Metabolism and Immunity in Dialogue: Exploring the Systemic Interface in Sports Medicine

Traditional approaches in (sports) medical research have long been focused on isolated organs. While this reductionist perspective has provided valuable insights into specific physiological functions, the complex and dynamic interactions between systems are often neglected. Advanced concepts, such as Holisitic Integrative Physiology (HIP), are valuable models for understanding health and disease not as a result of dysfunctions of individual organs, but as emergent properties of highly integrated physiological networks. At the same time, they provide a view of what exercise physiologically achieves: namely, a very holistic effect on diverse physiological systems that interact with each other.

One example of this systems-based perspective is the immunometabolic interface – the bidirectional interaction between the immune system and metabolism. These systems are closely linked through shared molecular signaling pathways and regulatory metabolites that control immune cell function, energy balance, and inflammatory responses. Rather than acting independently, they jointly regulate physiological adaptations and pathophysiological processes, particularly in response to external stimuli such as exercise.

Acute exercise and regular physical activity have numerous effects on the immune system. The numerous metabolic effects of physical activity are also well known. The interfaces are interesting here: immune cells are metabolically active and take up metabolites and react specifically. At the same time, cytokines influence metabolism. Multi-omics research has shown how the level of cardiorespiratory fitness influences metabolic and in particular mitochondrial responses in immune cells. By evaluating immunometabolic profiles – including mitochondrial capacity, cytokine balance and metabolite patterns – advanced insights can be gained for the prevention and therapy of diseases. These insights also provide exciting new information for the management of exercise and training for elite athletes.

At the 2025 Sports, Medicine and Health Summit in Hamburg, these topics will be discussed in detail in order to bring integrative models more strongly into the discussion of sports medicine.

KEY WORDS: Holistic Integrative Physiology, Immunometabolic Interface, Systems-Physiologic Approaches, Mitochondrial Function

For a long time, research in (sports-) medicine focused on single organs and tissues. While this reductionist approach allowed for detailed insights into the specific functioning and pathophysiology of individual structures, it often neglected the complex, dynamic interactions between different physiological systems. As a result, our understanding of systemic regulatory mechanisms and their role in health, disease development, and adaptation processes to external stimuli – such as physical activity – remained incomplete. Furthermore, there is a risk that therapeutic interventions may focus solely on one organ without adequately considering the impact on other systems.

Focusing on specific organ axes – such as the muscle-brain or gut-immune system axis – is undoubtedly a good step forward. These models underscore the bidirectional communication between individual organs and have significantly advanced our understanding of the health-promoting effects of physical activity (8). In such research, for example, many influences of signaling molecules such as myokines or exerkines have been described, and their release, receptors, and signaling pathways have been investigated. While these approaches provide valuable insights, they may only partially capture the complex and dynamic interplay of physiological systems involved in physical activity. A stronger integration of cross-systemic interactions could further enhance our understanding of how coordinated processes contribute to both the maintenance of health and the progression of disease. To better understand the holistic effects of physical activity, it is essential to adopt a systemic perspective. Such an approach emphasizes the integrative and reciprocal interactions among entire physiological systems, providing a more comprehensive view of how exercise influences the body as a whole. This systemic framework allows us to explore not only how physical activity improves individual organ functions but also how it orchestrates adaptive responses across multiple systems, ultimately promoting overall health and performance.

In the past, there have been repeated attempts to develop such models. A good example of this is provided by Sun et al. 2020 (13), who discussed the emerging concept of Holistic Integrative Physiology (HIP). HIP emphasizes systems integration over reductionism, arguing that the compartmentalized study of individual organs misses the inherent complexity of the human organism. According to HIP, physiological systems – such as cardiovascular, immune, endocrine, and metabolic networks – are in constant communication through molecular, cellular, and systemic signaling pathways. Health and disease are therefore understood as emergent properties of a highly interconnected, dynamic, and adaptive network rather than isolated functions or dysfunctions. We find this model-based view of physiology particularly well suited to the holistic effects we see through exercise.

A key aspect of HIP is the concept of homeodynamics, which views physiological regulation not as a static balance (homeostasis) but as a dynamic process continuously adjusting to internal and external perturbations. Stressors such as physical activity, nutritional changes, or psychosocial factors require ongoing recalibration of these systems to maintain systemic integration and health. Moreover, HIP reframes exercise not as an isolated mechanical load on muscles but as a holistic stimulus that affects nearly every system in the body. Exercise induces complex adaptations in the immune, endocrine, nervous, and metabolic systems that together contribute to improved resilience and systemic health. This comprehensive view aligns with emerging approaches in personalized and systems medicine, aiming to understand and modulate these integrative processes to prevent disease and promote optimal health (13).

An especially exciting area gaining importance in this holistic framework is the interface between the metabolic and immune systems. These two systems do not function in isolation; they share molecular signaling pathways, are regulated by common factors, and strongly influence each other. This immunometabolic interface is now recognized as a central factor in the development and progression of diseases, in training adaptations, and in promoting health. This topic will also be a focus of the Sports, Medicine and Health Summit 2025 in Hamburg.

Traditionally, metabolism was considered as the body’s energy regulation system, while the immune system was primarily responsible for defense. However, this perspective is too narrow. Immune cells are highly metabolically active, and their function, differentiation, and plasticity largely depend on their metabolic status. Conversely, immune system activation profoundly affects systemic and cellular metabolic processes (3). Recent studies, such as the comprehensive review by (5) on cancer and immunometabolism, illustrate that metabolic flexibility is not only a characteristic of high-performing muscle but also a critical requirement for immune competence. Immunological responses – whether fighting infections, resolving inflammation, or maintaining tolerance – rely on immune cells’ ability to adapt their metabolism to the respective context.

The interaction between metabolism and the immune system plays a pivotal role in regulating inflammatory responses, with glycolysis being particularly influential. During inflammation, immune cells such as M1 macrophages and Th1/Th17 T lymphocytes shift their metabolism toward glycolysis, a process known as the Warburg effect. This metabolic reprogramming provides the energy and biosynthetic intermediates needed for rapid cell proliferation and inflammatory signaling. Glycolysis in these cells is essential for generating key metabolites, including lactate, phosphoenolpyruvate (PEP), and succinate, which not only fuel energy production but also actively participate in inflammatory signaling, epigenetic regulation, and post-translational modifications that reinforce the pro-inflammatory phenotype (10).
Conversely, regulatory immune cells such as M2 macrophages and regulatory T cells (Tregs) rely more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) for energy, facilitating the resolution of inflammation. The metabolic transition from glycolysis to OXPHOS during the resolution phase helps to restore homeostasis and dampen prolonged inflammatory responses. This shift in metabolic preference reflects the dynamic nature of immune responses, where metabolism dictates immune cell behavior from activation to resolution.

Thus, the dominant type of metabolic pathway is not just a source of energy but also a key player in determining the inflammatory outcome. The metabolites produced during glycolysis, such as lactate and succinate, influence signaling pathways that control immune cell migration, cytokine production, and the polarization of macrophages and T cells. Understanding how these metabolic processes regulate inflammation opens new avenues for therapeutic strategies targeting immunometabolism to treat inflammation-related diseases, including those associated with aging, cardiovascular, and neurodegenerative conditions (12).

The core of these immunometabolic processes are mitochondria. While the primary function of mitochondria is to produce ATP through OXPHOS, they are also well known to regulate cell signaling, apoptosis, calcium homeostasis, and hormone synthesis. Their function is also essential for the polarization of immune cells. M2 macrophages and Tregs rely more on efficient energy production through OXPHOS, where mitochondria play a central role in maintaining their functional integrity and promoting anti-inflammatory mechanisms. The interplay between glycolysis and OXPHOS is orchestrated by mitochondrial signals, which influence immune cell function and the resolution of inflammation (1). As dynamic organelles, they are highly responsive to physiological stressors – especially physical activity. The concept of “Exercise as Mitochondrial Medicine,” described by David J. Bishop and colleagues (2025, (2)), highlights that physical activity provides a targeted stimulus for mitochondrial adaptation processes. Exercise leads to short- and long-term changes in mitochondrial biogenesis, function, and quality. Crucially, the dose matters: the type, intensity, frequency, and duration of exercise largely determine mitochondrial responses (2). Moreover, exercise is a unique approach to influence mitochondrial function. In the context of the differentiated adaptation of mitochondria to training stimuli, further research should investigate their role not only as the primary energy producers of the cell but also as key regulators of immune cell metabolism. Through this dual function, they significantly influence both the triggering and the resolution of inflammatory processes. Impaired mitochondrial function can contribute to persistent inflammation and the development of chronic diseases. Therefore, the targeted manipulation of mitochondrial metabolism represents a promising approach for therapeutic interventions aimed at modulating inflammation and improving health outcomes (4).

A striking example of disturbed immunometabolic balance is obesity and metabolic syndrome. Here, excessive energy intake and fat accumulation lead to chronic, low-grade inflammation. Hypertrophic adipocytes release increased danger signals, such as DAMPs (Damage Associated Molecular Patterns), attracting macrophages and triggering a pro-inflammatory cytokine response – particularly with TNF-α, IL-1β, and IL-6. This inflammatory environment exacerbates insulin resistance, disrupts glucose metabolism, and impairs metabolic flexibility – the ability to switch between glucose and fat as energy substrates as needed. Additionally, pro-inflammatory cytokines inhibit mitochondrial biogenesis and oxidative capacity in muscle tissue. The result is a vicious cycle of reduced metabolic efficiency and persistent inflammation, undermining not only metabolic health but also athletic performance and recovery (14).

Chronic immune system activation leads to metabolic reprogramming that extends far beyond local inflammation. Persistent inflammation promotes increased glycolysis in immune and other cells, even when oxygen is available – a hallmark of immunometabolic dysregulation in chronic conditions. While this shift allows for rapid energy production, it comes at the expense of long-term cellular resilience and homeostasis. Certain metabolites, such as succinate, lactate, and acetyl-CoA, act as potent immunomodulators. Succinate stabilizes HIF-1α in macrophages, promoting IL-1β production and maintaining a pro-inflammatory response. Lactate has immunosuppressive effects in the tumor microenvironment and influences T cell function during chronic inflammation. These findings call for a paradigm shift: metabolites are not merely metabolic intermediates but active signaling molecules, particularly for the immune system. This helps explain both the mechanistic links between exercise and the immune system and pathological connections to systemic chronic inflammation associated with cardiovascular and metabolic diseases. It also opens new opportunities for using physical activity as a targeted therapeutic intervention, allowing for reciprocal immunomodulation through metabolic processes (9).

Physical activity is one of the most effective non-pharmacological strategies to restore balance in the immunometabolic network. Acute exercise at high intensity and duration triggers a temporary inflammatory response characterized by elevated IL-6 levels from working muscles. However, this is followed by an anti-inflammatory cascade involving IL-10 and IL-1 receptor antagonists, which suppress TNF-α (11). Long-term training, especially moderate endurance training and HIIT, promotes mitochondrial biogenesis, improves fatty acid oxidation, and reduces systemic inflammation. With regard to the correlation with cardiorespiratory fitness, we were able to show through multi-omic approaches that the metabolic performance of T cells is even associated with the training status (7). In this respect, the immune system also seems to be trainable in terms of physical fitness. These adaptations enhance metabolic flexibility, lower pro-inflammatory cytokine levels, and shift immune cell populations toward an anti-inflammatory profile, such as an increase in regulatory T cells. This systemic reorientation is seen in both metabolically diseased individuals and elite athletes, underscoring the universal importance of exercise as a modulator of metabolism and immune response (6).

The immunometabolic perspective can enhance diagnostics, training and sports therapy at various levels. For example, metabolic markers can indicate immunological changes, and vice versa. Monitoring mitochondrial health, specific metabolite levels (e.g. lactate, succinate), cytokine profiles and immune function could thus become important in personalized training medicine. In addition, targeted nutrition strategies that reduce mitochondrial stress and alleviate chronic inflammation offer new approaches in integrative sports medicine.

These topics will be the focus of the Sports, Medicine and Health Summit 2025, which will promote interdisciplinary exchange between molecular biologists, physicians, exercise physiologists and immunologists. Focusing on systemic interfaces instead of isolated organs could make sports medicine a truly integrative discipline.

Holistic and integrative models, such as the HIP, enable a comprehensive view of the systemic physiological adaptations of the body to acute exercise and regular training.

The integrative view of the immune system and metabolism offers a good example here. Disturbances in this interplay are major contributors to the development of many chronic diseases – but they also provide opportunities for therapeutic intervention through exercise. Viewing physical activity through the lens of mitochondrial medicine and immunometabolism makes it clear: exercise is far more than fitness improvement; it is a powerful, systemic regulator that sustainably influences metabolic pathways, mitochondrial functions, and immune responses.

As understanding of these complex networks grows, sports medicine faces the challenge – and opportunity – of translating molecular insights into practice and exploring new paths toward prevention, healthy aging, and performance optimization.

Conflict of Interest
The authors have no conflict of interest.