The Impacts of Dietary Intervention on Brain Metabolism and Neurological Disorders: A Narrative Review

Simple Summary

This review explores the intricate connections between diet, neurological disorders, and metabolic health, highlighting their significant impact on physiological processes and the rising prevalence of conditions such as Parkinson’s and Alzheimer’s. It introduces novel diagnostic approaches based on molecular changes and promotes dietary interventions rich in omega-3 fatty acids and polyphenols to improve neurodegenerative and metabolic conditions. Discussions cover the effects of dietary interventions like calorie restriction and ketogenic diets on neurological disorders and the role of gut microbiota in brain function. Additionally, it emphasizes the link between brain metabolism, cognitive decline, and neurodegenerative diseases, advocating for dietary strategies like plant-based diets and polyphenols to enhance metabolic health and reduce associated neurological complications. The review provides valuable insights into potential therapeutic strategies, underscoring the importance of personalized dietary approaches in disease management.

Abstract

Neurological disorders are increasing globally due to their complex nature, influenced by genetics and environmental factors. Effective treatments remain limited, and early diagnosis is challenging. Recent evidence indicates that metabolic activities play a crucial role in the onset of neural defects. Molecular changes offer new diagnostic markers and dietary targets for disease management. Diets such as MIND, DASH, omega-3 fatty acids, and polyphenols show promise in protecting brain metabolism through their anti-inflammatory properties. Personalized dietary interventions could mitigate neurodegenerative diseases. This review highlights the effects of various dietary interventions, including calorie restriction, fasting, and ketogenic diets, on neurological disorders. Additionally, it emphasizes the nutritional impacts on immunomodulation and the underlying mechanisms, including the influence of gut microbiota on brain function. Dietary interventions could serve as adjunctive therapies in disease management.

1. Introduction

Diet is a significant environmental factor that impacts human physiology and metabolism, influencing traits such as survival and fitness. Over the last few decades, there has been a dramatic shift in dietary habits, particularly in industrialized Western countries and urban societies. Coinciding with these changes, there has been a notable increase in neurological diseases (ND) such as Parkinson’s disease (PD), Alzheimer’s disease (AD) Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) [1]. This rise in neurological diseases is a major public health concern, carrying both personal and financial consequences, and is projected to reach 100 million cases by 2050 [2,3]. In contrast to individuals in societies with traditional lifestyles, those in industrialized nations often consume diets low in dietary fiber and high in fat content [4]. The fundamental mechanisms of diverse dietary interventions primarily involve modifying neurotransmitter activity, restructuring neural networks, disrupting brain energy metabolism and mitochondrial function, and modifying inflammatory responses and oxidative stress levels (Figure 1). Additionally, these mechanisms encompass adjusting the composition and equilibrium of the gut microbiota, which subsequently affect ND processes through the intricate interplay of the gut-brain axis. For nearly a century, the ketogenic diet (KD) has been employed clinically as an alternative therapy for childhood intractable epilepsy. However, ample evidence suggests that a modified Atkins diet (MAD) is better tolerated and has a higher likelihood of reducing seizures compared to the classical KD [5,6,7]. For example, in preclinical KD models and patients’ cerebrospinal fluid (CSF), elevated levels of the inhibitory neurotransmitter GABA are evident, leading to reduced neuronal excitability [8]. Additionally, KD-fed rats exhibit heightened peroxisome proliferator-activated receptor gamma 2 (PPARγ2) expression and increased hippocampal catalase levels, potentially enhancing anti-inflammatory and antioxidant actions [9]. A KD can make the brain less prone to seizures by boosting certain potassium channels and is supported in this effect by beneficial gut bacteria like Akkermansia, Parabacteroides, and Bifidobacteria [10,11].

According to the World Health Organization (WHO), in association with ND, metabolic disorder patients have dramatically increased as a result of overeating behaviors, sedentary lifestyles, and the consumption of high-fat (HFD) and high-sugar diets (HSD) [12]. Later in life, dementia is more likely to occur in metabolic obese people [13,14]. It has been linked to sudden changes in cognitive performance, including executive functions (i.e., decision-making, planning, learning a language, and situational adaptation), and learning a stimulus–reward pattern [15,16,17]. Additionally, obesity has been linked to several comorbid conditions such as metabolic syndrome, hypercholesterolemia, hypertension, and type 2 diabetes (T2D), all of which have the potential to affect ND on their own negatively [18]. Even impaired glucose tolerance, preceding T2D, is recognized as a contributing factor to cognitive decline [19,20,21]. The present review discusses the dietary impact on brain function and metabolism of the body system that may reveal the therapeutic parameters for the management of neurological disorders and metabolic disorders.

2. Brain Metabolism and Neurological Disorders

Over the decades, there has been a growing focus on comprehending how metabolic function alteration contributes to susceptibility to various NDs, such as AD and PD [22,23]. The significant amount of energy that the brain uses in comparison to the rest of the body highlights how crucial mechanisms aid in the transport of energy from nutrients to neurons that regulate brain activity. Neuronal energy management mechanisms might affect synaptic plasticity [24]. Recently, researchers have revealed an interlinked connection between disturbances in brain cholesterol metabolism and insulin resistance. These investigations, involving models like murine models of diabetes and aging, have shown a decline in brain cholesterol synthesis associated with cognitive characteristics [25]. One essential signaling molecule that is closely associated with energy consumption and synaptic plasticity is the brain-derived neurotrophic factor (BDNF) [24]. The brain regions such as the hippocampus and the hypothalamus are the primary locations of BDNF, known to be involved in both ND and metabolic regulation, respectively [26]. Impaired hippocampus function and memory processing are connected to the Val66Met BDNF polymorphism, a common human genotype associated with aberrant BDNF trafficking and secretions [27,28]. Furthermore, BDNF affects several aspects of energy metabolism, including insulin sensitivity, and glucose and lipid metabolism [29,30]. Consistent with the strong relationship between energy metabolism and synaptic plasticity, the hypothalamic melanocortin 4 receptor regulates both the production of BDNF in the ventral medial hypothalamus and energy balance [31]. Learning and memory deficits and hyperphagic obesity in humans have been linked to de novo mutation in the BDNF receptor TrkB [31].

3. The Role of Diet in Brain Health

Dietary components such as lipids, carbohydrates, and proteins are responsible for the maintenance of brain functions [32,33,34]. Eating behavior, i.e., appetite and satiety, is regulated by the ratio of hormones such as leptin (secreted by adipose tissues) and ghrelin (secreted by the empty stomach) that maintain vital activities [35]. In addition to macronutrients, several vitamins like B1, B5, B6, B9, and C are involved in mood regulation by synthesizing neurotransmitters. Neurotransmitter serotonin, synthesized by tryptophan, and dopamine synthesized by phenylalanine amino acid associated with cognitive functions, and its imbalanced synthesis can misalign the mood regulation that can cause the ND [36].

People can consume all the required macronutrients and micronutrients in appropriate amounts to maintain their physiological functions (Figure 2). A variety of fruits and vegetables, legumes (such as beans and lentils), nuts, and whole grains (such as unprocessed maize, millet, oats, wheat, and brown rice) are great sources of macronutrients and micronutrients. Furthermore, it is essential to avoid processed foods, high sugar, high fat, and high salt content that may affect physiological functions [37]. It is thought that following an eating pattern will provide several health advantages and reduce the chance of developing several chronic illnesses, including neurological disorders and metabolic disorders [38,39]. Nutrients play several critical roles in the body, such as immunological response, neuroinflammatory processes, cellular communication, and substance transportation [40,41]. Additionally, the blood-brain barrier (BBB) and the choroid plexus are the two pathways through which nutrients enter the brain and play critical roles in normal brain functions [42]. For instance, unsaturated fats, polyphenols, and antioxidant vitamins prevent oxidative stress and neuroinflammation, but saturated fat increases inflammation, especially in the hypothalamus of the brain [43,44,45,46,47].

3.1. Dietary Interventions for Brain Metabolism

Numerous food ingredients have been identified as having great potential for brain Metabolism. By altering neurotransmitter routes, synaptic transmission, membrane flexibility, and signal transduction pathways, these dietary variables can have an impact on a variety of cerebral activities [34]. This makes sense because various nutrients (such as glucose, iron, branched-chain amino acids, and zinc) contribute to fundamental neuronal metabolism, thereby overseeing differentiation [48]. A ketogenic dietary regimen has been identified as having a favorable impact on reducing the volume of cortical contusion in an age-dependent manner in an animal model of cortical injury. This association is linked to the variations observed in brain ketone metabolism, which depends on maturation [49]. One of the studies conducted on mice has demonstrated that exercise influences the molecular processes underlying cognitive function in conjunction with a diet high in DHA [50]. Combining a flavonoid-rich diet with physical activity increases the expression of genes normally associated with neural plasticity and health while decreasing the expression of genes associated with harmful processes like inflammation and cell death [51]. A reduction in the use of glucose is frequently linked to these conditions.

More precisely, the interaction of ketone bodies with oxaloacetate produces acetyl-coA, subsequently initiating the Krebs cycle. Consequently, the activity of the Krebs cycle amplifies the generation of α-ketoglutarate. Following this, the reaction involving α-ketoglutarate consumes aspartate, resulting in a reduction in cellular levels and a substantial production of glutamate. Following this, a glutamic acid decarboxylase decarboxylates the glutamate, resulting in the production of GABA (γ-aminobutyric acid), an inhibitory neurotransmitter that is widely found in the brain [52].

Since several drugs intended to increase GABA activity target GABA, a known anti-seizure chemical, this metabolic route may be especially relevant in the setting of stroke or epilepsy. The finding was that children receiving therapy with low-carb diets had higher levels of GABA in their CSF fluid [53,54]. Furthermore, the diminished seizure activity brought on by ketone bodies is partially reversible by blocking KATP channels or by giving a GABA antagonist [55]. This obstruction of transmission would lead to a reduction in excitatory glutamate activity, which would subsequently inhibit neuronal activity [56]. There is a chance that synaptic vesicle recycling is connected to another plausible process. The mice that were treated with ketone bodies showed a decrease in endocytosis and an imbalance in exocytosis. The anticonvulsant effectiveness of the ketogenic diet in treating epilepsy is facilitated by this phenomenon [57].

3.2. Neurological Challenges through Dietary Interventions

In recent years, there has been an increasing focus on the connection between maintaining a healthy diet and lifestyle to mitigate the risk of brain disorders. Many studies have explored how different nutrients and dietary habits can help reduce neuroinflammation and lower susceptibility to ND. Due to their established anti-inflammatory properties, the MD and dietary methods to halt hypertension (DASH) food patterns have raised a lot of interest as possible disease-preventive parameters. For instance, research suggests that supplementing non-fermentable fiber, which is commonly found in vegetarian diets, during early adulthood can have a protective effect against ND. Dietary non-fermentable fiber has been shown to alter the composition of the gut microbiota and metabolic profile, leading to an increase in the abundance of long-chain fatty acids [58]. Conversely, adopting healthy dietary patterns like the MD, CR, and KD may deter AD progression. Following the MD may shield against memory decline and mediotemporal atrophy by reducing amyloid-β protein and phosphorylated tau levels, thus lowering AD risk (Figure 3). CR might prevent AD by reducing serum tyrosine levels, reversing TyrRS exhaustion, and activating the sirtuin pathway to curb the amyloidogenic processing of amyloid-β protein precursor (APP) [59]. KD could elevate β-hydroxybutyrate levels in red blood cells and brain tissue of AD patients, inhibiting NLRP3 inflammasome activation and reducing AD pathology [60]. Other NDs with lower incidence rates also warrant attention regarding dietary interventions. A clinical trial indicated that increased dairy product consumption might elevate the risk of photoconversion, leading to earlier onset of HD [61]. Moreover, elevated antigliadin antibody titers in HD patients suggest the potential efficacy of implementing a gluten-free diet for this population [62]. Dietary restriction regimens have shown promise in slowing the progression of neuropathological, behavioral, and metabolic abnormalities in HD models, extending lifespan by increasing levels of brain-derived neurotrophic factor and chaperone heat-shock protein-70 (HSP70) in the striatum and cortex, though the underlying mechanisms require further elucidation. Baseline analysis has suggested that a higher intake of antioxidants and carotenes may correlate with improved function in ALS. Additionally, meta-analyses have linked increased intake of omega-3 polyunsaturated fatty acids (PUFAs) with a reduced risk of ALS [63]. While weight loss is generally considered a negative prognostic factor, a high-calorie fatty acid diet offers significant survival benefits for fast-progressing ALS patients [64].

One of the studies conducted on rodents revealed that dietary intervention affects neurobehavioral development by demonstrating the dietary supplements with ω-3PUFA and vitamin A, which prevent the cognitive decline induced by the social instability stress during the adolescent stage that showed the great association of neuronal functions with dietary supplements [65] (Table 1). Decreased levels of inflammation and a lowered chance of mental degeneration have been linked to following the DASH regimen, which emphasizes fruits, vegetables, low-fat dairy, and whole grains [66,67]. Accordingly, the MD is shown to promote stroke prevention, as well as reduce severity. Additionally, studies have looked into the potential of a particular diet to reduce neuroinflammation [68]. Turmeric component curcumin has also been investigated for its anti-inflammatory properties and ways in which it might help people with moderate cognitive impairment think more clearly [69]. Caffeine’s neuroprotective effects may stem from its role as an antagonist of adenosine A2a receptors, potentially hindering glutamate excitotoxicity and enhancing neuronal survival. Moreover, caffeine is implicated in the downregulation of nitric oxide (NO) production, inflammatory cytokines, and microglial activation [70]. In addition to these, Researchers have indicated that certain gut microbes, such as Faecalibacterium and Akkermansia muciniphila, have anti-inflammatory characteristics and may offer protection against ND [71,72]. Clinical studies (refer to Table 1) show that those with this condition often lack essential amino acids. Supplementing with branched-chain amino acids can enhance cognitive function in these cases [73]. The hypothesis suggests that BCAAs could benefit liver encephalopathy (HE) by aiding ammonia detoxification, maintaining amino acid balance, and reducing aromatic AAs entering the brain. Moreover, SR8278, an antagonist of REV-ERBA α, exhibited time-dependent alterations in the behavioral manifestations of the PD mouse model. Furthermore, the mechanism underlying the action of SR8278 primarily targeted the interplay and genome-wide motif enrichment involving REV-ERBA α and NURR1, an additional transcription factor implicated in modulating dopamine signaling [23].

Although a dose-response association has been proposed [74], new findings from a meta-analysis conducted by Burckhardt et al. [75] revealed a lack of evidence supporting the efficacy of omega-3 PUFA supplementation in treating mild to moderate AD [76]. Over time, combined dietary patterns and daily routines have significant potential to enhance cognitive well-being [77]. These dietary interventions aim to influence physiological processes, potentially offering therapeutic benefits. They are retained in a visual aid illustrating the described dietary strategies and their associated mechanisms. Autism Spectrum disorder (ASD) is another neurological disorder with both behavioral and metabolic dysregulations since obesity and type 2 diabetes during pregnancy represent risk factors for this disease. After birth, dietary intervention in ASD-affected newborns has shown good results. For instance, in rodent models, a KD improves social interactions and dampens repetitive behaviors [78,79].

Table 1. Management of neurological disorders through Nutrient Interventions.

Sr. No.	Dietary Factors	Experimental Study Design/Participants	Results	Study Conclusion	Ref.
1.	MIND diet	There is baseline I (7983 participants included) and baseline II (4040 participants included) associated with dietary history used for the population-based Rotterdam study.	A 53% decrease in the incidence of AD was predicted for those in the top tertile of MIND scores.	Lower risk of dementia	[80]
2.	DASH diet	Used 4169 MESA participants and evaluated the association between DASH diet adherence and cognitive functions	Higher nut/legume consumption was linked to improved CASI scores on Exams 5 (p = 0.003) and 6 (p = 0.007) were enhanced.	Improved cognitive performance, with ethnic disparities perhaps existing.	[66]
3.	Omega-3 Fatty Acid	A randomized study including 9 participants, 5 of them assigned to low-fat diets and antioxidants and the other 4 being placebo groups with only a low-fat diet.	Long-chain omega-3 fatty acids in the early stages of AD to prevent or delay cognitive decline.	Involved in the cellular metabolism and multiple sclerosis-linked inflammatory processes.	[68,75]
4.	Polyphenols/Curcumin	In this randomized study, 60–85-year-old individuals with fluency in writing and speaking English, normal vision, and other specified criteria participated. A total of 61 participants, all free from bleeding and metabolic disorders, were enrolled.	Significantly reduced total and LDL cholesterol.	Effects of curcumin on cognition in healthy elderly population of human.	[69]
5.	Antioxidants	In this population-based study, 16,010 women participated based on educational qualifications and other parameters like health status.	Neuronal damage, AD progression, and oxidative stress production/aggregation	Dietary intake of flavonoids, especially derived from berries, appears to reduce cognitive decline in older adults.	[81]
6.	Carbohydrates	In this study, APP/PS1 double mutant transgenic mice express human amyloid beta precursor protein containing K595N/M596L Swedish mutations.	Simple carbohydrates impair cognition and increase risk of AD	Regulating the consumption of sugary beverages may be an effective way to curtail the risk of developing AD.	[82]
7.	Polyphenols/Resveratrol	A total of 119 participants were included and were randomized to resveratrol 500 mg orally once daily (with a dose escalation by 500 mg increments every 13 weeks, ending with 1000 mg twice daily).	Exploration of the capacity for mitigating the decline in mini-mental status evaluation scores in individuals diagnosed with AD.	Resveratrol can reduce or modulate neuroinflammation and induce adaptive immunity.	[83]
8.	Polyphenols/Glycyrhizic flavone	In this double-blinded trial study, 128 patients participated and were assessed for eligibility criteria.	Enhancement of the Parkinson’s assessment scale in diagnosed individuals.	Glycyrrhizic flavone could improve the symptoms of PD in patients without serious adverse side effects.	[84]
9.	Alkaloids/Trigonelline	40 patients participated, with inclusion criteria consisting of PD, ages from 18–70 years, and being on stable doses of L-DOPA with carbidopa.	Improvements in UPDRS for diagnosed neurologic patients.	Fenugreek seed has great potential as an adjuvant to L-DOPA therapy.	[85]
10.	Amino acid/Branched-chain amino acid	In this randomized study, patients with clinically proven cirrhosis of different etiologies were included at 30–70 years, body weight between 60–80 kg and a lack of BCAA treatment.	Enhanced cognitive function in cirrhosis-associated hepatic encephalopathy (HE).	Supplementations of diets with oral BCAA are better than casein for mental health management.	[86]
11.	α-linolenic acid	In this study, male offspring mice were reared on the same low or adequate alpha linoleninc acid diet till 4 months of age.	There is an increase in the level of docosahexaenoic acid (DHA) in the brain	Increasing the brain DHA can reduce neuroinflammation and improve functional recovery after TBI.	[87]

Table 1. Management of neurological disorders through Nutrient Interventions.

Sr. No.	Dietary Factors	Experimental Study Design/Participants	Results	Study Conclusion	Ref.
1.	MIND diet	There is baseline I (7983 participants included) and baseline II (4040 participants included) associated with dietary history used for the population-based Rotterdam study.	A 53% decrease in the incidence of AD was predicted for those in the top tertile of MIND scores.	Lower risk of dementia	[80]
2.	DASH diet	Used 4169 MESA participants and evaluated the association between DASH diet adherence and cognitive functions	Higher nut/legume consumption was linked to improved CASI scores on Exams 5 (p = 0.003) and 6 (p = 0.007) were enhanced.	Improved cognitive performance, with ethnic disparities perhaps existing.	[66]
3.	Omega-3 Fatty Acid	A randomized study including 9 participants, 5 of them assigned to low-fat diets and antioxidants and the other 4 being placebo groups with only a low-fat diet.	Long-chain omega-3 fatty acids in the early stages of AD to prevent or delay cognitive decline.	Involved in the cellular metabolism and multiple sclerosis-linked inflammatory processes.	[68,75]
4.	Polyphenols/Curcumin	In this randomized study, 60–85-year-old individuals with fluency in writing and speaking English, normal vision, and other specified criteria participated. A total of 61 participants, all free from bleeding and metabolic disorders, were enrolled.	Significantly reduced total and LDL cholesterol.	Effects of curcumin on cognition in healthy elderly population of human.	[69]
5.	Antioxidants	In this population-based study, 16,010 women participated based on educational qualifications and other parameters like health status.	Neuronal damage, AD progression, and oxidative stress production/aggregation	Dietary intake of flavonoids, especially derived from berries, appears to reduce cognitive decline in older adults.	[81]
6.	Carbohydrates	In this study, APP/PS1 double mutant transgenic mice express human amyloid beta precursor protein containing K595N/M596L Swedish mutations.	Simple carbohydrates impair cognition and increase risk of AD	Regulating the consumption of sugary beverages may be an effective way to curtail the risk of developing AD.	[82]
7.	Polyphenols/Resveratrol	A total of 119 participants were included and were randomized to resveratrol 500 mg orally once daily (with a dose escalation by 500 mg increments every 13 weeks, ending with 1000 mg twice daily).	Exploration of the capacity for mitigating the decline in mini-mental status evaluation scores in individuals diagnosed with AD.	Resveratrol can reduce or modulate neuroinflammation and induce adaptive immunity.	[83]
8.	Polyphenols/Glycyrhizic flavone	In this double-blinded trial study, 128 patients participated and were assessed for eligibility criteria.	Enhancement of the Parkinson’s assessment scale in diagnosed individuals.	Glycyrrhizic flavone could improve the symptoms of PD in patients without serious adverse side effects.	[84]
9.	Alkaloids/Trigonelline	40 patients participated, with inclusion criteria consisting of PD, ages from 18–70 years, and being on stable doses of L-DOPA with carbidopa.	Improvements in UPDRS for diagnosed neurologic patients.	Fenugreek seed has great potential as an adjuvant to L-DOPA therapy.	[85]
10.	Amino acid/Branched-chain amino acid	In this randomized study, patients with clinically proven cirrhosis of different etiologies were included at 30–70 years, body weight between 60–80 kg and a lack of BCAA treatment.	Enhanced cognitive function in cirrhosis-associated hepatic encephalopathy (HE).	Supplementations of diets with oral BCAA are better than casein for mental health management.	[86]
11.	α-linolenic acid	In this study, male offspring mice were reared on the same low or adequate alpha linoleninc acid diet till 4 months of age.	There is an increase in the level of docosahexaenoic acid (DHA) in the brain	Increasing the brain DHA can reduce neuroinflammation and improve functional recovery after TBI.	[87]

3.3. Nutritional Interventions to Metabolic Disorders

Evidence from epidemiological studies suggests that obesity independently raises the risk of AD, while a high-fat diet (HFD) is closely linked to obesity, exacerbating AD-related memory impairment in mice through increased levels of N-acetylneuraminic acid (NANA) in the blood, leading to immune exhaustion [88,89]. Furthermore, HFD may heighten neuroinflammation by elevating circulating free fatty acids and cytokines, potentially impairing cognition [90]. Metabolic disorders are consequences of various diseases typically including obesity, elevated fasting glucose levels, hypertension, and dyslipidemia [91]. Numerous nutritional intervention studies have assessed the impacts of dietary modifications on metabolic syndrome management [92]. The daily intake of foods rich in fiber and with a low glycemic index, along with fish and dairy products (yogurt and nuts) has a great potential to prevent or manage the metabolic disorder. In addition, both the MD and DASH diets had a positive effect on health in association with or without calorie restriction.

The most effective non-pharmacological strategy, i.e., caloric restriction (CR) has a significant capability to avoid chronic metabolic illness and attenuate aging [93]. In addition to CR, the metabolism of the metabolic tissues acts as a crucial factor for the management of metabolic diseases. One of the significant studies discloses the metabolism of white adipose tissue (WAT), which acts as a pivotal factor contributing to the positive outcomes associated with CR mentioned in Table 2 [94]. Additionally, to the metabolism, there are several plant-derived components like polyphenols that have a great impact on health and disease management at a cellular level. An animal model and human studies disclose that one of the naturally occurring polyphenols, resveratrol, has been shown to activate cellular factors like SIRT-1, inhibit the activation of NF-κB, and enhance glucose tolerance and insulin sensitivity [95,96,97]. Further investigations into how plant derivatives and animal derivatives affect β-cell function and insulin resistance are crucial to determining the most effective dietary approach for diabetes management [98]. Liu et al. suggested that a higher intake of total supplemental calcium is linked to a lower prevalence of metabolic syndrome by improving blood pressure and diabetes through control of weight loss and enhanced insulin function [99].

Baudrand et al. demonstrated a positive correlation between an elevated sodium diet and hypertension (HTN), insulin resistance (IR), and dyslipidemia (DLP) [100]. Nobiletin, a natural polyethoxylated flavone, acted as a significant modulator by diminishing peripheral lipid accumulation, enhancing glucose tolerance, and reinstating insulin sensitivity in the organism [101]. Altogether, obesogenic/diabetogenic diets induce a negative alteration of cognitive functions. However, it remains difficult to discriminate the cognitive decline from obesity or diabetes development.

Table 2. Managing Metabolic Issues through Nutrient Interventions.

Sr. No.	Dietary Factors	Metabolic Disease	Experimental Study Design/Participants	Study Conclusion	Reference
1.	Caloric restriction	Diabetes	In this study, male B6C3F1 hybrid mice were used, randomized into control or restricted groups at two months of age, and fed 87 kcal/week.	Calorie-restricted animals are metabolically distinct.	[94]
2.	Resveratrol and pterostilbene	Obesity	This study used 6-week-old male Wistar rats and divided them into four groups, i.e., control, high-fat high sugar group, resveratrol-treated group, and pterostilbene-treated group with different concentrations of appropriate conditions.	Adipokines, NOV/CC3 seem to be involved in the weight changes observed in adipose tissue under obesogenic feeding conditions.	[95,96]
3.	Plant-based diet	Diabetes	Used baseline that followed 2918 participants; nonsmoking, nonalcohol, etc., for a median of 5 years with 183 incident diabetes cases.	A vegetarian diet may protect against diabetes.	[98]
4.	Sodium	Hypertension	370 adults, 70% being women, associated with 72% hypertension.	A high-sodium diet was associated with hypertension and insulin resistance.	[100]

Table 2. Managing Metabolic Issues through Nutrient Interventions.

Sr. No.	Dietary Factors	Metabolic Disease	Experimental Study Design/Participants	Study Conclusion	Reference
1.	Caloric restriction	Diabetes	In this study, male B6C3F1 hybrid mice were used, randomized into control or restricted groups at two months of age, and fed 87 kcal/week.	Calorie-restricted animals are metabolically distinct.	[94]
2.	Resveratrol and pterostilbene	Obesity	This study used 6-week-old male Wistar rats and divided them into four groups, i.e., control, high-fat high sugar group, resveratrol-treated group, and pterostilbene-treated group with different concentrations of appropriate conditions.	Adipokines, NOV/CC3 seem to be involved in the weight changes observed in adipose tissue under obesogenic feeding conditions.	[95,96]
3.	Plant-based diet	Diabetes	Used baseline that followed 2918 participants; nonsmoking, nonalcohol, etc., for a median of 5 years with 183 incident diabetes cases.	A vegetarian diet may protect against diabetes.	[98]
4.	Sodium	Hypertension	370 adults, 70% being women, associated with 72% hypertension.	A high-sodium diet was associated with hypertension and insulin resistance.	[100]

4. Mechanisms of Action

Research in the realm of ND has advanced multiple hypotheses concerning the mechanisms driving the effectiveness of the ketogenic diet in mitigating seizures. Among these hypotheses, certain ones directly implicate ketone bodies—end products of lipid oxidation that are synthesized in response to diminished carbohydrate availability [102,103]. Furthermore, it is postulated that mitochondria and gene regulation exert considerable influence within these mechanistic pathways.

4.1. Inflammation and Oxidative Stress

Chronic inflammation is implicated in various ND. Certain dietary patterns, such as the Mediterranean diet rich in fruits, vegetables, and olive oil, have anti-inflammatory properties due to high levels of antioxidants and polyphenols [104]. These components can mitigate oxidative stress and inflammation in the brain, potentially slowing the progression of diseases like PD and MS. The imbalance between the generation of free radicals and antioxidant defenses is known as oxidative stress. Several studies have demonstrated that the severity of oxidative stress damage may be influenced by diets and some of their constituents [105]. Western dietary patterns are distinguished by excessive intake of saturated fats, refined sugars, and animal-derived protein, alongside insufficient consumption of plant-derived fiber. Individuals adhering to such diets frequently exhibit elevated oxidative stress levels and an increased susceptibility to chronic diseases [106]. ROS production is interestingly dependent on nutritional fluxes [107]. Particularly, because nutrition can enter mitochondria directly, where a significant amount of ROS can be produced within cells. It can be reduced in various ways such as by promoting the elevation of NADH oxidation and mitochondrial respiration [108]. These processes prevent the mitochondrial permeability transition (MPT), which delays the process of cell death. As oxidative fuels, redox potential modulators ketone bodies affect mPT, this process may help to understand why the ketogenic diet has an anti-epileptic effect. A study on mice with epilepsy models shows an increase in the mPT threshold [109]. Studies on stroke have also shown that diabetes and high blood sugar levels increase the risk of stroke and have a detrimental effect on recovery [107,110]. In addition to ketone bodies, being a common water-soluble antioxidant and cofactor for several enzymes, ascorbate (also known as ascorbic acid) may directly scavenge the ROS and restore other oxidized scavengers [111].

4.2. Gut-Brain Axis

Emerging research suggests a bidirectional communication pathway between the gut and brain, known as the gut-brain axis. Dietary interventions that modulate gut microbiota composition, such as probiotics, prebiotics, and fiber-rich diets, can influence neurotransmitter production and neuroinflammation [112]. Manipulating the gut microbiome may have therapeutic implications for brain disorders like depression and anxiety. Changes in the gut environment can potentially initiate PD through the gut-brain axis, evidenced by the presence of α-synuclein and Lewy bodies in the enteric nervous system and the strong correlation between PD and gut inflammation [113]. Studies have identified alterations in the gut microbiome among PD patients compared to healthy individuals, underscoring the potential advantages of dietary interventions in managing PD [114]. Elevated serum sodium levels are linked to cognitive decline, particularly in the elderly population [115].

However, a recent study challenges the link between a high-salt diet (HSD) and ND or α-synuclein accumulation in a PLP-hαSyn model, indicating the need for further investigation into the mechanism of HSD [116]. Adhering to the MD is associated with a reduced incidence of PD, potentially through mechanisms like reducing neuroinflammation, akin to AD [117]. The KD improves both motor and non-motor symptoms in PD patients by suppressing microglial activation. Furthermore, fasting-mimicking diet (FMD) promotes a beneficial gut microbiota composition and metabolites while inhibiting neuroinflammation, thereby mitigating the loss of dopaminergic neurons in the substantia nigra in a PD model [118]. Additionally, dietary choices may influence AD by modulating the gut microbiome and metabolites; for example, the Mediterranean-ketogenic diet (MMKD) shows promise in improving AD biomarkers by boosting Akkermansia muciniphila levels, affecting GABA levels, and gut transit time [119].

For instance, the MD abundant in plant-based foods is likely to reshape the microbiome to support bacteria engaged in the breakdown of dietary fiber, including Akkermansia municiphilla, Ruminococcus bromii, Faecalibacterium prausnitzii, Eubacterium rectale, Eubacterium hallii, and Ruminococcus bromii [120], and this alteration promotes the synthesis of short-chain fatty acids (SCFA). Similarly, a diet with a low glycemic index (GI), characterized by significant fiber content, sustains bacteria involved in fiber breakdown, resulting in the release of SCFA. Some important biomarkers like bile acids are affected by the makeup of diet. In essence, a high-fat diet content causes the creation of more bile acid. Gut bacteria can then modify these bile acids to produce substances that interact with specific brain receptors to regulate satiety. It is interesting to note that bile acids may also have anti-inflammatory and antioxidant effects. Consequently, we cannot rule out the possibility that foods impact bile acids and the gut microbiota [121]. Hence, although it is being extensively researched at present, the impact of the microbiota on brain disorders demands further attention, particularly regarding dietary interventions [122].

5. Clinical Studies and Evidence

Clinical studies and evidence regarding the impacts of dietary intervention on brain metabolism and neurological disorders:

Ketogenic Diet and Epilepsy:

• Clinical Studies: Numerous clinical trials have investigated the efficacy of the ketogenic diet in managing epilepsy, particularly in drug-resistant cases. For example, a study published in The Lancet Neurology in 2008 conducted a randomized controlled trial involving children with drug-resistant epilepsy, showing that the ketogenic diet led to a significant reduction in seizure frequency compared to controls [6].
• Evidence: Meta-analyses and systematic reviews have consistently supported the effectiveness of the ketogenic diet in reducing seizure frequency and improving seizure control in both children and adults with epilepsy. A meta-analysis published in the Cochrane Database of Systematic Reviews in 2020 concluded that the ketogenic diet significantly reduced seizure frequency compared to controls in randomized controlled trials [123].

Omega-3 Fatty Acids and Cognitive Function:

• Clinical Studies: Clinical trials have investigated the effects of omega-3 fatty acid supplementation on cognitive function and neurodegenerative diseases. For instance, a randomized controlled trial published in J. Alzheimer’s Dis. 2016 examined the effect of omega-3 fatty acids on cognitive decline in older adults and found that supplementation was associated with slower cognitive decline over 4.5 years [124].
• Evidence: Observational studies have also suggested a protective effect of omega-3 fatty acids against cognitive decline and dementia. A systematic review and meta-analysis published in Eur. J. Nutr. 2022 concluded that higher dietary intake or blood levels of omega-3 fatty acids were associated with a lower risk of dementia and Alzheimer’s disease [125].

Mediterranean Diet and Alzheimer’s Disease:

• Clinical Studies: Clinical trials and observational studies have investigated the impact of the Mediterranean diet on Alzheimer’s disease risk and progression. For example, the PREDIMED-NAVARRA trial, published in JAMA Internal Medicine in 2015, demonstrated that adherence to a Mediterranean diet supplemented with extra-virgin olive oil was associated with improved cognitive function in older adults with high cardiovascular risk [126,127].
• Evidence: Longitudinal cohort studies have provided consistent evidence linking adherence to the Mediterranean diet with a reduced risk of Alzheimer’s disease and slower cognitive decline. A meta-analysis published in the Journal of Alzheimer’s Disease in 2014 found that greater adherence to the Mediterranean diet was associated with a 33% reduction in the risk of Alzheimer’s disease [128].

Antioxidants and Parkinson’s Disease:

• Clinical Studies: Clinical trials and observational studies have investigated the role of antioxidants in Parkinson’s disease prevention and management. For example, the DATATOP trial, published in the Archives of Neurology in 1993, found that treatment with the antioxidant vitamin E delayed the progression of disability in early Parkinson’s disease [129].
• Evidence: Epidemiological studies have provided mixed evidence regarding the association between dietary antioxidants and Parkinson’s disease risk. While some studies have suggested a protective effect of antioxidants such as vitamin E and flavonoids, others have found no significant association [130].

These clinical studies and evidence highlight the potential of dietary interventions in modulating brain metabolism and mitigating neurological disorders. However, further research, including large-scale randomized controlled trials and longitudinal studies, is needed to better understand the optimal dietary strategies and their long-term effects on brain health.

6. Methodology

The methodology employed in this review adhered to stringent protocols to ensure the methodological soundness and reliability of the findings.

Systematic Literature Search: We conducted a comprehensive literature search to identify content for inclusion in the review [131]. A meticulous and exhaustive search strategy is devised, leveraging various scholarly databases including PubMed, Web of Science, and Scopus. This strategy involves the utilization of controlled vocabulary and Boolean operators to optimize search efficiency for dietary intervention in neurological disorders.

Inclusion and Exclusion Criteria Establishment: Establishing stringent inclusion and exclusion criteria facilitates the identification of pertinent studies. These criteria encompass parameters such as study design, participant demographics, intervention modalities, and outcome metrics, enhancing the review process’s precision and enriching our understanding of the topic [131].

Screening and Selection Process: Articles retrieved through the literature search undergo meticulous screening, initially based on titles and abstracts, and subsequently on full-text examination. This process ensures that only studies meeting pre-defined criteria are included in the review, maintaining the rigor and relevance of the analysis [132].

Quality Appraisal: Rigorous quality assessment protocols have been implemented to evaluate the methodological robustness and risk of bias inherent in the included studies. Established tools and frameworks specific to the study design are employed [126,127].

Data Extraction: Systematic data extraction methodologies are employed to procure pertinent information from the included studies of dietary interventions. This encompassed comprehensive retrieval of study characteristics, intervention details, outcome measures, and key findings [133].

Synthesis and Analysis: Lastly, the findings from the selected studies are synthesized utilizing meticulous analytical techniques, including thematic analysis and, where applicable, quantitative meta-analytical methods. This has facilitated the extraction of overarching themes, patterns, and trends from the literature [133].

7. Challenges and Limitations

Heterogeneity of Study Populations: Variability in genetic predispositions, lifestyle factors, and medical backgrounds among study participants introduces confounding variables that may obscure the true effects of dietary interventions on brain health. This diversity challenges the generalizability of findings across populations and necessitates careful consideration of subgroup analyses [134].

Compliance and Adherence: Ensuring consistent adherence to prescribed dietary protocols poses a significant challenge in longitudinal studies assessing the effects of dietary interventions on brain metabolism and neurological disorders. Non-adherence compromises the internal validity of study outcomes and complicates the interpretation of intervention efficacy [135].

Nutrient Interactions and Synergistic Effects: Dietary interventions often entail the manipulation of multiple nutrients and bioactive compounds, leading to intricate interactions that influence brain function and neurological outcomes. Isolating the specific effects of individual dietary components within complex dietary patterns presents methodological challenges in elucidating mechanistic pathways [136].

Measurement and Assessment Methods: The reliance on self-reported dietary intake data and subjective outcome measures introduces potential biases, including recall bias and measurement error, which may attenuate the accuracy of study findings. Objective assessment methods and validated biomarkers are essential for robustly quantifying dietary intake and evaluating neurobiological outcomes [137].

Ethical Considerations: Ethical dilemmas arise in conducting dietary intervention studies, particularly in vulnerable populations, necessitating careful consideration of informed consent procedures, participant safety, and equitable access to interventions. Balancing scientific rigor with ethical standards is imperative in safeguarding participant welfare and upholding research integrity [138].

Long-term Effects and Sustainability: Evaluating the sustained effects of dietary interventions on brain health and neurological disorders over extended durations poses logistical and methodological challenges. Longitudinal studies with extended follow-up periods are essential for elucidating the long-term efficacy and sustainability of dietary interventions in mitigating neurological conditions [139].

Confounding Factors and Bias: Dietary intervention studies are susceptible to confounding variables, including socioeconomic status, educational attainment, and lifestyle factors, which may obscure the true association between diet and neurological outcomes. Rigorous study design, including robust control for confounding factors and bias mitigation strategies, is paramount for enhancing the internal validity of study findings [140].

Addressing these challenges requires interdisciplinary collaboration, rigorous methodological approaches, and adherence to ethical standards to advance our understanding of the complex interplay between diet, brain metabolism, and neurological disorders.

8. Future Perspective and Research Opportunities

Nutrition confers a protective influence on neuronal integrity through the interplay of diverse elements, including diet quality, calorie intake, and their impact on insulin secretion. Neuronal function is compromised by the detrimental effects of insulin resistance, which triggers the secretion of pro-inflammatory cytokines. When conducting clinical studies to assess the impact of nutrition on ND, it is imperative to consider calorie ingestion and insulin sensitivity as indispensable indicators of cellular function, in addition to changes in body weight. Both dietary restriction and energy expenditure play pivotal roles as determining factors in the progression of ND [141]. The regulation of gut microbiota emerges as a critical aspect in controlling ND, and the concept of transplanting selected microbiota through fecal transplantation may be contemplated as an innovative therapeutic strategy for treating these conditions. Several dietary and neurological interlinked studies have been conducted on different models that resolved the complication of cognitive disease in association with dietary interventions. Nevertheless, specific cause-and-effect associations in extensive populations over extended studies to evaluate the connection between nutrition and disease progression are still lacking.

9. Conclusions

Our review presents compelling evidence that various dietary interventions, including calorie restriction, fasting, ketogenic diet (KD), protein restriction diet, high-salt diet (HSD), high-fat diet (HFD), and high-fiber diet, hold substantial potential for modulating metabolism, influencing disease progression, and improving therapeutic responses. These findings underscore the pivotal role of diet, as a significant environmental factor, in shaping brain metabolism and impacting the trajectory of various diseases, particularly neurodegenerative conditions. In conclusion, dietary interventions offer great promise as a novel approach to disease management. However, to fully realize their potential, rigorous scientific investigations into their mechanisms of action, safety profiles, and efficacy across diverse patient populations are imperative. Through further research, dietary interventions could emerge as integral components of personalized medicine, opening new avenues for the prevention and treatment of a wide range of diseases.