European Journal of Cardiovascular Medicine

The ketogenic diet (KD), characterized by high-fat, moderate-protein, and very low-carbohydrate intake, has garnered widespread attention for its therapeutic potential in various clinical conditions. ^[1] Traditionally used in the management of refractory epilepsy, KD has evolved to demonstrate beneficial effects in metabolic disorders such as obesity, type 2 diabetes, and even neurological conditions like Alzheimer's disease. ^[2] The core mechanism of KD involves shifting the body's primary energy source from glucose to ketone bodies, resulting in altered metabolic and physiological processes. ^[3]

Furthermore, promising research explores its neuroprotective effects in conditions such as Alzheimer's disease, Parkinson's disease, and even certain brain cancers. The core physiological driver of these effects is the induction of nutritional ketosis. ^[4] By drastically restricting carbohydrates, the body depletes its glycogen stores and shifts its primary energy substrate from glucose to ketone bodies (β-hydroxybutyrate, acetoacetate, acetone), synthesized in the liver from fatty acids. ^[5] This metabolic switch initiates profound alterations in cellular signaling, gene expression, mitochondrial function, and neurotransmitter balance, impacting diverse physiological systems. ^[6]

In recent years, the gut has emerged as a central player in overall health, influencing not only digestion but also immunity and systemic inflammation. The gastrointestinal (GI) tract is rich in immune cells and microbiota, both of which are sensitive to dietary patterns. ^[7] Therefore, dietary interventions like the KD could significantly impact gastric functions, motility, and immune responses. ^[8] However, while numerous studies have explored KD's effects on weight loss and metabolic parameters, limited data are available on its influence on gastric motility and immunological markers in human subjects, especially in the Indian population. ^[9]

Gastric motility, encompassing the coordinated muscular contractions responsible for food storage, mixing, grinding, and controlled emptying into the duodenum, is a finely tuned process essential for efficient digestion. It is regulated by a complex interplay of neural signals (vagus nerve, enteric nervous system), hormonal factors (e.g., ghrelin, motilin, CCK, GLP-1), and intrinsic properties of the ingested meal itself, including its macronutrient composition, volume, and osmolarity. ^[10] The drastic macronutrient shift inherent in the KD—replacing carbohydrates with high levels of fats and moderate protein—raises critical questions about its impact on gastric function. ^[11]

The gut-brain axis is another area of interest. KD may influence gut microbiota composition, leading to changes in short-chain fatty acid (SCFA) production and microbial diversity, which in turn can affect gastrointestinal health and immune regulation. ^[12] Given the centrality of the GI tract in nutrient absorption, immunity, and systemic health, studying the effects of KD on gastric functions and immunity is both timely and crucial. ^[13]

India presents a unique demographic with distinct dietary habits, genetic predispositions, and disease patterns. Despite the increasing popularity of KD in urban populations, there is a lack of region-specific research evaluating its safety, efficacy, and physiological impact. Understanding how KD affects gastric motility and immunity among Indian subjects can help develop culturally sensitive dietary interventions, potentially benefiting a broader population segment. ^[14]

This is a Case-control study was conducted in the Department of Physiology at Index Medical College. Data was collected from consenting participants attending the outpatient departments (OPD) of General Medicine and Physiology at Index Medical College and hospital from January 2023 to December 2024. Participants were recruited after meeting inclusion criteria and providing informed consent.

Inclusion Criteria

• Adults aged 18–50 years
• BMI between 18.5–29.9 kg/m²
• Willing to follow a ketogenic diet or standard Indian diet for 8 weeks
• Able to give informed consent

Exclusion Criteria

• Known gastrointestinal disorders (e.g., IBD, peptic ulcer, celiac disease)
• Diabetes mellitus requiring insulin
• Chronic use of medications affecting gastric motility (e.g., prokinetics, anticholinergics)
• Pregnant or lactating women
• Recent antibiotic use (<3 months)
• Immunocompromised status

Sample Size Calculation

• Sample size is estimated based on previous literature indicating moderate effect sizes for changes in gastric motility parameters due to dietary intervention. Using an expected effect size (Cohen’s d = 0.5), alpha = 0.05, and power = 80%, the calculated sample size is 264 subjects (132 in KD group and 132 in control group). Accounting for a 10% dropout rate, 264 subjects will be enrolled (132 in each group).

Methodology
Participants will be divided into two groups:

1. Ketogenic Diet Group (Case): Participants will follow a monitored KD consisting of <10% carbs, ~70% fats, and ~20% proteins.
2. Control Group: Participants will continue a balanced Indian diet based on standard dietary recommendations.

Both groups will undergo baseline and post-intervention (8-week) evaluations for:

• Gastric motility: Using non-invasive techniques such as ultrasonographic assessment of gastric emptying and/or scintigraphy where feasible.
• Gastric functions: Including measurement of gastric acid output, stool fat content, and bowel transit time.
• Immunity markers: Including serum cytokines (IL-6, TNF-alpha), CRP levels, and fecal calprotectin.
• Microbiota analysis: Stool samples analyzed using 16S rRNA sequencing to evaluate changes in microbial diversity and abundance.

Dietary Adherence Monitoring:

Weekly dietary logs and ketone monitoring (urine or blood strips) will ensure compliance in the KD group. The control group will maintain food diaries.

Statistical Analysis

Data will be entered into SPSS (v28). Continuous variables will be expressed as mean ± SD; categorical data will be presented as frequencies. Independent t-test or Mann-Whitney U test. Paired t-test or Wilcoxon signed-rank test. Pearson or Spearman correlation tests between diet adherence and outcomes. A p-value <0.05 will be considered statistically significant.

Table 1. Baseline Characteristics of Study Participants

Table 2. Changes in Immunological Markers

Table 3. Microbiota Diversity and Abundance Changes

Graph 1. Microbiota Diversity and Abundance Changes

The KD group demonstrated substantial reductions in CRP (−0.8 mg/L), IL-6 (−0.9 pg/mL), TNF-α (−1.3 pg/mL), and fecal calprotectin (~15% decline). These improvements are in agreement with several clinical and preclinical studies. For example, Paoli et al. (2013) observed decreased CRP and IL-6 levels in athletes following KD, suggesting an anti-inflammatory effect independent of weight loss. ^[15] Similarly, Forsythe et al. (2008) reported reductions in systemic inflammatory markers with very low-carbohydrate diets, hypothesizing that decreased postprandial glucose and insulin excursions attenuate oxidative stress and inflammatory cascades. ^[16]

Mechanistically, ketone bodies, particularly β-hydroxybutyrate (BHB), have been shown to inhibit the NLRP3 inflammasome pathway (Youm et al., 2015),

providing a plausible link between KD and reduced systemic inflammation. ^[17] The decrease in fecal calprotectin further suggests a local gut anti-inflammatory effect, which could be mediated by altered microbial metabolites such as short-chain fatty acids (SCFAs) and changes in mucosal immune cell activity. ^[18]

Our microbiota data revealed a reduction in alpha diversity (Shannon index) and a significant increase in beta diversity compared with baseline in the KD group, indicating substantial restructuring of the gut ecosystem. Taxonomically, KD was associated with an increased Firmicutes/Bacteroidetes ratio. Similar patterns have been reported in KD studies for epilepsy patients (Xie et al., 2017) and in high-fat diet animal models (Turnbaugh et al., 2006). ^[19-23] While reduced diversity is often interpreted as detrimental, in KD contexts it may reflect selective enrichment of taxa capable of metabolizing fats and ketone bodies, such as certain Clostridia species.

One concern is that chronic reduction in diversity could predispose to reduced resilience of the microbiome; however, short-term changes may be reversible upon diet cessation. The decreased relative abundance of Bacteroidetes may also be linked to reduced fiber intake, as many Bacteroides species thrive on complex carbohydrates.

This study provides novel evidence that an 8-week KD in healthy Indian adults accelerates gastric emptying, increases gastric acid secretion, alters distal gut transit, reduces systemic and intestinal inflammation, and reshapes the gut microbiota. These changes are directionally consistent with several prior KD studies but offer new insights into gastrointestinal physiology in a non-Western dietary context. While the anti-inflammatory and motility effects may hold clinical promise, caution is warranted regarding microbiota diversity and distal transit changes. Personalization and careful monitoring should guide KD implementation for gastrointestinal and immunological health optimization.

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