Human microbiome research has long focused on barrier surfaces such as the gut and skin. However, a neglected class of "invisible inhabitants" lurks within the body's internal tissues and circulating cells. Though small in number, they may have a profound impact on health and disease. Recently, in a new review published in Immunity & Inflammation , Professor Chen-Yu Zhang's team at Nanjing University systematically proposed the novel concept of “Persistent Intracellular Extraintestinal Microbes” (PIEM). This expands the scope of microbiome research from external surfaces to the body's interior, opening a new direction for understanding the long-term symbiotic relationship between humans and microbes and the pathogenesis of numerous complex diseases.
PIEM: From “Invisible Inhabitants” to “System Tuners”
The article defines PIEM as a special class of microbes. They are not “abundant residents” like the gut microbiota, but rather microbes that reside long-term within tissues or circulating cells outside the gut. They persist in a latent or low-replication state, exhibiting specific host cell tropism and a dynamic of latency and reactivation. This category includes latent viruses, chronic intracellular bacteria, and tissue-resident parasites. The importance of PIEM lies not in their "quantity," but in their persistence, specific tissue and cellular localization, and regulatory capabilities over the host. They act like the body’s “system tuners,” subtly yet profoundly “calibrating” the body's physiological baseline over timescales of years to decades, including the threshold of immune responses, vascular homeostasis, metabolic levels, and tissue repair capabilities. This, in turn, influences an individual's susceptibility and response patterns to infection, injury, and chronic diseases.
Human Cytomegalovirus (HCMV): An Ideal Model for Studying PIEM
The article uses Human Cytomegalovirus (HCMV) as a model to systematically elucidate the mechanisms of PIEM. HCMV is an ideal model for studying PIEM due to its high prevalence, lifelong latency, broad cell tropism, and powerful host-regulatory abilities. Its long-term "interplay" with the host continuously influences the host's immune, vascular, and metabolic systems through various mechanisms, such as interfering with antigen presentation, reshaping T-cell memory, regulating angiogenesis, and reprogramming cellular metabolism. This long-term interaction may be a long-overlooked key factor behind the development of many complex diseases, such as autoimmune diseases, atherosclerosis, and cancer.
Circulating Viral miRNAs: A New "Liquid Biopsy" Window for Monitoring PIEM
Facing the challenges of PIEM's low abundance and difficult detection, the review innovatively proposes using circulating viral miRNAs in peripheral blood as a new "liquid biopsy" window for monitoring their activity. Its core advantage is that miRNA levels can reflect the virus's "real-time activity" rather than just "prior exposure," offering a potential method for non-invasively and dynamically monitoring the latency and reactivation of PIEM. Professor Chen-Yu Zhang's team has already validated the biomarker potential of HCMV miRNAs in various clinical scenarios, such as predicting the efficacy of interferon therapy for hepatitis B and aiding in the diagnosis of oral lichen planus, laying a solid foundation for developing PIEM-based precision medicine strategies.
The theoretical framework of PIEM proposed in this work holds significant importance:
(1) Theoretical Breakthrough: It expands the boundaries of microbiome research from "external surfaces" to the "body's interior," revealing a hidden regulatory layer of microbes within the human body and serving as a major supplement and deepening of the existing microbiome concept.
(2) Conceptual Innovation: It provides a new paradigm of "latent microbial infection" for the etiology of many complex diseases, suggesting that PIEM may be a common and overlooked risk factor.
(3) Technological Foresight: It pioneers the concept of using circulating viral RNAs as novel biomarkers for monitoring PIEM activity, pointing the way for the development of liquid biopsy technologies and precision diagnostic tools.
(4) Clinical Implications: It suggests that PIEM, represented by HCMV, and their regulatory molecules (like miRNAs) could become novel drug targets, opening new avenues for the prevention and treatment of complex diseases.
Looking ahead, with the rapid development of multi-omics technologies and artificial intelligence, research on PIEM is expected to help construct a "viromics"-driven framework for precision medicine, ultimately enabling the personalized assessment, monitoring, and management of PIEM-related risks.
Reference
Title of original paper: Beyond the gut microbiome: human cytomegalovirus as a model for persistent intracellular extraintestinal microbes in human homeostasis and disease
Journal: Immunity & Inflammation
DOI: https://doi.org/10.1007/s44466-026-00048-y
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Professor Chen-Yu Zhang from Nanjing University, China
Prof. Chen-Yu Zhang is Dean at the School of Life Sciences, Nanjing University. A recipient of the National High-Level Talent Program and member of the Academic Advisory Committee of the Chinese Academy of Medical Sciences, he pioneered the discovery of functional extracellular RNA and developed related diagnostic and therapeutic technologies. As primary awardee, he has received the Second Prize of the National Natural Science Award, two First Prizes of the Ministry of Education, and the Tan Jiazhen Life Science Award. His research focuses on RNA biomedicine and its engineering applications, as well as the physiology and pathophysiology of endocrine metabolism.
Immunity & Inflammation
Beyond the gut microbiome: human cytomegalovirus as a model for persistent intracellular extraintestinal microbes in human homeostasis and disease
20-Jul-2026
The authors declare no competing interests.