended study periods will be crucial to substantiate these findings and assess their potential therapeutic applications in humans.

Maalouf, M., Sullivan, P.G., Davis, L., Kim, D.Y. and Rho, J.M., 2007. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience, 145(1), pp.256-264.

Overview: The study investigates how ketone bodies—specifically β-hydroxybutyrate (BHB) and acetoacetate (ACA)—affect neurons exposed to glutamate-induced toxicity, a condition known as excitotoxicity. Excitotoxicity is a process where excessive glutamate leads to neuronal injury and is implicated in various neurological disorders. The researchers found that a combination of BHB and ACA reduced neuronal death and prevented adverse changes in neuronal membrane properties caused by glutamate. They concluded that ketones decrease the production of harmful reactive oxygen species (ROS) in mitochondria by enhancing NADH oxidation, thereby offering neuroprotective effects. ​

Strengths: This study provides valuable insights into the potential neuroprotective mechanisms of ketone bodies. By focusing on mitochondrial function and ROS production, the researchers addressed a critical aspect of neuronal health. The use of electrophysiological and fluorescence imaging techniques allowed for precise measurements of neuronal responses, strengthening the validity of their findings. ​

Limitations: The experiments were conducted on isolated rat neurons, which may not fully replicate the complex environment of a living brain. Additionally, the study did not explore the long-term effects of ketone body administration, leaving questions about the duration and sustainability of the observed neuroprotective effects. Furthermore, the exact pathways through which ketones enhance NADH oxidation remain to be fully elucidated.​

Conclusion: The research suggests that ketone bodies like BHB and ACA can protect neurons from glutamate-induced damage by reducing mitochondrial ROS production through increased NADH oxidation. These findings contribute to our understanding of how metabolic interventions might mitigate excitotoxic neuronal injury. However, further research, particularly in vivo studies, is necessary to confirm these effects and explore their potential therapeutic applications.​

Scientific Power: MODERATE - While the research offers important insights into the neuroprotective effects of ketone bodies, the reliance on in vitro experiments with isolated neurons limits the direct applicability of the findings to living organisms. Future in vivo studies are essential to validate these results and assess their relevance in clinical contexts.​

Pavón, S., Lázaro, E., Martínez, O., Amayra, I., López-Paz, J.F., Caballero, P., Al-Rashaida, M., Luna, P.M., García, M., Pérez, M. and Berrocoso, S., 2021. Ketogenic diet and cognition in neurological diseases: a systematic review. Nutrition Reviews, 79(7), pp.802-813.

Overview: The systematic review examines the impact of the ketogenic diet (KD) on cognitive function in individuals with neurological diseases. The authors analysed various studies that investigated how the KD influences cognitive outcomes in conditions such as epilepsy, Alzheimer's disease, and other neurological disorders. The review aimed to consolidate existing evidence to determine whether the KD offers cognitive benefits across these conditions.​

Strengths: A notable strength of this review is its comprehensive analysis of multiple neurological conditions, providing a broad perspective on the potential cognitive effects of the KD. By including a diverse range of studies, the authors offer a holistic view of the current research landscape. Additionally, the systematic approach enhances the reliability of their conclusions.​

Limitations: The studies included exhibit variability in design, sample size, and methodologies, which complicates direct comparisons and the formation of definitive conclusions. Furthermore, the reliance on existing literature means that any inherent biases or limitations within those studies may influence the overall findings. The review also highlights a scarcity of large-scale, randomised controlled trials, underscoring the need for more rigorous research in this area.​

Conclusion: The systematic review suggests that the ketogenic diet may have positive effects on cognitive function in various neurological diseases. However, the evidence remains inconclusive due to inconsistencies across studies and methodological limitations. The authors emphasise the necessity for more well-designed, large-scale studies to better understand the KD's potential cognitive benefits and its applicability across different neurological conditions.​

Scientific Power: MODERATE - While it provides a valuable synthesis of existing research, the variability and limitations of the included studies, along with the lack of large-scale randomised controlled trials, restrict the strength of the conclusions. Further high-quality research is essential to draw more definitive insights into the cognitive effects of the ketogenic diet in neurological diseases.​

Polito, R., La Torre, M.E., Moscatelli, F., Cibelli, G., Valenzano, A., Panaro, M.A., Monda, M., Messina, A., Monda, V., Pisanelli, D. and Sessa, F., 2023. The ketogenic diet and neuroinflammation: the action of beta-hydroxybutyrate in a microglial cell line. International Journal of Molecular Sciences, 24(4), p.3102.

Overview: The study investigates how β-hydroxybutyrate (BHB), a ketone body produced during a ketogenic diet (KD), affects microglial cells, which are immune cells in the brain involved in neuroinflammation. Using BV2 microglial cells, the researchers examined BHB's impact on cell polarisation (shifting towards pro-inflammatory or anti-inflammatory states), migration, and cytokine expression, both with and without exposure to lipopolysaccharide (LPS), a substance that induces inflammation. The findings revealed that BHB promotes an anti-inflammatory (M2) phenotype in microglia, reduces their movement following LPS stimulation, decreases levels of the pro-inflammatory cytokine IL-17, and increases levels of the anti-inflammatory cytokine IL-10. These results suggest that BHB may contribute to neuroprotection by modulating microglial activity and reducing neuroinflammation. ​

Strengths: A key strength of this study is its focus on the molecular mechanisms by which BHB influences microglial cells, providing insights into how the KD might exert neuroprotective effects. The use of BV2 cells as a model allowed for controlled experimentation on microglial behaviour. Additionally, assessing both pro-inflammatory and anti-inflammatory cytokines offered a comprehensive view of BHB's immunomodulatory effects.​

Limitations: The study was conducted in vitro (outside a living organism), which may not fully replicate the complex environment of the brain. Therefore, the results might not directly translate to in vivo (within a living organism) scenarios. Furthermore, the research focused solely on BHB's effects; other ketone bodies or components of the KD were not examined, leaving a gap in understanding the diet's overall impact on neuroinflammation.​

Conclusion: The research indicates that BHB can modulate microglial activity by promoting an anti-inflammatory state and altering cytokine production, suggesting a potential mechanism for the neuroprotective effects of the KD. While these findings enhance our understanding of BHB's role in neuroinflammation, further in vivo studies are necessary to confirm these effects and explore their relevance in clinical settings.​

Scientific Power: MODERATE - The research provides valuable mechanistic insights into BHB's effects on microglial cells. However, the reliance on in vitro models limits the direct applicability of the findings to living organisms. Future in vivo studies are essential to validate these results and determine their clinical significance.

Rondanelli, M., Gasparri, C., Pirola, M., Barrile, G.C., Moroni, A., Sajoux, I. and Perna, S., 2024. Does the Ketogenic Diet Mediate Inflammation Markers in Obese and Overweight Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Nutrients, 16(23), p.4002.

Overview: The systematic review and meta-analysis evaluate the effects of the ketogenic diet (KD) on inflammatory markers in overweight and obese adults. The authors analysed seven randomised controlled trials involving 218 participants who followed either a KD or a control diet for durations ranging from 8 weeks to 2 years. The primary outcomes assessed were levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both of which are indicators of inflammation. The analysis revealed a significant reduction in CRP levels (mean decrease of 0.62 mg/dL), while the decrease in IL-6 levels was modest and not statistically significant. ​

Strengths: A notable strength of this study is its rigorous methodology, including a comprehensive search of multiple databases (Web of Science, PubMed, Scopus, and Google Scholar) to identify relevant randomised controlled trials. This approach enhances the reliability and comprehensiveness of the findings. Additionally, focusing on well-established inflammatory biomarkers like CRP and IL-6 provides clinically relevant insights into the potential anti-inflammatory effects of the KD.​

Limitations: The number of studies included was relatively small, comprising only seven trials, which may limit the generalisability of the results. There was also considerable heterogeneity among the studies in terms of participant characteristics, diet composition, and study duration, making direct comparisons challenging. Furthermore, the analysis was limited to two inflammatory markers; other relevant markers were not assessed due to insufficient data.

Conclusion: The meta-analysis suggests that the ketogenic diet may have a modest effect in reducing certain inflammatory markers, particularly CRP, in overweight and obese individuals. However, the variability among studies and the limited scope of assessed biomarkers indicate that further research is needed to fully understand the KD's impact on inflammation. Future studies should aim for greater consistency in design and explore a broader range of inflammatory markers to provide more definitive conclusions.​

Scientific Power: MODERATE - While the systematic review and meta-analysis design are robust, the limited number of included studies, heterogeneity among them, and restricted assessment of inflammatory markers suggest that the evidence is not yet strong enough to make definitive claims about the ketogenic diet's effects on inflammation. Further, more homogeneous and comprehensive research is warranted to strengthen the evidence base.​

Rong, L., Peng, Y., Shen, Q., Chen, K., Fang, B. and Li, W., 2024. Effects of ketogenic diet on cognitive function of patients with Alzheimer's disease: a systematic review and meta-analysis. The Journal of Nutrition, Health and Aging, 28(8), p.100306.

Overview: The systematic review and meta-analysis assess the effects of the ketogenic diet (KD) on cognitive function in patients with Alzheimer's disease (AD). The authors analysed data from multiple randomised controlled trials (RCTs) to determine whether adherence to a KD could lead to measurable improvements in cognitive performance among AD patients.​

Strengths: A significant strength of this study is its rigorous methodology, combining data from various RCTs to enhance statistical power and reliability. By focusing on AD patients, the research addresses a critical area of concern, given the increasing prevalence of dementia worldwide. Additionally, the use of standardised cognitive assessment tools across studies allows for comparability and strengthens the validity of the findings.​

Limitations: The included studies varied in design, sample size, and duration, which may introduce heterogeneity and affect the consistency of the results. Some studies had small sample sizes, limiting the generalisability of their findings. Moreover, the quality of the included studies varied, with some lacking blinding or having high dropout rates, which could introduce bias. The KD's long-term effects remain uncertain, as most studies had relatively short follow-up periods.​

Conclusion: The meta-analysis suggests that the ketogenic diet may have a positive impact on cognitive function in patients with Alzheimer's disease. However, due to the variability in study designs and the quality of evidence, more large-scale, long-term RCTs are needed to confirm these findings and determine the KD's efficacy and safety for AD patients.​

Scientific Power: MODERATE - While the meta-analysis provides valuable insights, the heterogeneity among included studies and the limitations mentioned above suggest that the evidence is not yet robust enough to draw definitive conclusions. Future research with standardised protocols and rigorous methodologies is essential to strengthen the evidence base.​

Sampson, T.R., Debelius, J.W., Thron, T., Janssen, S., Shastri, G.G., Ilhan, Z.E., Challis, C., Schretter, C.E., Rocha, S., Gradinaru, V. and Chesselet, M.F., 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell, 167(6), pp.1469-1480.

Overview: The study investigates the role of gut microbiota in Parkinson’s disease (PD) by using a preclinical model to study how changes in the gut microbiome affect motor deficits and neuroinflammation associated with the disease. The researchers found that the absence of certain gut bacteria in mice led to reduced neuroinflammation and improved motor function, suggesting that the gut microbiota influences the progression of PD. The study also explored how microbiota-driven changes could impact brain inflammation and the overall neurodegenerative process in PD.

Strengths: One of the key strengths of this study is its innovative approach to understanding Parkinson’s disease by focusing on the gut-brain connection. The researchers used a comprehensive array of methods, including germ-free mice (mice without gut microbiota) and microbiota transplantation, to determine how changes in gut bacteria affect the brain and motor function. This multi-pronged approach adds credibility to the findings and provides strong evidence for the role of gut microbiota in neuroinflammation and motor deficits in PD. The study also lays the groundwork for future research into microbiota-based therapies for neurodegenerative diseases.

Limitations: The findings were based on animal models, which do not always fully represent human biology. Additionally, while the study identified a connection between gut microbiota and neuroinflammation, the specific mechanisms through which gut bacteria influence PD progression remain unclear. The results need to be further validated in human clinical studies.

Conclusion: The research provides compelling evidence that gut microbiota can influence the progression of Parkinson’s disease, specifically by regulating neuroinflammation and motor function. This highlights the potential for targeting the microbiome as a novel therapeutic approach for neurodegenerative diseases.

Scientific Power: MODERATE to STRONG - The study provides robust evidence for the gut-brain connection in Parkinson’s disease, using a well-designed experimental model and diverse methodologies. Its findings are highly relevant to the emerging field of microbiome-based therapies for neurodegenerative diseases, however, the findings were based on animal models, which do not always represent human biology.

Wan, S.R., Teng, F.Y., Fan, W., Xu, B.T., Li, X.Y., Tan, X.Z., Guo, M., Gao, C.L., Zhang, C.X., Jiang, Z.Z. and Xu, Y., 2023. BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway. Aging (Albany NY), 15(22), p.13384.

Overview: The study investigates the role of BDH1-mediated β-hydroxybutyrate (βOHB) metabolism in mitigating diabetic kidney disease (DKD). The research demonstrated that BDH1 facilitates the conversion of βOHB, leading to the activation of the NRF2-mediated antioxidative pathway. This activation enhances the kidney's antioxidant defences, thereby ameliorating the progression of DKD. ​

Strengths: A significant strength of this study is its focus on BDH1, an enzyme involved in ketone body metabolism, providing novel insights into its protective role against DKD. The research effectively links metabolic processes to kidney health, offering potential therapeutic avenues for managing DKD. Additionally, the study's findings are supported by previous research, such as the work by Xu et al. (2021), which also highlighted BDH1's role in activating NRF2 to alleviate hepatic injury. ​

Limitations: The study's limitations include a lack of in vivo validation, as the experiments were conducted in vitro. This absence raises questions about the applicability of the findings to living organisms. Moreover, the research does not explore the long-term effects of BDH1-mediated βOHB metabolism on kidney function, leaving the sustainability of the observed benefits uncertain.​

Conclusion: The study suggests that BDH1-mediated βOHB metabolism activates the NRF2 antioxidative pathway, offering a potential therapeutic strategy for DKD. Nonetheless, further research, including in vivo studies and long-term evaluations, is essential to fully understand the clinical relevance and therapeutic potential of these findings.​

Scientific Power: MODERATE - While the research introduces a promising mechanism linking BDH1, βOHB metabolism, and NRF2 activation in the context of DKD, the lack of in vivo studies and long-term data limits the strength of the conclusions. Future studies addressing these gaps are necessary to substantiate the therapeutic potential of this approach.​

Yang, H., Shan, W., Zhu, F., Wu, J. and Wang, Q., 2019. Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms. Frontiers in Neurology, 10, p.585.

Overview: The study reviews the role of ketone bodies, particularly β-hydroxybutyrate (βOHB), in neurological diseases, focusing on their neuroprotective effects and underlying mechanisms. The article discusses how ketone bodies, produced during ketosis (such as from a ketogenic diet), may offer therapeutic benefits for a range of neurological conditions, including Alzheimer's disease, Parkinson's disease, and epilepsy. The authors explore how βOHB helps in protecting neurons from oxidative stress, inflammation, and energy deficits, which are common features of neurological disorders. They also review various molecular mechanisms, such as modulation of gene expression and mitochondrial function, that contribute to the neuroprotective effects of ketone bodies.

Strengths: One major strength of this review is its comprehensive analysis of the current literature on ketone bodies and neurological diseases. The article not only highlights the potential therapeutic benefits of ketone bodies but also explains the molecular mechanisms behind their effects. This dual approach enhances the understanding of how ketones function at both the cellular and system levels. Additionally, the paper ties together research from diverse fields, including biochemistry, neurology, and nutrition, offering a holistic view of the topic.

Limitations: A limitation of the article is that it primarily focuses on preclinical studies, such as animal models and in vitro research, rather than human clinical trials. Although the insights are valuable, translating these findings to human therapies remains uncertain. The review also does not delve deeply into the potential side effects or risks of using ketone bodies therapeutically.

Conclusion: The review suggests that ketone bodies, particularly βOHB, have strong neuroprotective effects and could play a key role in treating neurological diseases. However, further clinical research is needed to validate these findings and assess their long-term effectiveness in humans.

Scientific Power: MODERATE to STRONG - The article synthesises a wide range of studies and provides a solid foundation for understanding the neuroprotective roles of ketone bodies. However, the lack of human clinical trials and potential side effects means that the evidence remains somewhat preliminary, though promising.

Youm, Y.H., Nguyen, K.Y., Grant, R.W., Goldberg, E.L., Bodogai, M., Kim, D., D'agostino, D., Planavsky, N., Lupfer, C., Kanneganti, T.D. and Kang, S., 2015. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature Medicine, 21(3), pp.263-269.

Overview: The study explores the role of β-hydroxybutyrate (βOHB), a ketone metabolite, in blocking the NLRP3 inflammasome, a key player in inflammation. The authors investigated how βOHB inhibits NLRP3 inflammasome activation, which is implicated in various inflammatory diseases such as arthritis, diabetes, and cardiovascular conditions. Their findings show that βOHB, produced during ketosis (e.g., fasting or ketogenic diets), suppresses the NLRP3 inflammasome pathway by regulating key signalling molecules, leading to reduced inflammation. This study provides insights into the potential therapeutic use of βOHB to manage chronic inflammatory diseases.

Strengths: A notable strength of this study is its clear and detailed mechanistic approach. The authors used a combination of in vitro, in vivo, and genetic models to demonstrate how βOHB specifically targets and inhibits NLRP3 inflammasome activation. This multi-method approach strengthens the validity of their findings. Additionally, the focus on βOHB offers a novel perspective on how metabolic states (like ketosis) can influence immune responses, which has potential therapeutic implications.

Limitations: One limitation of the study is that it primarily focuses on animal models, particularly mice, and in vitro experiments. Although these models are useful, the results may not fully translate to humans. Moreover, the study does not explore the long-term effects or any possible side effects of using βOHB as a therapeutic intervention for inflammatory diseases.

Conclusion: The study suggests that βOHB can block the NLRP3 inflammasome, offering a potential new avenue for treating inflammatory diseases. However, further research, including human clinical trials, is needed to fully understand its therapeutic potential.

Scientific Power: STRONG - The comprehensive methodology, including genetic and animal models, provides robust evidence supporting the role of βOHB in modulating inflammation. The study also opens up important avenues for further research into ketosis and immune modulation, contributing valuable insights to the field of metabolic medicine.

Zhao, Y., Yang, H., Wu, P., Yang, S., Xue, W., Xu, B., Zhang, S., Tang, B. and Xu, D., 2024. Akkermansia muciniphila: A promising probiotic against inflammation and metabolic disorders. Virulence, 15(1), p.2375555.

Overview: The study explores the potential of Akkermansia muciniphila, a type of beneficial gut bacteria, as a promising probiotic for combating inflammation and metabolic disorders. The review highlights the role of A. muciniphila in improving gut barrier function, modulating immune responses, and promoting metabolic health. By focusing on its ability to regulate systemic inflammation and its potential therapeutic effects on conditions such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), the article emphasises the significance of this bacterium in maintaining gut health and preventing metabolic diseases.

Strengths: One major strength of this article is its comprehensive review of the literature on A. muciniphila and its therapeutic potential. The authors synthesise data from various studies that demonstrate the bacterium's positive effects on the gut microbiota, immune modulation, and metabolic regulation. The clear and systematic presentation of evidence makes the article accessible and informative for readers, particularly those new to the topic. Moreover, the review offers promising insights into future research directions and the potential clinical applications of A. muciniphila as a probiotic.

Limitations: While the article provides a valuable summary of the current knowledge on A. muciniphila, one limitation is the lack of detailed discussion on the challenges of translating these findings into clinical practice. Most of the studies reviewed are preclinical or animal-based, and the evidence for its efficacy in humans is still limited. Additionally, the review does not explore potential side effects or risks associated with using A. muciniphila as a probiotic.

Conclusion: The review provides strong evidence supporting Akkermansia muciniphila as a promising probiotic for treating inflammation and metabolic disorders. However, further clinical studies are needed to confirm its efficacy and safety in humans.

Scientific Power: MODERATE to STRONG - The article thoroughly reviews existing literature, presenting solid evidence for the beneficial effects of A. muciniphila. However, its reliance on preclinical studies and limited human data suggests that more research is needed to fully establish the therapeutic potential of this bacterium.