Ketogenic Therapy as a Metabolic–Psychiatric Intervention

Mechanisms, Gut–Brain Axis, and Early Clinical Evidence

Ketogenic therapy is increasingly recognized as a powerful metabolic intervention with downstream benefits for mental health. Its therapeutic potential derives from multiple mechanisms, including shifting substrate utilization, reducing insulin and inflammatory signaling, modulating neurotransmitter balance, and strengthening gut–brain axis function (Puchalska & Crawford, 2017, 2021). Central to these effects is the ketone body β-hydroxybutyrate (BHB), which functions as both a high-efficiency neural fuel and a pleiotropic signaling molecule that regulates gene expression, cellular stress responses, and immune activity (Breuling et al., 2024; Puchalska & Crawford, 2017, 2021).

Metabolic Reprogramming and Systemic Restoration

A well-formulated ketogenic diet (WFKD), defined as a diet low in carbohydrate, moderate in protein, and high in fat, with an emphasis on whole, nutrient-dense foods (Volek & Phinney, 2012), shifts whole-body metabolism away from glucose reliance and toward fat-derived ketones, primarily BHB (Puchalska & Crawford, 2017). This shift lowers circulating insulin, releasing the “brake” on lipolysis and allowing adipose tissue to mobilize fatty acids (Cavaleri & Bashar, 2018). Clinical studies have demonstrated significant improvements in body composition on WFKD, with reductions in body mass and fat mass observed even in the absence of explicit caloric restriction (Decker et al., 2025). In parallel, adipokine signaling improves, with decreases in leptin reflecting enhanced leptin sensitivity and reduced inflammatory tone (Decker et al., 2025).

At the cellular level, BHB supports pancreatic β-cell mitochondrial function and survival, enhancing insulin production capacity (Sampson et al., 2017). Ketones and short-chain fatty acids also signal via G-protein–coupled receptors such as GPR41 and HCAR2, tuning autonomic balance and conserving energy under carbohydrate restriction (Kimura et al., 2011; Puchalska & Crawford, 2021).

Mental Health and Cognitive Outcomes

Metabolic dysfunction and mood disorders are increasingly understood as bidirectionally linked, with insulin resistance and neuroinflammation serving as shared drivers (Cavaleri & Bashar, 2018; Puchalska & Crawford, 2021). Early clinical evidence suggests ketogenic therapy may address both. In the Ohio State University KIND pilot trial, college students with major depressive disorder (MDD) following a 10–12-week WFKD exhibited rapid and substantial symptom reduction (≈69–71% improvements on PHQ-9 and HAM-D), accompanied by gains in global well-being and cognitive performance. Nutritional ketosis was confirmed biochemically, and no serious adverse events occurred (Decker et al., 2025). These promising findings are now being tested in larger randomized controlled trials such as KETO-MOOD (Hongler et al., 2025).

Mechanistically, ketones provide an insulin-independent cerebral fuel that compensates for impaired glucose metabolism, a feature of several neuropsychiatric and neurodegenerative conditions (Cavaleri & Bashar, 2018). Ketosis is also associated with upregulation of brain-derived neurotrophic factor (BDNF), which supports synaptic plasticity and resilience (Decker et al., 2025).BHB may elevate BDNF through histone deacetylase (HDAC) inhibition and downstream transcriptional changes (Breuling et al., 2024; Puchalska & Crawford, 2017). Furthermore, BHB has been shown to block the NLRP3 inflammasome, a key driver of inflammation often implicated in depression (Youm et al., 2015). Importantly, contrary to concerns about excitotoxicity, evidence suggests that ketogenic diets mitigate excessive glutamate signaling and restore inhibitory–excitatory balance, a mechanism thought to underlie both its antiepileptic and mood-stabilizing effects (Hongler et al., 2025; Qi et al., 2022).

The Gut–Brain Axis: Strengthening Two Pillars

The gut–brain axis can be conceptualized as a two-way superhighway of neural, hormonal, and immune signaling. Its integrity rests on two interdependent “pillars”: the gut microbiome (ecosystem) and the gut lining (epithelial barrier). Ketogenic therapy influences both pillars in ways that may enhance mental health.

Pillar 1: Reshaping the Gut MicrobiomeDiet is the primary determinant of microbial community composition. By reducing fermentable sugars and starches while increasing fats, ketogenic diets shift the “fuel sources” available to gut microbes. Depending on formulation, WFKD has been associated with increases in anti-inflammatory taxa such as Faecalibacterium prausnitzii (Hongler et al., 2025). This bacterium produces butyrate, a short-chain fatty acid that reduces inflammation and fuels colonocytes (Breuling et al., 2024). A microbiome enriched in such taxa sends “calming” anti-inflammatory signals to the brain, thereby reducing neuroinflammation, a key factor in depression and anxiety.

Pillar 2: Strengthening the Gut LiningThe gut epithelium, a single-cell layer renewed every 4–5 days, acts as the body’s nutrient gatekeeper and immune sentinel. BHB, through HDAC inhibition, supports intestinal stem-cell renewal and epithelial homeostasis, thereby reinforcing barrier integrity and maintaining immune quiescence (Urbauer et al., 2021). A strong gut barrier prevents “leaky gut,” lowering systemic immune activation and protecting against chronic low-grade inflammation that can propagate to the brain.

The Oxygen–Dysbiosis ConnectionHealthy epithelial metabolism consumes large amounts of oxygen, maintaining a low-oxygen (anaerobic) luminal environment that favors beneficial microbes. When epithelial metabolism falters, oxygen leaks into the lumen, creating conditions that support opportunistic, pro-inflammatory bacteria (e.g., E. coli). This dysbiosis alters gut–brain signaling from one of calm to one of alarm, promoting systemic inflammation and negative mood states (Schwärzler et al., 2024).

Conclusion

Ketogenic therapy, particularly when delivered as a WFKD, addresses the metabolic and neuropsychiatric roots of depression through an integrated set of mechanisms: improved substrate utilization, lower insulin and inflammation, enhanced neurotrophic support, reduced glutamate excitotoxicity, and a healthier gut–brain axis. While preliminary clinical evidence is compelling, further large-scale, controlled trials are necessary to define efficacy, durability, and optimal patient populations. Nevertheless, ketogenic therapy stands as a promising adjunct within metabolic psychiatry, offering a coherent framework to restore both metabolic health and mental well-being.

References

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