Introduction

Nutritional psychiatry is a new area that links dietary habits to mental health and microbial function [1, 2]. Therefore, nutritional psychiatry must include the role of the gut microbiome as a diagnostic tool to identify targets for personalized treatments, and for integrative strategies that combine dietary, pharmacological, and psychological interventions.

Dietary patterns refer to the quantity, diversity, and types of foods and nutrients in a diet, as well as to the frequency of their consumption. Some of the major dietary patterns include: high-calorie diets such as the Western diet; mixed-balance diets such as the Mediterranean and Japanese diets; plant-based diets such as the vegetarian and vegan diets; and low-carbohydrate diets such as the ketogenic diet (KD). These diets exert diverse effects on physiological well-being, and share common attributes and characteristics [3–8]. However, adherence to a specific dietary pattern is influenced by geographic location, cultural norms, ethical beliefs, and environmental consciousness, as well as by physical health and psychological well-being [9–11].

The KD is an emerging dietary pattern, which consists of a normocaloric, high-fat, very low-carbohydrate diet that provokes a state of ketosis [12]. There are numerous reports in the literature stating that KD has a significant positive effect on epileptic seizures and mood disorders, thus suggesting KD as a potential therapeutic tool [13]. In addition, several modified KDs are currently widely applied to the treatment of obesity [14], diabetes [15], cancer [16], migraine [17], and metabolic syndrome [18]. However, the involvement of this diet in mental health outcomes, as well as its role in the modulation of the gut microbiome, has been poorly studied. For this reason, the present narrative review examines the therapeutic effects of the KD and its variants on physiological and mental health, including their role in modulating the gut microbiome.

Effects of KDs on physiological health

KDs have become increasingly popular due to their effects in promoting weight loss, enhancing insulin sensitivity, and potentially lowering dyslipidemia [14, 15, 19]. These factors are crucial in the prevention of cardio-metabolic diseases, which represent one of the most significant health challenges today [19], although there is no clear evidence regarding the advantageous effects of these diets on other cardio-metabolic risk markers [20].

There are diverse variants of KDs that primarily differ in their composition of fats, proteins, and carbohydrates. (i) The modified Atkins diet (MAD) consists of 65% fats, 25% proteins, and 10% carbohydrates [21]. In the classic KD, the ratio of fats and carbohydrates is 4:1. This ratio can be altered to 3:1 for moderating metabolism activity, with restricted calories and fluids. In contrast, the MAD does not require calorie, protein, or fluid restriction and may be a good alternative for patients who cannot tolerate a more restrictive diet like the classic KD [22]. (ii) The medium-chain triglyceride diet (MCTD) contains a higher production of ketone bodies (KBs) than any other types of fats, including long-chain triglycerides (LCT). This diet, which consists of 71% fats, 10% proteins, and 19% carbohydrates, is more appropriate for children because it diminishes the need for other micronutrients, and contributes to a lower cholesterol ratio, thereby decreasing the risk of cardiovascular disease [23]. (iii) Low glycemic index therapy (LGIT) is an alternative diet treatment consisting of 60% fats, 30% proteins, and 10% carbohydrates with a low glycemic index [24]. While the KD and MAD are associated with ketosis, the exact role of KBs in LGIT is unclear. For instance, Muzykewicz et al. [25] reported that of the 12 patients with less than 90% seizure reduction, only 33.3% had elevated serum levels of β-hydroxybutyrate (BHB) (0.7–1.7 mM). Therefore, it seems that ketosis is not required for optimal seizure control.

All KDs result in increased amounts of KBs, such as acetoacetate, BHB, medium-chain triglyceride (MCT), and acetone in the blood and urine [26]. These compounds are involved in several physiological mechanisms, including enhanced mitochondrial activity, inhibition of apoptotic proteins, reduction of oxidative stress, expression of antioxidant proteins, as well as modulation of autophagy, neurotransmitter levels [γ-aminobutyric acid (GABA), glutamate, and monoamines], and neuroinflammatory pathways [27–33]. In addition, KBs can act as an alternative energy source when glucose metabolism is compromised [34], potentially addressing the bioenergetic deficiencies in several physiological and mental disorders [35, 36]. In this sense, Augustin et al. [37] reported a pivotal role of ketones directly inhibiting glutamate receptors (AMPA receptors) and altering cell energetics through mitochondrial biogenesis. Interestingly, KD therapy also induces an epigenetic mechanism by means of DNA methylation [38].

Although a low-carbohydrate, high-fat, and high-protein diet, like KD, could be considered unhealthy for individuals with obesity, diverse studies have shown its effectiveness in treating this condition [39]. Lowering carbohydrate consumption has also been shown to result in substantial reductions in cholesterol, triglycerides, and diastolic blood pressure levels, while simultaneously raising high-density lipoprotein (HDL) levels [40]. KDs provide benefits through several mechanisms, such as appetite diminishment associated with greater levels of cholecystokinin, glucagon-like peptide 1, and ghrelin, or appetite suppression promoted by the ketones themselves. In short, it can be hypothesized that the results of KD in obese patients may also be related to its efficacy in increasing fat consumption and lipolysis while decreasing lipogenesis. In addition, KD inhibits gluconeogenesis in the liver by a decrease in insulin and an increase in glucagon, which then leads to a higher rate of resting energy expenditure [41].

By lowering glucose levels, KDs also restrict the metabolism of cancer cells, which are unable to effectively utilize KDs as an energy source [42]. Furthermore, KDs induce low glucose levels with an inhibition of the lactate/pyruvate cycle, thereby blocking neovascularization, hypoxia-induced epidermal growth factor activation, and angiogenesis [42]. Elevated KB levels inhibit NLRP3 inflammasome, limiting inflammation, which is central to cancer pathogenesis [43].

Effects of KDs on mental health

KD stabilizes neural networks, improves neuroplasticity, and has direct benefits in brain bioenergetics, which are related to several mental disorders [59, 60]. These effects of the KD confer health benefits by alleviating the symptoms of several neuropsychiatric and psychological conditions, such as epilepsy, anxiety, depression, schizophrenia, bipolar disorder, ASD, and certain neurodegenerative diseases [29, 61–67].

Discussion

The potential of dietary interventions as a therapeutic tool in the treatment of diverse health conditions is immense and widely recognized [10, 120]. This review summarizes studies related to the effects of KD therapy on various physiological and mental disorders, as well as those on the changes provoked by this diet on the composition and function of the gut microbiome. From the studies reviewed, it is clear that KD exerts a reduction in seizure frequency in refractory epileptic patients; therefore, the diet and its modifications may be considered as the primary feeding choice for intractable epilepsy in children. In addition, KDs support neural stability, neuroplasticity, and brain bioenergetics [121], prompting preclinical and clinical trials to explore their capability in treating psychiatric, psychological, and neurodegenerative disorders [122].

KD plays a neural protective role through various mechanisms at the mitochondrial level, including increased levels of uncoupling proteins, enhanced antioxidant activity [reduced production of reactive oxygen species (ROS)], and ATP synthesis in the brain and brain mitochondria [123]. KD exerts its antioxidant effects on mitochondria mainly by regulating the function of mitochondrial respiratory complexes, decreasing ROS, and increasing antioxidant levels [124].

Several studies have reported that KDs and KBs confer neuroprotective effects by supplying alternative energy substrates to neurons and enhancing mitochondrial structure and function [123]. Additionally, KBs and KDs exhibit positive impacts by reducing oxidative stress and apoptosis [125, 126], promoting autophagic flux, and regulating gene expression and other cellular functions through epigenetic and post-translational modifications of histones and non-histone proteins [123]. KBs and KD also suppress neuroinflammation, and modulate neurotransmitter systems and the gut microbiota [123, 127].

Collectively, the encouraging findings from existing preclinical studies, case reports, and uncontrolled clinical trials suggest a clinically significant potential for KD therapy in the treatment of mental illnesses of varying severity, providing hope to millions of individuals globally affected by these conditions. However, randomized controlled clinical trials are necessary to determine the impact of the ketotic metabolic state on the desired outcomes. Additionally, extensive long-term clinical research on mental disorders is essential to assess the adverse effects, efficacy, and sustainability of the KD. Furthermore, addressing potential methodological limitations in studies on dietary effects is pivotal, as such limitations can compromise the validity of results, similar to issues observed in research on other dietary patterns [128, 129].

Considering the potential of KD in treating neuropsychiatric and psychological disorders [96], understanding its impact on the gut microbiome is crucial. Changes in microbiome composition and function may underlie some of the observed therapeutic effects, providing insights into how KD modulates brain function and mental health. The field of omics encompasses a range of high-throughput methodologies, including genomics, transcriptomics, proteomics, and metabolomics, along with their corresponding meta-omics derivatives, such as meta-proteomics, metagenomics, and meta-transcriptomics [130]. These methodologies will constitute an essential strategy to know the influence of the gut microbiome and its metabolites on the effects of the KD on mental disorders. Multi-omics approaches, in fact, could enhance our understanding of the changes and interactions occurring within the gut microbial community following the consumption of a diet, such as KD [131]. Ultimately, integrating these advanced techniques could lead to novel insights into the therapeutic potential of dietary interventions in mental health and support the development of more effective, personalized treatment strategies.

Beyond individual metabolic effects, the KDs seem to show important implications for public health, clinical practice, and dietary policy. Given its potential to influence physiological and mental health, KDs could be particularly beneficial for populations with limited success using conventional diets, especially individuals with metabolic syndrome, diabetes, epilepsy, and neuropsychiatric disorders. This dietary approach also has potential relevance for aging populations vulnerable to neurodegenerative diseases, where the neuroprotective properties of KDs may improve quality of life and reduce healthcare burdens, and may also complement other interventions with relatively limited effectiveness [132]. Additionally, practitioners in mental health, neurology, endocrinology, and nutrition could benefit from a robust understanding of KD principles to apply in therapeutic contexts, while healthcare systems, public health organizations, and policymakers should consider the KDs in the context of broader dietary frameworks and interventions. Comparative studies with other diet plans, such as Mediterranean or vegetarian diets, could be essential to elucidate the long-term sustainability of KDs, as well as their efficacy and feasibility for diverse populations. Ethical and educational initiatives will be necessary to ensure it is accessible, equitable, and aligned with individual health needs, maximizing its therapeutic potential while acknowledging the challenges of widespread adoption. In this respect, given that the KD relies heavily on animal-based fats and proteins, raising critical concerns for both environmental sustainability and animal well-being, its application should be restricted to specific populations with a demonstrated therapeutic need.

This narrative review presents several limitations: (i) the studies reviewed encompass different types of KDs, making it difficult to generalize the reported results; (ii) many of the studies included both animal models and human subjects, which complicates direct comparisons and the establishment of a clear relationship between KDs and the gut microbiome; (iii) the microbiological methodologies employed in the reviewed studies varied widely, with different omics techniques potentially offering varying degrees of precision in bacterial taxonomy, which may explain the contradictory findings observed; (iv) most of the studies focused on short-term KD intake, and there has been limited investigation into long-term dietary effects and follow-up; (v) the inclusion of studies with small sample sizes, either in terms of participants or animals, undermines the statistical power of the reported results; (vi) the heterogeneity of the included studies in terms of design, sample characteristics, and methodology may have influenced the ability to make direct comparisons, thereby limiting the interpretation of the findings; and (vii) several of the studies reviewed focused on patients with epilepsy or other medical conditions, who already exhibit gut microbiome alterations inherent to these disorders, which constitute a significant source of bias and confounding factors.

Conclusions

In general terms, KDs promote weight loss, enhance insulin sensitivity, and may reduce dyslipidemia. That is why KDs are used as a therapeutic tool for a variety of metabolic-related conditions, including obesity, diabetes, and skin diseases. In addition, the beneficial effects of KDs on epilepsy symptoms, particularly in refractory epilepsy, are well known due to the antiepileptic efficacy and reduced toxicity of these diets. By raising KBs, KDs boost mitochondrial function, reduce oxidative stress, modulate autophagy, and impact neurotransmitters and neuroinflammation. KDs also offer benefits by reducing appetite and enhancing fat consumption and lipolysis while decreasing lipogenesis. Furthermore, KDs boost gluconeogenesis, leading to increased energy expenditure. Their low-glucose composition has the potential to restrict cancer cell metabolism and inhibit neovascularization, hypoxia response, and angiogenesis. KDs also have the capability of shaping the gut microbiome, potentially managing autoimmune diseases by reducing inflammation, despite they may lower beneficial bacteria levels. The alteration of the gut microbiome composition produced by KDs depends on the KD type, and existing controversial results of the consequence of this dysbiosis. In this regard, it has been reported that the administration of these diets exacerbated the inflammatory state of the intestinal mucosa, whereas it has been also noted that these diets induce a reduction of pro-inflammatory Th17 cells. In mental health, KDs seem to stabilize neural networks, enhance neuroplasticity, and improve brain energy use, with possible benefits for neurodegenerative diseases, as well as for other psychiatric and psychological disorders. Within this context, KDs appear to exert an influence due to their antioxidant properties and low carbohydrate content, which open a new window for the implementation of these diets in dietary protocols within hospital and geriatric settings. Thus, KDs may serve as promising tools both as adjuvant therapies and as dietary patterns for specific populations across physiological, metabolic, and mental conditions. However, more randomized, long-term studies are required to assess their efficacy, sustainability, and safety, including methodological rigor to strengthen findings on dietary impacts.

Despite the potential benefits and growing attention focused on KDs, it remains premature to draw definitive conclusions regarding their overall feasibility for widespread clinical application. Their use should be targeted at specific medical conditions rather than promoted as a general dietary pattern. Moreover, ethical and environmental considerations should not be overlooked, as KDs often rely on animal-derived resources. In this respect, KDs do not necessarily have to be based on animal products, as the key principle is to maintain a low carbohydrate intake while prioritizing a sufficient supply of healthy fats, regardless of their source.