Immune Function Augmentation in Low-Carbohydrate Diet (LCD)
Bando H, Ebe K and Wood M
Published on: 2025-04-05
Abstract
Immune function improvement is frequently observed after initiating a low-carbohydrate diet (LCD). There are many mechanistic explanations that explain this phenomenom. Additionally, there are data supporting anti-inflammatory mechanisms that could make any symptoms associated with acute infectious illness less severe. Chronic illness is characterized by elevated inflammatory markers and dyslipidemia which improve after treatment. This article will discuss the various data available regarding LCDs and immune function.
Keywords
Low-carbohydrate diet (LCD); Immunity; T-cell; Inflammation; Ketone bodies; Reactive oxygen species (ROS)Introduction
Various forms of Low-Carbohydrate Diets (LCDs) have been used for centuries to treat a variety of conditions including diabetes [1] and seizure disorder [2]. More recent application has broadened to include treatment for obesity [3], hypertension [4], NAFLD [5], neurologic disorders [6], mental disorders [7,8], gastrointestinal issues [9], and rheumatologic disorders [10]. Many individuals experience common infectious illness less frequently and to a lesser degree after starting an LCD. Data quantifying infectious illness frequency or severety in individuals consuming LCDs are lacking. However, both animal and human studies suggest that a KD both attenuates chronic inflammation (innate immunity) while augmenting adaptive immunity. There is no consensus on what constitutes an LCD. A Very LCD (VLCD) has been described as containing ≤20 to 50 g per day or ≤5% to 10% of carbohydrates as a share of energy intake [11]. We recommend 3 varying degrees of LCD based on the needs and goals of the patient. They are petite LCD, standard LCD, and super LCD, in which the percentage of energy from carbohydrate is 40%, 26%, and 12%, respectively [12]. Many forms of LCD are ketogenic in nature, although there is variation in how ketogenic any given diet will be in each individual. A traditional Ketogenic Diet (KD) used in the treatment of epilepsy is a 4:1 ratio of fat to protein/carbohydrate, although a Modified Atkins Diet (MAD) is less restrictive on protein intake has been shown to be beneficial and easier to impliment with less side effects [13]. Overall health status, goals, and lifestyle will direct which form of LCD to pursue.
The positive effects of LCDs from an immunological perspective are multi-factorial and affect most organ systems. Improvements in Insulin Resistance (IR), glycemic control, chronic inflammation, and weight can be seen from carbohydrate restriction in general. The ketone body β-hydroxybutyrate (BHB) has anti-inflammatory properties independent of carbohydrate restriction [14]. Actions include suppressing pro-inflammatory cytokines and reducing neutrophil Reactive Oxygen Species (ROS) production by various mechanisms. These reductions in inflammatory processes are associated with improvements in many of the conditions mentioned above and could also minimize many of the negative symptoms associated with infectious illnesses which act to activate these pathways.
While innate immunity is attenuated, adaptive immunity appears to be bolstered. A KD enhances multiple lines of cells. γδ T cell proliferation and function in the lungs of mice [15]. CD8+ T memory cell function was improved in rodents [16]. CD8+ T cell function was improved after ketone treatment in COVID-19 patients [17]. Moreover, LCDs are known to affect LDL levels. LDL is known to correlate positively with patient survival in sepsis [18].
Innate Immunity
The discovery of the first inflammasome in 2002 marked a significant milestone in understanding innate immunity, particularly with the identification of the NLRP3 inflammasome as a key player in inflammation. The NLRP3 inflammasome is increasingly recognized as the most relevant to metabolic changes [19], and its aberrant activation is triggered in conditions like diabetes, where diminished disease healing is common. Activating factors of the NLRP3 inflammasome include Damage-Associated Molecular Patterns (DAMPs) such as ATP and hyperglycemia, among others. BHB uniquely inhibits the NLRP3 inflammasome without reliance on carbohydrate restriction (as it inhibits ATP-induced activation), distinguishing it from other ketone bodies like acetoacetate (AcAc) or acetone [20]. This activation leads to elevated secretion of pro-inflammatory cytokines such as IL-1β and IL-18, reprogramming immune cells toward inflammatory phenotypes and driving chronic diseases such as Alzheimer’s, Parkinson’s, atherosclerosis, Type 2 Diabetes (T2D), and gout [21].
Figure: Effects of Carbohydrate Restriction on the NLRP3 Inflammasome.
The NLRP3 inflammasome’s role in chronic disease is profound, contributing to systemic inflammation through mechanisms like increased IL-1β production, which is implicated in insulin resistance, β-cell damage, and metabolic stress in conditions like obesity [19]. For instance, in rodent models, BHB suppressed IL-1β in the placenta during endotoxin-induced inflammation, improving pregnancy outcomes [22]. Similarly, blocking IL-1β with antagonists (e.g., IL-1RA) nearly eliminates the induction of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) in human islet cultures exposed to diabetic conditions [23], highlighting IL-1β’s upstream role in inflammatory cascades. Clinical use of IL-1β antagonists like anakinra or canakinumab could be effective but carry significant risk secondary to immunosuppression.
Chronic hyperinsulinemia and post-prandial inflammation further exacerbate this cycle, with macrophage-derived IL-1β stimulating insulin secretion while promoting inflammation [24], a process that could add to cytokines released in acute infections. BHB supplementation significantly raises circulating BHB levels, reduces IL-1β and TNF-α, lowers NLRP3 inflammasome activity (via decreased caspase-1), and shifts immune profiles toward less inflammatory states without notable adverse effects [14]. This suggests BHB could offer a safer, diet-derived alternative to pharmacological interventions for managing inflammation in metabolic diseases like T2D. Dietary Polyunsaturated Fatty Acid (PUFA) intake provides substrate for oxidized LDL (oxLDL). Exposure of monocytes to oxLDL results in a long-lasting pro-inflammatory response, even after the removal of the stimulus [25]. Production of IL-6, TNF-α, and other cytokines is increased during this response due to epigenetic reprogramming. Unfortunately, oxLDL also leads to accumulation of foam cells in atherosclerotic plaques.
In addition to treating metabolic conditions, the KD and BHB therapy show broader immunomodulatory potential. For example, a KD in Experimental Autoimmune Uveitis (EAU) in mice altered immune cell gene expression, reduced inflammation, and reduced disease severity, possibly by suppressing pro-inflammatory pathways (e.g., Th17 activity) and enhancing anti-inflammatory mechanisms [26]. Similarly, the KD’s benefits extend to neuromuscular diseases like muscular dystrophies [27], where inflammation plays a pathogenic role. While clinical data remain conflicting (as noted in broader reviews), these findings collectively underscore BHB and KD as promising tools for mitigating NLRP3-driven inflammation across diverse conditions, though further research is needed to clarify mechanisms and optimize therapeutic applications.
Adaptive Immunity
Recent investigations have elucidated the multifaceted protective roles of a KD and its associated metabolic derivatives in bolstering immune responses across various pathological contexts. The KD confers a protective shield agained influenza in murine models [15]. This protective effect manifests through a notable inverse relationship between viral titers in pulmonary tissues and the proliferation and functional activation of γδ T cells, which exhibit heightened activation and expansion. The authors posit that ketone bodies may serve as an alternative, potentially superior, energy substrate or exert their influence via an undisclosed mechanism to yield these salutary outcomes. Parallel findings in rodent studies revealed enhanced functionality of CD8+ T memory cells under ketogenic conditions [16]. This augmentation of immune memory was further corroborated in human subjects with COVID-19, where it was observed that exogenous ketone treatment invigorated CD8+ T cell performance [17]. Specifically, the researchers documented increased cytokine expression and secretion, amplified cytotoxic capacity, elevated mitochondrial respiratory chain activity, and intensified mitochondrial ROS signaling which collectively augment robust immune function.
Moreover, BHB modulates mast cell activity, effectively suppressing inflammatory cascades [28]. This anti-inflammatory property suggests potential therapeutic applications in managing asthma and allergic conditions, broadening the scope of ketogenic interventions in immune-mediated disorders.
Lipid Metabolism in Chronic Inflammatory Conditions
Chronic inflammatory dieases such as Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Psoriasis (Ps) are associated with an increase in total cholesterol, LDL, Triglycerides (TAG), oxLDL, small dense LDL (sdLDL), and Lipoprotein (a) (Lp (a)), and a decrease in High Density Lipoprotein (HDL) (29). There is a positive correlation with disease severity and degree of dyslipidemia. Furthermore, medical treatment of the underlying condition improves the dyslipidemia. T2D is another chronic inflammatory condition with comparable dyslipidemia [30,31] to the above mentioned conditions (Table 1). RA is associated with a 23% relative increase in T2D, which is likely a result of inflammatory process [32]. CRP and IL-6 are early markers of T2D [33], meaning that inflammation is ongoing before glucose intolerance is detected. hsCRP is lowered greatly in T2D subjects utilizing LCD [34].
Table 1: Dyslipidemia in Various Inflammatory Conditions.
Lipid |
Type 2 |
Rheumatoid |
Systemic Lupus |
Psoriasis |
Periodontal |
IBD, Sjogren's |
Acute Infections |
TC |
Increased |
Variable |
Variable |
Increased |
Increased |
Variable, tends to ↓ |
Decreased |
LDL-C |
Normal |
↓ with severity |
↓ with severity |
Increased |
Increased |
Variable, tends to ↓ |
Decreased |
sdLDL |
Increased |
Increased |
Increased |
Increased |
Increased |
SS ↓ , others ↑ |
Increased |
TG |
Increased |
Increased |
Increased |
Increased |
Increased |
Increased |
Normal to ↑ |
CRP |
Increased |
Increased |
Increased |
Increased |
Increased |
Increased |
Decreased |
HDL-C |
Decreased |
Decreased |
Decreased |
Decreased |
Decreased |
Decreased |
Decreased |
IBD = Irritable bowel syndrome, SS = Sjogren's syndrome, AS = Ankylosing spondylitis
TC = Total cholesterol, LDL-C = Low-density lipoprotein cholesterol, sdLDL = Small dense LDL
TG = Triglyceride, CRP = C-reactive protein, HDL-C = High-density lipoprotein cholesterol
The KD was tested in a phase II study for safety, tolerability, and potential benefits for treating multiple sclerosis [35]. The KD was generally safe and well-tolerated with high adherence rates (83%) confirmed by urine ketone measurement and participant inspection. Participants had reduced fatigue, improved quality of life, lower levels of disability progression markers, and fewer relapses. LDL increased by 10±27 mg/dL from a baseline of 127±35 mg/dL over 6 months. Markers of metabolic health all improved, including a decrease in BMI, HbA1c, fasting insulin, and TAG. Leptin, a pro-inflammatory marker decreased.
A mini review examined the impact of the KD on inflammatory arthritis and cardiovascular health in patients with rheumatic conditions [10]. The review suggests that the KD may reduce inflammation in rheumatic diseases like RA by modulating immune responses, potentially through mechanisms such as decreasing pro-inflammatory cytokines or enhancing anti-inflammatory pathways. A KD may improve lipid profiles, reduce oxidative stress, or influence metabolic parameters, though outcomes vary depending on individual patient factors and study design.
Lipid Metabolism in Immune Modulation
Acute infections are found to decrease total cholesterol, LDL, oxLDL, HDL, and Lp (a), while TAG may be inappropriately normal to high and sdLDL elevated [29]. Hypocholesterolemia is a well-established predictor of poor outcomes in sepsis [18], a condition often driven by Lipopolysaccharide (LPS), a key component of bacterial endotoxins. Earlier research on rodents demonstrates that LPS-induced sepsis disrupts lipid homeostasis in rodents [36]. Specifically, LPS increases LDL levels through a dose-dependent mechanism: at lower doses, it enhances hepatic Very-Low-Density Lipoprotein (VLDL) production, whereas at higher doses, it reduces clearance by inhibiting Lipoprotein Lipase (LPL) activity.
This cytokine-mediated dysregulation extends to humans, as evidenced by observations in HIV patients where elevated tumor necrosis factor-alpha (TNF-α) correlates with reduced LPL activity and hypertriglyceridemia, underscoring the role of TNF-α in chronic inflammation. TNF-α-induced LPL inhibition was shown to be a central driver of cachexia, a wasting syndrome characterized by depleted fat stores and dysregulated circulating lipids [37]. This inhibition impairs triglyceride clearance, amplifying lipid imbalances during inflammatory states. Concurrently, sympathetic activation triggered by endotoxins stimulates the release of stress hormones, such as catecholamines (e.g., adrenaline), which enhance lipolysis in adipocytes, further elevating circulating non-esterified fatty acids (NEFAs) [38]. TNF-α exacerbates the surge of NEFAs by suppressing insulin signaling on adipocytes, leading to unchecked NEFA release from adipose tissue [39]. Cholesterol biosynthesis is upregulated in hamsters, where LPS exposure increases hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA levels within 4 hours, an effect persisting for at least 24 hours [40]. This elevation in HMG-CoA reductase activity may enhance lipoprotein production, potentially bolstering serum lipid levels as part of the host’s defense strategy against infection.
Serum lipoproteins, including LDL and HDL, play a critical role in innate immunity, particularly in the pulmonary environment. LDL and HDL neutralize Auto Inducing Peptides (AIPs) produced by the accessory gene regulator (agr) system, disrupting Staphylococcus aureus quorum-sensing pathways that regulate virulence [41]. This binding reduces bacterial pathogenicity, mitigates lung infection severity, and enhances host innate immunity in both in vitro and in vivo models. Thus, serum lipoproteins may be vital components of pulmonary defense, with potential implications for therapeutic interventions against S. aureus infections.
Interestingly, the effects of lipoproteins on inflammation vary by context and type. Coadministration of human HDL with LPS in mice exacerbates neuroinflammatory markers in the brain, whereas LDL appears to attenuate LPS-induced inflammation in both the brain and liver [42]. This differential impact suggests that ketogenic diets, which elevate circulating ketones and alter lipoprotein profiles, may modulate immune responses through lipid-mediated mechanisms.
Recent evidence also points to the therapeutic potential of statins, which inhibit HMG-CoA reductase and modulate lipid metabolism. Continuing statin therapy in ICU-admitted sepsis patients without liver dysfunction improves outcomes, possibly due to the pleiotropic anti-inflammatory effects of statins [43]. This aligns with findings from the JUPITER trial [44], which demonstrated statistically significant reductions in inflammatory markers in relatively healthy individuals treated with statins. Collectively, these studies suggest that ketogenic diets, by shifting lipid metabolism toward ketogenesis and altering lipoprotein dynamics, may enhance immune function by mitigating inflammation and supporting innate defenses against pathogens.
Addressing Concerns with Elevated LDL
LDL and total cholesterol have been accepted as risk factors for CVD. In the 1988 Banting Lecture, Gerald Reaven layed out the evidence for syndrome X, or metabolic syndrome, suggesting that insulin resistance drove most of the risk factors for CVD [45]. Glycemic control positively affected microvascular comorbidities of T1D but not the macrovascular complications [46]. Moreover, the degree of insulin resistance in T1D patients is more predictive of CVD risk than glycemic control [47]. Moreover, even pharmaceutical company funded researchers concluded that there was no evidence that statin therapy lowered vascular risk among persons who had neither hyperlipidemia nor elevated high-sensitivity CRP (hsCRP) levels [48].
A prospective study reported no correlation between LDL-C and plaque burden over 4.7 years when comparing 80 healthy subjects on a typical diet (control group) with 80 healthy lean mass hyper-responder (LMHR) subjects on a carbohydrate restricted diet (test group) [49]. LMHR was defined as LDL-C >= 200 mg/dL, TAG <= 80 mg/dL, and HDL-C >= 60 mg/dL. The LDL-C was 123 +/- 38 and 272 +/- 91 mg/dL in the control and study groups, respectively. Coronary Artery Calcium (CAC) score and Coronary Computed Tomography Angiography (CCTA) were used to monitor plaque burden. The inflammatory marker hsCRP was 0.7 and 0.5 in the control and study groups, respectively. This further supports the notion that inflammation may play more of a role in atherosclerosis than LDL-C. Population studies also address concerns with elevated LDL. The Leiden Longevity Study (LLS) explored the relationship between lipid metabolism and exceptional longevity by examining families with a history of long-lived individuals [50]. The offspring of 90-year-old siblings (who are predisposed to longevity) compared to their partners as controls were found to exhibit a distinct lipid metabolism profile characterized by lower levels of total cholesterol, LDL-C, and TAG, alongside a higher HDL-to-LDL ratio. These differences suggest a genetic or metabolic basis for reduced cardiovascular risk and enhanced longevity.
Discussion
The KD itself and BHB, a byproduct of fat metabolism, emerge as potent modulators of immune function, weaving a complex tapestry of effects that span both innate and adaptive immunity. Historically employed for centuries to ameliorate conditions such as diabetes and epilepsy, LCDs have recently garnered attention for their expansive therapeutic potential. This includes ameliorating obesity, hypertension, MASLD, neurological and psychiatric disorders, gastrointestinal disorders, and rheumatologic conditions. Central to LCD is a dual immunological action that includes attenuation of chronic inflammation via suppression of innate immune pathways, notably the NLRP3 inflammasome, and the simultaneous fortification of adaptive immunity through enhanced T-cell functionality.
The anti-inflammatory properties of BHB, independent of carbohydrate restriction, is particularly noteworthy. By inhibiting NLRP3 inflammasome activation and reducing pro-inflammatory cytokines such as IL-1β and TNF-α, BHB disrupts the inflammatory cascades that underpin metabolic diseases like T2D, atherosclerosis, and neurodegenerative disorders. This is complemented by its capacity to shift immune profiles toward less inflammatory states, offering a safer, diet-derived alternative to pharmacological interventions like IL-1β antagonists, which carry immunosuppressive risks. Concurrently, the KD bolsters adaptive immunity, as evidenced by enhanced γδ T-cell proliferation and function against influenza in mice, improved CD8+ T memory cell performance in rodents, and increased CD8+ T-cell responses in COVID-19 patients. Moreover, BHB suppresses mast cell-driven inflammation, evidence of a possible role in infectious and allergic diseases.
Given the relationship between chronic lifestyle-related diseases such as T2D and chronic inflammatory diseases such as RA, which share common underlying inflammatory pathways, it is logical to postulate that the etiology could be the same. Given that KD improve these chronic conditions in practice and that there are biochemical pathways to describe the mechanism in the scientific literature provides more support to this hypothesis. The cytokines that drive inflammation in acute infectious illness are also present in chronic inflammatory disease. Any amplification of these cytokines in an individual suffering from chronic inflammatory disease could quite possibly result in an augmentation of the baseline inflammatory processes, causing exaggerated symptoms when these individuals are acutely ill. Additionally, the pathologic dyslipidemia seen in chronic inflammation can result in inadequate immune function downstream of LDL and HDL alterations. These data provide insight into possible mechanisms for why LCDs tend to decrease symptoms of acute infectious illness frequency and severity. Research is needed in randomized clinical trials in humans to provide further subjective and objective data for this topic.
Conflict of interest: The authors declare no conflict of interest.
Funding: There was no funding received for this paper.
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