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Cambridge University Science Magazine
Evolutionary Background:

Life on Earth has been perpetually challenged by a variety of microbial threats, from viruses to bacteria and fungi, necessitating the development of robust defensive mechanisms. These microbial threats have acted as a significant selective pressure, shaping the evolutionary trajectory of life forms and their immune strategies. The primordial immune system likely consisted of basic recognition and effector mechanisms, designed to be energetically and materially economical, leveraging simple biochemical reactions to distinguish self from non-self.

In these early stages, immune recognition relied on generic molecular patterns that were broadly conserved across microbial species. Effectors of these systems included rudimentary antimicrobial peptides and the basic components of what would eventually evolve into more complex complement systems. These molecules were capable of directly neutralizing pathogens or marking them for destruction. This form of immunity, which is still observable in modern prokaryotes and serves as the foundation for innate immunity in higher organisms, exemplifies the principle of using minimal resources for maximum effect.

As life evolved from unicellular to multicellular organisms, the immune system's complexity increased significantly. This transition necessitated the development of more sophisticated immune strategies to manage the increased risk of infection and internal coordination within a larger organism. The evolution of multicellularity brought with it the compartmentalization of functions and the development of specialized cells and tissues, including those dedicated to defense, such as phagocytes. These cells specialized in patrolling and protecting larger bodies, capable of engulfing and digesting pathogens.

With the specialization of immune cells and the expansion of their roles, there came an increased demand for energy and biosynthetic materials, thus requiring intricate metabolic support. Moreover, the evolution of adaptive immunity in vertebrates introduced even greater metabolic complexities. In essence, the evolutionary background of the immune system reflects a continuous interplay between the need to maintain energy efficiency and the need to adapt to increasingly complex threats. This balance has driven the co-evolution of metabolic and immune strategies, crafting a system where metabolism is not just supporting immune function but is integral to its regulatory and effector mechanisms. This deep integration highlights the evolutionary imperative of metabolic flexibility as a cornerstone in the development of effective immune responses across all life forms.

Metabolic Evolution in Single-Celled Organisms

Origins of Immune Metabolism:
  1. ATP as an Energy Source and Signaling Molecule: Adenosine triphosphate (ATP) is widely acknowledged as the primary energy currency of the cell, essential for driving various cellular processes across all forms of life. Bacteria and archaea utilize ATP not only for energy but also as a signaling molecule in their rudimentary immune-like responses. For instance, ATP can be released in response to stress or cellular damage, acting as a danger signal that prompts defensive responses in nearby cells. This dual role of ATP illustrates an early evolutionary adaptation where energy metabolism and immune signaling are intricately linked, setting the stage for more complex immune mechanisms seen in higher organisms.
  2. Evolution of Glycolysis and Oxidative Phosphorylation: The emergence and evolution of metabolic pathways such as glycolysis and oxidative phosphorylation mark significant milestones in the history of life. Glycolysis, an ancient metabolic pathway that predates the presence of oxygen in the atmosphere, provides a quick release of energy by breaking down glucose. This pathway is crucial for many immune cells, especially under conditions where oxygen is scarce, such as in inflamed or infected tissues. On the other hand, oxidative phosphorylation, which evolved later as atmospheric oxygen levels rose, involves the production of ATP through electron transport and chemiosmosis. This pathway is highly efficient and powers many of the sustained activities of immune cells in aerobic conditions. The evolution of these pathways provided a metabolic foundation that allowed early life forms to manage energy needs during immune responses, illustrating a primitive form of immunometabolism.

Metabolic Responses to Environmental Stress:
  1. Adaptive Mechanisms in Extremophiles: Extremophiles, organisms that thrive in environments once thought to be inhospitable, exhibit metabolic strategies that provide insights into the resilience and adaptability of life. These organisms have developed unique metabolic responses that mirror immune metabolic adaptations in more complex organisms. For example, thermophilic archaea that inhabit high-temperature environments make extensive modifications to their lipid membranes and enzyme structures to maintain cellular integrity and function at elevated temperatures. This adaptation is metabolically expensive but crucial for survival and offers parallels to how immune cells modify their metabolism to sustain activity under the stress of infection.
  2. Shift Between Metabolic Pathways: In response to varying environmental conditions, extremophiles demonstrate a remarkable ability to switch between metabolic pathways, a capacity that is echoed in the metabolic flexibility of immune cells. For example, certain halophilic archaea, which live in highly saline environments, switch from using one energy source to another depending on the salinity levels. This metabolic switching is similar to how immune cells, like macrophages and lymphocytes, alter their metabolic pathways (e.g., from oxidative phosphorylation to glycolysis) during activation and effector phases of immune responses. Such shifts enable these cells to optimize energy production for immune functions in different physiological contexts, highlighting an evolutionary continuity in the metabolic adaptability necessary for survival and defense.

Development of Metabolic-Immune Integration in Multicellular Life

Innate Immunity and Metabolism:
  1. Co-option of Metabolic Pathways for Defense: As life transitioned to multicellular forms, the complexity of organismal structures and functions increased, including the defense mechanisms against pathogens. Innate immunity, characterized by its quick and non-specific response, evolved sophisticated tactics by harnessing existing metabolic pathways. Early multicellular organisms utilized components of metabolic pathways, such as the production of antimicrobial peptides, which are small proteins synthesized from amino acids, the building blocks made available through general metabolic processes. These peptides disrupt pathogen membranes, showcasing how basic metabolic processes were adapted for defensive functions.
  2. Phagocytes and Metabolic Pathways for Reactive Oxygen Species Production: Among the critical developments in innate immunity was the evolution of phagocytes—cells capable of engulfing and destroying pathogens. The effectiveness of phagocytes is heavily reliant on the production of reactive oxygen species (ROS), a potent antimicrobial weapon. The generation of ROS is an energy-intensive process that depends on metabolic pathways, primarily the oxidative phosphorylation system in mitochondria, which, under certain conditions, can "leak" electrons that react with oxygen to form ROS. This dependency highlights a direct link between mitochondrial metabolism and immune capability, underlining how energy-producing pathways have been repurposed for immune defense in multicellular organisms.

Adaptive Immunity and Metabolic Specialization:
  1. Emergence of Lymphocytes and Specialized Metabolic Needs: The evolution of adaptive immunity in vertebrates brought about the development of lymphocytes, including B cells and T cells, with highly specialized functions and corresponding metabolic demands. Lymphocytes exhibit dynamic metabolic behavior; they remain in a relatively quiescent state with minimal metabolic activities when inactive but rapidly switch to high-throughput metabolic pathways upon activation. This switch is crucial for supporting the energy-intensive tasks of clonal expansion and effector function, such as cytokine production and proliferation. The metabolic reprogramming in lymphocytes is tailored to ensure that energy and biosynthetic demands are met during the immune response.
  2. Role of the Warburg Effect in Activated Immune Cells: A notable aspect of metabolic adaptation in immune cells is the utilization of the Warburg effect, a phenomenon initially observed in cancer cells, where cells preferentially use glycolysis over oxidative phosphorylation, even in the presence of ample oxygen. Activated immune cells, particularly lymphocytes, adopt this metabolic strategy to fulfill the immediate energy needs required for rapid cell division and function. The Warburg effect allows for the accumulation of biosynthetic precursors for nucleotides, amino acids, and lipids, crucial for building new cells and supporting effector functions. This metabolic shift enhances the responsiveness and proliferation capacity of immune cells, illustrating a sophisticated level of metabolic specialization that supports complex immune responses in vertebrates.

Immunometabolic Complexity in Mammals

Metabolic Programming of Immune Cell Fate:
  1. Influence of Metabolic Pathways on Differentiation and Function: In mammals, the immune system exhibits a remarkable capacity for metabolic programming that intricately influences the differentiation and functional fate of immune cells such as macrophages and T cells. The choice between different metabolic pathways—glycolysis, fatty acid oxidation, or oxidative phosphorylation—can determine whether a macrophage adopts a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. M1 macrophages, which are involved in acute inflammatory responses, primarily utilize glycolysis, which supports their rapid response and high-energy demand. Conversely, M2 macrophages, which aid in tissue repair and resolution of inflammation, predominantly use oxidative phosphorylation, a more sustainable energy source that supports their longer-term activities and functions. For T cells, activation and subsequent differentiation into effector or memory cells are closely linked to changes in their metabolic activities. Effector T cells rapidly upregulate glycolysis to support quick proliferation and effector function. This metabolic switch is pivotal not just for immediate immune response but also for establishing a pool of memory cells that provides lasting immunity. This is further discussed below.
  2. Impact on Immune Memory and Tolerance: The metabolic state of immune cells also critically impacts immune memory and tolerance, key features of the adaptive immune response. Memory T cells with high mitochondrial mass and a preference for lipid oxidation are better equipped for long-term survival and rapid response upon re-exposure to antigen. This metabolic conditioning thus underpins the functional longevity of memory cells. Additionally, regulatory T cells (Tregs), which play a crucial role in maintaining immune tolerance, also exhibit unique metabolic characteristics. Tregs predominantly utilize oxidative phosphorylation, which supports their function in regulating immune responses and preventing autoimmune reactions. These observations highlight a novel perspective where manipulating metabolic pathways could enhance vaccine efficacy or ameliorate autoimmunity by influencing the balance between memory and regulatory functions.

Diet, Metabolism, and Immune Function:
  1. Influence of Dietary Components on Immunometabolic Pathways: The relationship between diet and immune function is a critical area of research, particularly in understanding how different nutrients can modulate immune responses through metabolic pathways. Dietary components such as fatty acids, amino acids, and micronutrients can profoundly influence the metabolic programming of immune cells. For example, short-chain fatty acids, produced through microbial fermentation of dietary fibers in the gut, can enhance the production of Tregs and thus promote an anti-inflammatory environment. Conversely, high-fat diets can lead to an increase in the glycolytic activity of immune cells, contributing to inflammation and potentially exacerbating conditions like arthritis and cardiovascular diseases.
  2. Evolutionary Perspectives on the Modern Diet and Autoimmune Diseases: From an evolutionary standpoint, the modern diet, characterized by high sugar, high fat, and processed foods, is drastically different from the diets of our ancestors, which were rich in fibers, unprocessed plants, and lean meats. This mismatch between our evolutionary-adapted metabolism and contemporary dietary habits may contribute to the current rise in metabolic disorders and autoimmune diseases. The immune system's development in an environment with vastly different nutritional availability has implications for how it reacts to modern dietary patterns. Chronic overnutrition and the resultant metabolic inflammation can disrupt gut microbiomes and immune homeostasis, leading to an increased prevalence of autoimmune diseases. Understanding these evolutionary mismatches can offer novel insights into dietary interventions that might restore a more ancestral immunometabolic balance, potentially reducing the burden of chronic inflammatory and autoimmune diseases.


The evolutionary basis of the interplay between metabolism and the immune system highlights a fundamental aspect of biological adaptation that is crucial for understanding organismal health and disease. As scientific inquiry continues to unravel the complex relationships between these two systems, it becomes increasingly apparent that they did not evolve in isolation. Instead, they have co-evolved as interconnected networks intricately woven together to optimize the health and survival of organisms.

This perspective not only enriches our understanding of human physiology and pathology but also provides a framework for exploring new treatments and interventions. The potential to manipulate these systems in a controlled manner offers hope for combating some of the most challenging diseases facing humanity today, including chronic inflammatory diseases, cancer, and emerging infectious diseases. As we delve deeper into the molecular and evolutionary intricacies of immunometabolism, our capacity to intervene in these processes in a precise and informed way will likely become a cornerstone of future therapeutic developments.

In conclusion, the ongoing exploration of how metabolic processes influence immune function—and vice versa—promises to not only broaden our understanding of biological science but also pave the way for novel therapeutic paradigms grounded in the evolutionary architecture of life.

Article by Swetha Kannan, PhD Student, Dept. of Medicine, University of Cambridge

Image Credit

Title: T Lymphocyte

Author: NIAID

Source: T Lymphocyte | Colorized scanning electron micrograph of a T… | Flickr

License: CC by 2.0 deed