What if metabolism and immune function aren’t separate systems, but part of one continuous conversation? In this episode of the Root Cause Medicine Podcast, Dr. Jeffrey Bland joins Kate Kresge to explore immunometabolism , the study of how immune activity and cellular metabolism influence one another. They discuss how inflammation can affect energy use across tissues, why metabolic health is about far more than weight, and how systems biology is changing the way clinicians think about chronic disease. (O'Neill 2016) Dr. Bland also introduces emerging inflammatory indices—including the Systemic Immune-Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI) —that can be derived from components of a routine CBC with differential. (Islam 2024) The conversation explores their potential role as contextual markers of inflammatory activity, while emphasizing how Journeys can help to automate CBC calculations and help create customized reports for practitioners using blood labs values, history, symptoms and more. The episode closes with a practical look at nutrition, polyphenol-rich foods, lifestyle medicine, large-scale health data, and the growing potential for personalized care. Clinical Takeaways from This Episode Immunometabolism connects immune signaling with cellular energy use. Immune cells alter their metabolic activity when activated, and immune-derived signals can influence the function of tissues throughout the body. (O'Neill 2016) Chronic inflammation is a systems-level process. Rather than viewing inflammation as an isolated problem within one organ, immunometabolism highlights communication among adipose tissue, the liver, brain, muscles, immune cells, and other tissues. (Burak 2024) (Juárez-Rojas 2024) A CBC may contain more information than clinicians traditionally use. SII and SIRI combine routinely measured blood-cell populations into indices being studied as markers of systemic inflammatory and immune activity. (Islam 2024) They should be interpreted in clinical context rather than used independently to diagnose disease or dictate treatment. (Mangoni 2024) Lifestyle interventions affect multiple biological systems at once. Dr. Bland discusses dietary patterns rich in diverse plant compounds alongside movement, sleep, and stress management as components of a broader approach to metabolic and immune health. (Koelman 2022) Practitioners can order Dr. Jeff Bland’s Immunometabolic Journey on Fullscript.com Guest Introduction Dr. Jeffrey Bland is a longtime leader in functional and systems-based approaches to health and one of the influential voices behind the development of functional medicine. His work focuses on translating complex biology—including immunology, metabolism, nutrition, genetics, and systems medicine—into clinically meaningful ways of thinking about health. In this conversation, he brings that systems perspective to immunometabolism and explores how clinicians may begin connecting familiar laboratory data with a deeper understanding of immune and metabolic function. FAQ What is immunometabolism? Immunometabolism examines the two-way relationship between immune function and metabolism. Immune cells require energy to perform their functions, and changes in their metabolic state can influence inflammatory signaling and communication with other tissues. (O'Neill 2016) What are SII and SIRI? SII and SIRI are calculated indices derived from blood-cell counts commonly included in a CBC with differential. They have been studied across several clinical populations as markers associated with systemic inflammatory and immune activity, but they are nonspecific and should be interpreted alongside the broader clinical picture. (Islam 2024) Can SII or SIRI diagnose chronic inflammation? No single index can establish the cause or clinical significance of inflammation on its own. These measures may provide additional context, but symptoms, medical history, other laboratory findings, medications, acute illness, and underlying conditions can all influence blood-cell counts. (Mangoni 2024) Why does mitochondrial function come up in a discussion about immunity? Immune activation changes cellular energy demands. Because mitochondria and other metabolic pathways help determine how cells generate and use energy, cellular metabolism is closely connected with immune-cell behavior. (O'Neill 2016) How can practitioners order a CBC with SIRI and SII calculations included? Ordering a CBC and other biomarkers included in the Immuno-Metabolic Journey from Dr. Jeff Bland allows for automatic calculation of SIRI and SII, as well as recommending next steps for clinicians depending on findings. Timestamps 02:22 — What immunometabolism means Why immune function and metabolism can no longer be viewed as separate biological systems. 06:15 — From “angry fat” to systems biology How communication between immune cells and adipose tissue helped shape modern thinking about immunometabolism. 09:31 — Immunometabolism and root-cause thinking Looking upstream from organ dysfunction toward the processes that may be influencing it. 17:23 — Metabolism is more than weight Cellular energy production, mitochondria, inflammation, and why metabolic function affects the entire body. 22:01 — What a routine CBC may reveal Moving beyond gross abnormalities to explore patterns within the CBC with differential. 23:20 — Introducing SII and SIRI How researchers combine neutrophils, lymphocytes, platelets, and monocytes into inflammatory indices. 34:06 — Translating biomarkers into whole-person care Nutrition, polyphenols, movement, sleep, and stress management enter the conversation. 39:27 — Why food complexity matters Dr. Bland uses buckwheat to illustrate the diversity of plant polyphenols. 46:38 — Big data and personalized medicine How large health datasets may help researchers identify more individualized biological patterns. 54:43 — Owning your health Dr. Bland closes with a message about agency, personalization, and creating healthier patterns over time. Want to elevate your practice? This episode is sponsored by Fullscript , a comprehensive care delivery platform designed to support whole-person, integrative healthcare. Fullscript allows clinicians to streamline supplement dispensing, lab ordering, and patient education in one free, centralized system—helping reduce administrative burden while supporting clinical decision-making. For practitioners, Fullscript offers access to professional-grade supplements, evidence-informed protocols, and lab integrations that can support more efficient planning and follow-up. For patients, it provides a clear, organized way to receive recommendations, manage refills, and stay engaged in their care. The goal is not to replace clinical judgment, but to make it easier for clinicians to focus on what matters most: thoughtful, individualized patient care. Disclaimer: The views expressed on this podcast are those of the hosts and guests and don’t necessarily reflect those of Fullscript or any affiliated organizations. This podcast is for informational and educational purposes only and is not intended to be medical advice. For your safety, always check with your doctor or healthcare provider before making changes to your health routine. Citations Burak, M. F., Stanley, T. L., Lawson, E. A., Campbell, S. L., Lynch, L., Hasty, A. H., Domingos, A. I., Dixit, V. D., Hotamışlıgil, G. S., Sheedy, F. J., Dixon, A. E., Brinkley, T. E., Hill, J. A., Donath, M. Y., & Grinspoon, S. K. (2024). Adiposity, immunity, and inflammation: Interrelationships in health and disease—A report from the 24th Annual Harvard Nutrition Obesity Symposium, June 2023. The American Journal of Clinical Nutrition, 120 (1), 257–268. https://www.sciencedirect.com/science/article/abs/pii/S0002916524004556 Islam, M. M., Osoydan Satici, M., & Eroglu, S. E. (2024). Unraveling the clinical significance and prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and delta neutrophil index: An extensive literature review. Turkish Journal of Emergency Medicine, 24 (1), 8–19. https://pubmed.ncbi.nlm.nih.gov/38343523/ Juárez-Rojas, J. G., Reyes-Barrera, J., & Medina-Urrutia, A. X. (2024). Adipose tissue immunometabolism: Unveiling the intersection of metabolic and immune regulation. Revista de Investigación Clínica, 76 (2), 65–79. https://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S0034-83762024000200001 Koelman, L., Egea Rodrigues, C., & Aleksandrova, K. (2022). Effects of dietary patterns on biomarkers of inflammation and immune responses: A systematic review and meta-analysis of randomized controlled trials. Advances in Nutrition, 13 (1), 101–115. https://pmc.ncbi.nlm.nih.gov/articles/PMC8803482/ Mangoni, A. A., & Zinellu, A. (2024). The diagnostic role of the systemic inflammation index in patients with immunological diseases: A systematic review and meta-analysis. Clinical and Experimental Medicine, 24 (1), Article 27. https://link.springer.com/article/10.1007/s10238-024-01294-3 O'Neill, L. A. J., Kishton, R. J., & Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nature Reviews Immunology, 16 (9), 553–565. https://pubmed.ncbi.nlm.nih.gov/27396447/ Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., Weinberger, A., Ben-Yacov, O., Lador, D., Avnit-Sagi, T., Lotan-Pompan, M., Suez, J., Mahdi, J. A., Matot, E., Malka, G., Kosower, N., Rein, M., Zilberman-Schapira, G., Dohnalová, L., Pevsner-Fischer, M., … Segal, E. (2015). Personalized nutrition by prediction of glycemic responses. Cell, 163 (5), 1079–1094. https://www.cell.com/cell/fulltext/S0092-8674(15)01481-6