PLMI Blog

Chronic diseases are a leading cause of morbidity and mortality worldwide (1). At the core of these conditions lies a complex interplay between impaired immune function and dysregulated metabolism, both of which are critical drivers of disease onset and progression. Disruptions to appropriate immune responses and metabolic processes create a vicious cycle that accelerates the development of various chronic illnesses. By unraveling these connections, we can develop and implement more efficacious strategies to mitigate disease while improving life and healthspan.

The Pivotal Roles of the Immune System and Metabolism

The immune system is essential not only in defending against pathogens but also in governing systemic balance in the body (2). Dysfunction, including overstimulation or understimulation, can wreak havoc on health. An impeded immune response from inefficient reactions can increase susceptibility to illness, while overactivation can result in excessive inflammation and contribute to tissue damage (such as autoimmune conditions).

Similarly, dysregulated metabolism, a hallmark of obesity and diabetes, disrupts pathways such as glucose and lipid metabolism, triggering inflammation and oxidative stress that can exacerbate immune dysfunction, contributing to a vicious cycle perpetuating chronic disease progression (3).

The Gut Microbiome – A Key Regulator of Immunity and Metabolism

Mounting findings demonstrate the interconnectedness between the gut microbiome, host metabolism, and immunity. Altered microbial balance (dysbiosis) disrupts immune and metabolic balance, contributing to chronic diseases, including obesity and insulin resistance (4). Dysbiosis increases intestinal permeability, allowing paracellular flux of lipopolysaccharides and other endotoxins into circulation. This triggers systemic inflammation, compromises tissue health, and exacerbates dysregulated immune and metabolic health (5). Research indicates that obesity-induced microbiota changes lead to immune activation, chronic inflammation, and impaired glucose metabolism, further disrupting insulin signaling and immune function (6-7).

Alterations in gut microbiota from diet and lifestyle factors can also impede the gut-brain axis, which is responsible for governing bidirectional crosstalk between the peripheral and central nervous system. The mechanisms underlying this communication include neuro-immuno-endocrine regulators, underscoring the role of the gut microbiome in governing homeostasis.

Immunometabolism – A Modulator of Health

Immunometabolism refers to the interaction of metabolism with the immune system and can highlight the underlying mechanisms of chronic disease. Natural killer (NK) cells – key components of both the innate and adaptive immune systems – play pivotal roles in defending against infections and tumors while also regulating metabolic processes (9). Research demonstrates that NK cell function is impaired in chronic diseases, particularly obesity, where dysregulated metabolism disrupts essential pathways,  including glycolysis and oxidative phosphorylation, weakening NK cell responses and increasing susceptibility to infections and cancers (10).

Immunosenescence – A Driving Factor In Chronic Disease

Aging is a major risk factor for chronic disease (10) as immune function declines with age, a process known as immunosenescence. This decline is marked by a reduction in appropriate immune cell response and antibody production, as well as increased systemic inflammation (inflammaging).

Age-related changes also include disruptions in NK cell functioning, which play a central role in the immune surveillance of senescent cells. As NK cell function declines, the accumulation of senescent cells grows, increasing the secretion of inflammatory cytokines. This further impedes immune function and contributes to metabolic dysregulation, increasing susceptibility to illness. These connections underscore the importance of understanding immune-metabolic interactions in the context of chronic disease.

Chronic Inflammation & Metabolic Disorders

A persistent low-grade inflammatory response is a hallmark of chronic disease, often driven by metabolic dysregulation, such as obesity and insulin resistance. In diabetes, advanced glycation end products trigger immune activation and inflammation, contributing to complications such as neuropathy and nephropathy (11-12). Obesity exacerbates immune dysfunction, as it induces inflammation through increased leptin, reduced adiponectin, NEFA-induced inflammation, endoplasmic reticulum stress, and hypoxia in adipose tissue while also driving conditions such as inflammatory bowel disease (13) and atherosclerosis. Visceral adiposity plays a pivotal role in driving the inflammatory process and associated metabolic complications.

Chronic inflammation induced by metabolic imbalances also activates the NLRP3 inflammasome, a multiprotein complex that plays a critical role in modulating inflammatory cytokines, such as interleukin-1β (IL-1β) (14).  Dysregulated metabolism triggers the NLRP3 inflammasome, further perpetuating inflammation and contributing to the progression of metabolic disease.

Impeded Immunity, Metabolism & Progression of Chronic Disease

A growing body of research highlights that impaired immune function is correlated with obesity. The chronic state of inflammation observed in obesity disrupts systemic balance by altering communication between immune and metabolic responses. Obesity, therefore, further perpetuates immune dysfunction, resulting in compromised immune response, altered leukocyte count, and the accumulation of senescent immune cells (7). This immune dysfunction also contributes to conditions where chronic inflammation promotes tissue damage and disease progression (15).

The Interplay Between Immunity & Metabolism: Gut-Immune Metabolic Axis

Impaired immune function and dysregulated metabolism are deeply interconnected in the pathogenesis of chronic diseases. Gut microbiota, adipose tissue, NK cells, and inflammaging all play crucial roles in this complex relationship (16). Dysbiosis and impaired gut barrier integrity contribute to inflammation and metabolic dysfunction, while obesity triggers systemic inflammation that impedes immune responses and disrupts metabolism. Aging further exacerbates these processes by inducing immunosenescence and increasing systemic inflammation.

Research shows that successful aging is marked by a healthy balance of inflammation and efficient innate and adaptive immune mechanisms. Modulation of these factors has been shown to be related to immunometabolism, while imbalance is correlated with immunosenescence and inflammaging – making one more susceptible to chronic disease (16).

In autoimmune diseases, chronic inflammation disrupts metabolic processes, with elevated cytokines (TNF-α, IL-6, and IL-1) altering metabolism and contributing to conditions such as obesity and insulin resistance. Autoimmune diseases, including Hashimoto’s and Graves’ disease, further impact metabolism by disrupting thyroid hormone balance, leading to metabolic alterations and fatigue (17). An imbalanced microbiome, as emphasized, also plays a key role in immune dysregulation and metabolic disruption in these conditions, further driving disease progression.

Chronic inflammation, in conjunction with immune and metabolic dysfunction, has been shown to be prevalent in mental health etiology.  Mental health conditions are increasingly recognized as comorbidities of compromised metabolic and immune health, compounding efficient treatment modalities (18). Alterations in the gut-immune metabolic axis – crucial for communication between the CNS and gut – can increase intestinal permeability, trigger systemic inflammation, impair neurotransmitter release, and reduce brain trophic factors that regulate mood and reduce inflammation, further connecting immune and metabolic dysfunction to mental health conditions (19).

Supporting Immune Function & Metabolism

Nutrition, lifestyle, and environmental factors play a crucial role in modulating immune function and metabolism (20). A balanced, nutrient-dense diet rich in a diverse array of fruits and vegetables, quality proteins, minimally processed grains, and anti-inflammatory fats supports immune function and metabolism. Micronutrients (including Vitamins A, B12, C, D, E, selenium, zinc, and polyphenols known for their anti-inflammatory and antioxidant properties) influence key transcription factors, such as NF-kB and Nrf-2, promoting immune and metabolic health (21). Ensuring adequate amounts of prebiotics and probiotics is also imperative for modulating immune function, inflammation, and gut microbiome balance.

Refraining from the consumption of processed foods is also essential, as their chemical additives can impede metabolic, microbiome, and immune health, further driving inflammation, oxidative stress, and chronic disease progression  (22). Being mindful of environmental toxins is also significant, as these can disrupt immune and metabolic pathways (23).

Intermittent fasting may further promote immune and metabolic health through many of these altered mechanisms (24). Intermittent fasting (IF) reduces inflammation and combats metabolic dysfunction associated with obesity. IF can improve glucose metabolism and alter the gut microbiota in favorable ways, which in turn influences immune responses and metabolism. Research shows that IF promotes autophagy and favorably modulates senescence and inflammasome activities (25), while obesity reduces metabolic flexibility and activates inflammatory immune responses.

Slowing down and listening to your body can further support immune and metabolic health. Recognizing the need for rest or stillness can activate the lymphatic system, promoting immune health. Aligning with your body’s natural biological rhythms by maintaining a consistent sleep-wake cycle, getting sunlight exposure in the morning, and limiting artificial light at night are all important for modulating metabolic and immune health by promoting circadian rhythm balance (26).

In fact, circadian rhythms are present in nearly all cells and are vital for regulating biological processes that govern health, as supported by a 2024 review (27). Circadian balance plays a role in modulating cellular and systemic rhythms that are essential for promoting homeostasis, critical for maintaining metabolic and immune functions. Disruptions can impede the expression of clock and cancer-related genes, disrupt metabolic pathways, and impede immune function driving chronic disease progression (26-27).

These disruptions are similar to the effects of chronic stress and may be focal to the development of stress-related disorders. Research on PTSD highlights the link between circadian misalignment and the dysregulation of sleep, neuroendocrine, immune, metabolic, and autonomic systems – all of which are integral to its pathophysiology (28-29).

Sleep and immunity are closely interconnected (30). Immune system activation can impact sleep, while sleep influences both innate and adaptive immunity. Quality sleep is essential for promoting the glymphatic system, in addition to the lymphatic system, which are significant for modulating immune health. Regular sleep is also crucial for regulating metabolic health via microbiota, inflammatory, and immune mechanisms, as well as promoting circadian rhythm balance (31).

Appropriate movement is also imperative for modulating immune and metabolic health. Yoga may be especially beneficial in supporting immune function and modulating metabolism through a number of homeostatic mechanisms, including stress reduction. A 2022 review published in Brain, Behavior & Immunity demonstrated the benefits of yoga on levels of circulating cortisol, inflammatory markers that include C-reactive protein (CRP), interleukin-1 beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) (32).

Sufficient nutrition, rest, and movement, thereby, are pivotal for immune health, regulating the gut microbiome, reducing inflammation, and supporting metabolic function. Immersing oneself in nature further promotes immune and metabolic health while reducing stress, inflammation, and susceptibility to chronic disease. Forest bathing has been shown to support these processes (33). This underscores the importance of bringing it back to the basics when it comes to supporting our health – through the consumption of whole, natural foods, appropriate movement, rest, connection with nature, and a restorative environment.

For more information on the topic, view our recorded webinar, Immunonutrition for Healthspan: Nutritional Targets to Rejuvenate Immunity and Slow Aging, in which experts Stephan van Vliet, PhD, Jeff Bland, PhD, Austin Perlmutter, MD, and Mary Purdy, MS, RDN dive deeper into the bidirectional crosstalk between immunity, metabolism, and chronic disease – revealing important insights for enhancing systemic health and mitigating disease.

References:

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