Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.

OBJECTIVE: KCNT1-related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep-related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug-resistant seizures and global developmental delays. In addition to conventional anti-seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD-including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients. METHODS: We performed a literature review on PubMed and EMBase with the keyword "KCNT1" and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype. RESULTS: A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%-25% of patients). SIGNIFICANCE: Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug-resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1-related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors. PLAIN LANGUAGE SUMMARY: We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti-seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

Impact of the ketogenic diet as a dietary approach on cardiovascular disease risk factors: a meta-analysis of randomized clinical trials.

BACKGROUND: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, and the scarcity of scientific evidence regarding the impact of ketogenic diets on CVD risk factors necessitates urgent attention and redress. OBJECTIVES: This meta-analysis evaluates the impact of the ketogenic diet on CVD risk factors compared with control diets through randomized controlled trials (RCTs). METHODS: The study was registered in advance in the PROSPERO database (CRD42023491853). A systematic search was conducted across PubMed, Web of Science, EMBASE, and Cochrane Library to identify relevant RCTs. Fixed and random effects were employed to calculate the mean differences and 95% confidence intervals (CIs) for changes in CVD risk factors pre- and postketogenic diet intervention. RESULTS: A total of 27 RCTs with 1278 participants were analyzed. The ketogenic diet intervention presented increase in total cholesterol (mean differences: 0.36 mmol/L; 95% CI: 0.15, 0.57; I2: 85.1%), low-density lipoprotein cholesterol (mean differences: 0.35 mmol/L; 95% CI: 0.20, 0.50; I2: 73.9%) and high-density lipoprotein cholesterol (mean differences: 0.16 mmol/L; 95% CI: 0.09, 0.23; I2: 86.7%) concentrations. Reductions were observed in the triglyceride (mean differences: -0.20 mmol/L; 95% CI: -0.29, -0.11; I2: 72.2%), blood glucose (mean differences: -0.18 mmol/L; 95% CI: -0.33, -0.02; I2: 76.4%), blood insulin (mean differences: -8.32 pmol/L; 95% CI: -14.52, -2.12; I2: 81.5%), diastolic blood pressure (mean differences: -1.41 mmHg; 95% CI: -2.57, -0.26; I2: 49.1%), weight (mean differences: -2.59 kg; 95% CI: -3.90, -1.28; I2: 87.4%), and body mass index (mean differences: -1.59 kg/m2; 95% CI: -2.32, -0.86; I2: 84.5%) concentrations after implementing ketogenic diets. CONCLUSIONS: Although the ketogenic diet demonstrates benefits in terms of triglyceride, blood pressure, weight, and glycemic control, its impact on CVD risk factors, especially the elevated total cholesterol and low-density lipoprotein cholesterol concentrations, warrants a cautious approach.

Targeting fatty acid oxidation enhances response to HER2-targeted therapy.

Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients.

Metabolic Effects of Ketogenic Diets: Exploring Whole-Body Metabolism in Connection with Adipose Tissue and Other Metabolic Organs.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body's dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.

An open-label, randomized controlled trial to assess a ketogenic diet in critically ill patients with sepsis.

Patients with sepsis experience metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutrition. A ketogenic diet (KD) may offer an immunologically advantageous alternative, although clinical evidence is limited. We conducted a single-center, open-label, randomized controlled trial to assess whether a KD could induce stable ketosis in critically ill patients with sepsis. Secondary outcomes included assessment of feasibility and safety of KD, as well as explorative analysis of clinical and immunological characteristics. Forty critically ill adults were randomized to either a ketogenic or standard high-carbohydrate diet. Stable ketosis was achieved in all KD patients, with significant increases in ß-hydroxybutyrate levels compared with controls [mean difference 1.4 milimoles per liter; 95% confidence interval (CI): 1.0 to 1.8; P < 0.001). No major adverse events or harmful metabolic side effects (acidosis, dysglycemia, or dyslipidemia) were observed. After day 4, none of the patients in the KD group required insulin treatment, whereas in the control group, insulin dependency ranged between 35% and 60% (P = 0.009). There were no differences in 30-day survival, but ventilation-free [incidence rate ratio (IRR) 1.7; 95% CI: 1.5 to 2.1; P < 0.001], vasopressor-free (IRR 1.7; 95% CI: 1.5 to 2.0; P < 0.001), dialysis-free (IRR 1.5; 95% CI: 1.3 to 1.8; P < 0.001), and intensive care unit-free days (IRR 1.7; 95% CI: 1.4 to 2.1; P < 0.001) were higher in the ketogenic group. Next-generation sequencing of CD4+/CD8+ T cells and protein analyses showed reduced immune dysregulation, with decreased gene expression of T-cell activation and signaling markers and lower pro-inflammatory cytokine secretion. This trial demonstrated the safe induction of a stable ketogenic state in sepsis, warranting larger trials to investigate potential benefits in sepsis-related organ dysfunction.

Effects of a Ketogenic Diet on Body Composition in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.

This study investigates the effects of a ketogenic low-carbohydrate high-fat (LCHF) diet on body composition in healthy, young, normal-weight women. With the increasing interest in ketogenic diets for their various health benefits, this research aims to understand their impact on body composition, focusing on women who are often underrepresented in such studies. Conducting a randomized controlled feeding trial with a crossover design, this study compares a ketogenic LCHF diet to a Swedish National Food Agency (NFA)-recommended control diet over four weeks. Seventeen healthy, young, normal-weight women adhered strictly to the provided diets, with ketosis confirmed through blood ß-hydroxybutyrate concentrations. Dual-energy X-ray absorptiometry (DXA) was utilized for precise body composition measurements. To avoid bias, all statistical analyses were performed blind. The findings reveal that the ketogenic LCHF diet led to a significant reduction in both lean mass (-1.45 kg 95% CI: [-1.90;-1.00]; p < 0.001) and fat mass (-0.66 kg 95% CI: [-1.00;-0.32]; p < 0.001) compared to the control diet, despite similar energy intake and physical activity levels. This study concludes that while the ketogenic LCHF diet is effective for weight loss, it disproportionately reduces lean mass over fat mass, suggesting the need for concurrent strength training to mitigate muscle loss in women following this diet.

The Liver Circadian Metabolic Homeostasis Influence by Combining Ketogenic Diet with Exercise.

The ketogenic diet (KD) and regular exercise (EX) are both capable of orchestrating circadian metabolism homeostasis during losing weight. However, the combined effects of these two factors on circadian metabolism remain poorly understood. To determine if the combined treatment yields a superimposed physiological phenotype, we measured weight loss, white adipose, the respiratory exchange ratio (RER), heat production, and activity parameters in individual and combined treatment groups. Surprisingly, none of these metrics displayed a cumulative effect when administered in the combined treatment approach. Additionally, we investigated the impact of combination therapy on molecular homeostasis through using high-throughput liver transcriptomic approaches. The results revealed that individual and combined treatments can reprogram the circadian rhythm; yet, the combined group exhibited a minimum quantity of cyclic transcript genes. Noteworthy, the amplitude of 24 h circadian expression genes was not significantly increased in the combination treatment, indicating that the combined approach has non-overlapping effects on maintenance peripheral metabolism homeostasis. This may be due to the liver requiring less ketogenic and gluconeogenic potential during metabolic processes. This research suggests that combined treatment may have adverse effects on the body's homeostasis and provide crucial insights for the homeostatic health of athletes or individuals who wish to lose weight.

A Multi-Omics Approach to Disclose Metabolic Pathways Impacting Intestinal Permeability in Obese Patients Undergoing Very Low Calorie Ketogenic Diet.

A very low calorie ketogenic diet (VLCKD) impacts host metabolism in people marked by an excess of visceral adiposity, and it affects the microbiota composition in terms of taxa presence and relative abundances. As a matter of fact, there is little available literature dealing with microbiota differences in obese patients marked by altered intestinal permeability. With the aim of inspecting consortium members and their related metabolic pathways, we inspected the microbial community profile, together with the set of volatile organic compounds (VOCs) from untargeted fecal and urine metabolomics, in a cohort made of obese patients, stratified based on both normal and altered intestinal permeability, before and after VLCKD administration. Based on the taxa relative abundances, we predicted microbiota-derived metabolic pathways whose variations were explained in light of our cohort symptom picture. A totally different number of statistically significant pathways marked samples with altered permeability, reflecting an important shift in microbiota taxa. A combined analysis of taxa, metabolic pathways, and metabolomic compounds delineates a set of markers that is useful in describing obesity dysfunctions and comorbidities.

Ketogenic diet therapy leads to antiseizure medication reduction in children and adults with drug-resistant epilepsy.

AIMS: This study aimed to evaluate the safety of reducing or withdrawing anti-seizure medications (ASMs) in a cohort comprising both adults and children with drug-resistant epilepsy (DRE) undergoing ketogenic diet therapy (KDT). METHODS: We conducted a comprehensive analysis of clinical profiles in adults and children with DRE who had adhered to KDT for at least 6 months. Successful withdrawal or reduction of an ASM was defined as discontinuation or dose reduction without subsequent resumption or increase and without initiation of any new ASM throughout the entire follow-up period. Changes in the ASM load were calculated specifically for adult patients. RESULTS: The study enrolled 56 participants (34 children and 22 adults) with DRE, with 64.3% achieving successful withdrawal of at least one ASM. The probability of ASM withdrawal remained consistent for children (64.7%) versus adults (63.6%), as well as for responders (62.5%) versus non-responders (68.8%), and it was not associated with other clinical factors. Early ASM reduction (including withdrawal) after diet initiation occurred in 15 patients (26.8%), with treatment outcomes comparable to those of the remaining participants. Among the 22 adults, the mean values of ASM load reduced by 24.5%, with a similar magnitude observed for responders (24.2%) versus non-responders (25.1%). In addition, adults tend to have a slower elevation in serum ketone levels compared to children. CONCLUSION: This study demonstrates the safe achievability of ASM withdrawal through KDT in most patients with DRE, irrespective of age or seizure frequency reduction.

Metagenomic and metabolomic analysis showing the adverse risk-benefit trade-off of the ketogenic diet.

BACKGROUND: Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity. METHODS: Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents. RESULTS: Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity. CONCLUSIONS: The study suggest that the ketogenic diet had an unfavorable risk-benefit trade-off and may compromise metabolic homeostasis in obese mice.

Current advances in cancer energy metabolism under dietary restriction: a mini review.

The manipulation of the energy or source of food for cancer cells has attracted significant attention in oncology research. Metabolic reprogramming of the immune system allows for a deeper understanding of cancer cell mechanisms, thereby impeding their progression. A more targeted approach is the restriction of cancer cells through dietary restriction (CR), which deprives cancer cells of the preferred energy sources within the tumor microenvironment, thereby enhancing immune cell efficacy. Although there is a plethora of CR strategies that can be employed to impede cancer progression, there is currently no comprehensive review that delineates the specific dietary restrictions that target the diverse metabolic pathways of cancer cells. This mini-review introduces amino acids as anti-cancer agents and discusses the role of dietary interventions in cancer prevention and treatment. It highlights the potential of a ketogenic diet as a therapeutic approach for cancer, elucidating its distinct mechanisms of action in tumor progression. Additionally, the potential of plant-based diets as anti-cancer agents and the role of polyphenols and vitamins in anti-cancer therapy were also discussed, along with some prospective interventions for CR as anti-tumor progression.

Effects of the Ketogenic Diet on Strength Performance in Trained Men and Women: A Systematic Review and Meta-Analysis.

Ketogenic diets (KDs) are an alternative to improve strength performance and body composition in resistance training participants. The objective of this review and meta-analysis is to verify whether a ketogenic diet produces an increase in the strength of resistance-trained participants. We have evaluated the effect of the ketogenic diet in conjunction with resistance training on the strength levels in trained participants. Boolean algorithms from various databases (PubMed, Scopus, and Web of Science) were used. Meta-analyses were carried out, one on the 1-RM squat (SQ), with 106 trained participants or athletes, and another on the 1-RM on the bench press (BP), evaluating 119 participants. We did not find significant differences between the groups in the variables of SQ or BP, although the size of the effect was slightly higher in the ketogenic group. Conclusions: KDs do not appear to impair 1-RM performance; however, this test does not appear to be the most optimal tool for assessing hypertrophy-based strength session performance in resistance-trained participants.

Advances in Diet and Physical Activity in Breast Cancer Prevention and Treatment.

There is currently a growing interest in diets and physical activity patterns that may be beneficial in preventing and treating breast cancer (BC). Mounting evidence indicates that indeed, the so-called Mediterranean diet (MedDiet) and regular physical activity likely both help reduce the risk of developing BC. For those who have already received a BC diagnosis, these interventions may decrease the risk of tumor recurrence after treatment and improve quality of life. Studies also show the potential of other dietary interventions, including fasting or modified fasting, calorie restriction, ketogenic diets, and vegan or plant-based diets, to enhance the efficacy of BC therapies. In this review article, we discuss the biological rationale for utilizing these dietary interventions and physical activity in BC prevention and treatment. We highlight published and ongoing clinical studies that have applied these lifestyle interventions to BC patients. This review offers valuable insights into the potential application of these dietary interventions and physical activity as complimentary therapies in BC management.

Neurodevelopment Is Dependent on Maternal Diet: Placenta and Brain Glucose Transporters GLUT1 and GLUT3.

Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

PURA-Related Neurodevelopmental Disorders with Epilepsy Treated with Ketogenic Diet: A Case-Based Review.

PURA syndrome is a congenital developmental disorder caused by de novo mutations in the PURA gene, which encodes a DNA/RNA-binding protein essential for transcriptional and translational regulation. We present the case of an 11-year-old patient with a de novo frameshift variant in the PURA gene, identified through whole exome sequencing (WES). In addition to the classical PURA deficiency phenotype, our patient exhibited pronounced sialorrhea and seizures, which were effectively treated with the ketogenic diet (KD). Our integrative approach, combining a literature review and bioinformatics data, has led to the first documented clinical case showing improvement in both sialorrhea and seizures with KD treatment, a phenomenon not previously reported. Although a direct relationship between the de novo PURA mutation and the KD was not established, we identified a novel frameshift deletion associated with a new clinical phenotype.

Anticancer restrictive diets and the risk of psychological distress: Review and perspectives.

INTRODUCTION: The most studied anticancer restrictive diets include fasting, fasting-mimicking diets (FMDs) and ketogenic diets (KDs). Besides the current lack of established clinical benefit and the significant risk of malnutrition and micronutrient deficiencies, dietary restrictions in cancer patients might have relevant psychological effects. MATERIALS AND METHODS: We reviewed the randomized and non-randomized controlled clinical trials (CCTs) reporting data on the psychological impact of fasting, FMDs and KDs in cancer patients. We excluded trials on restrictive diets performed for weight reduction in obese or overweight patients, studies on dietary restrictions lasting less than 24 h, and studies on fasting related to cultural or religious beliefs. RESULTS: Three CCTs on fasting or FMDs and eight CCTs on KDs in cancer patients were included. In terms of diet-related distress, emotional, social, and family well-being, none of these studies showed a detrimental impact of fasting, FMDs and KDs. However, clinical trials specifically assessing the psychological aspects in the long term are lacking. CONCLUSIONS AND PERSPECTIVES: In the absence of a conclusive evidence on the clinical benefits of restrictive diets, which carry significant risks especially if unsupervised, further studies are needed to clarify their psychological impact in cancer patients. Multidisciplinary approaches including psychological evaluations should be used to ameliorate patient selection for clinical trials, identify early distress symptoms, and increase patient compliance to dietary recommendations.

Advances in Ketogenic Diet Therapies in Pediatric Epilepsy: A Systematic Review.

Objective: To review the effects of the ketogenic diet on epilepsy in children and adolescents.Data Sources: A literature search was conducted in PubMed with no publication date or language restrictions based on the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. Keywords used included children, adolescent, ketogenic diet, epilepsy, and seizure.Study Selection: After excluding articles that did not meet the inclusion criteria, such as missing variables of study, adult population, and nonrandomized clinical trials, a total of 12 studies were included in the final review.Data Extraction: Data on study design, duration, sample size, population, and type of intervention were collected using a standard template.Results: The ketogenic diet and its modified versions were noted to have beneficial effects in reduction of seizure frequency and severity, with manageable adverse effects such as gastrointestinal disturbances, dehydration, dyslipidemia, hyperuricemia, infection, and metabolic acidosis.Conclusions: Depending on patient compliance and comorbidities, all variations of the ketogenic diet were found to be helpful for seizure treatment, whether as an additive or an alternative treatment option, for children and adolescents with epilepsy.Prim Care Companion CNS Disord 2024;26(3):23r03661. Author affiliations are listed at the end of this article.

Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial.

BACKGROUND: Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota. METHODS AND FINDINGS: A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study. CONCLUSIONS: We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05200468).