In a groundbreaking exploration of the intricate relationship between obesity, cardiovascular health, and immune system dynamics, recent research has shed light on why elevated cardiovascular risks persist long after significant weight loss through metabolic bariatric surgery. While bariatric surgery is renowned for its capacity to induce profound and sustained weight loss in individuals classified as obese, the lingering threat of atherosclerotic cardiovascular disease (ASCVD) remains a pressing clinical conundrum. The new study uncovers how innate immune cells, pivotal players in atherogenesis, may maintain a hyperresponsive and inflammatory state through a process known as trained immunity, thereby contributing to continuous cardiovascular vulnerability despite metabolic improvements.
Obesity has long been established as a major risk factor for cardiovascular disease, in particular ASCVD, which encompasses conditions such as coronary artery disease and stroke. The inflammation chronicled in adipose tissue during obesity is a critical contributor to systemic immune activation and vascular pathology. While weight reduction typically ameliorates many metabolic dysfunctions, it appears insufficient in fully extinguishing the inflammatory memory within the innate immune system. This phenomenon implicates epigenetic reprogramming—whereby immune cells undergo lasting molecular changes that reinforce heightened responsiveness—as a key mechanism underpinning residual cardiovascular risk.
Innate immune cells, including monocytes and macrophages, orchestrate frontline defense against pathogens but also regulate inflammatory processes within blood vessels. The study reveals that these cells can adopt a long-lasting hyperinflammatory phenotype following exposure to obese adipose tissue environments. This hyperresponsiveness is sustained via epigenetic modifications that prime innate immune cells for exaggerated cytokine production upon subsequent stimuli, a characteristic known as “trained immunity.” Such a state perpetuates vascular inflammation, promoting plaque formation and instability within arterial walls, which can precipitate life-threatening cardiovascular events.
Addressing this enigma, the research team conducted a translational observational case-cohort study focusing on patients undergoing metabolic bariatric surgery. By analyzing innate immune cell function and phenotype before and up to one year after surgery, researchers aimed to assess whether profound weight loss translates into normalization of immune cell behavior. Surprisingly, despite significant reductions in body weight and improvement in traditional cardiovascular risk markers, innate immune cells continued to exhibit enhanced inflammatory potential, indicating persistence of an altered immune set point.
The investigative effort also probed the role of adipose tissue itself as a modulator of immune training. Using ex vivo models, adipose tissues extracted from obese donors were shown to impose inflammatory programming on naïve immune cells. This crosstalk underscores the contribution of the adipose microenvironment in sustaining systemic inflammation and provides mechanistic insight into how immune cell memory is established and maintained. Importantly, these findings indicate that interventions targeting innate immunity alongside metabolic correction may be necessary to fully mitigate cardiovascular risk.
These revelations challenge the conventional notion that weight loss alone suffices in reversing obesity-induced cardiovascular damage. The persistence of trained immunity after bariatric surgery suggests a decoupling between metabolic health improvements and immune cell reprogramming. It further posits obesity as a trigger for long-term epigenetic remodeling within innate immunity, rendering patients vulnerable to cardiovascular events well beyond the period of active weight gain. Consequently, addressing epigenetic immune memory emerges as a novel therapeutic frontier.
Technological advances in epigenomics and immunophenotyping allowed researchers to comprehensively characterize changes in immune cell subsets and their functional responses. Monocytes isolated from post-bariatric surgery patients continued to display heightened production of pro-inflammatory cytokines such as TNF-α and IL-6 upon ex vivo stimulation. Moreover, molecular assays identified persistent epigenetic marks on gene loci associated with inflammation, substantiating the concept of trained immunity as a durable imprint rather than a transient activation state.
The study’s implications extend beyond the realm of cardiovascular disease, offering a window into the broader impact of metabolic insults on innate immune regulation. Obesity-induced immune training may contribute to increased susceptibility not only to atherogenesis but also to other chronic inflammatory diseases. Such insights provide impetus for developing targeted strategies to reverse or modulate immune cell epigenetics post-intervention, possibly through pharmacologic agents or lifestyle modifications designed to recalibrate immune responsiveness.
In clinical practice, this research advocates for a paradigm shift in post-bariatric care. Monitoring innate immune cell phenotype alongside traditional metabolic parameters could identify patients at elevated risk of ongoing vascular inflammation despite surgical success. By integrating immune profiling into risk assessment, clinicians could personalize interventions to include anti-inflammatory therapies or novel epigenetic modulators, tailored to extinguish the trained immunity imprint.
The study also opens avenues for future research aimed at deciphering the molecular triggers within obese adipose tissue that initiate immune training. Adipocytes and resident immune cells produce a complex milieu of cytokines, chemokines, and metabolic signals capable of modulating immune cell epigenomes. Understanding these interactions may reveal pivotal nodes where therapeutic intervention could prevent the establishment or perpetuation of trained immunity.
Furthermore, emerging evidence hints at the potential reversibility of trained immunity under certain conditions, albeit with variable efficacy. Investigating factors that influence the plasticity of epigenetic modifications in innate immune cells could inform combination therapies to fully restore immune homeostasis. Such approaches may prove critical to reducing residual cardiovascular risk and improving long-term outcomes for patients who have undergone bariatric surgery.
This study stands as a testament to the intricate interplay between metabolism and immunity, emphasizing that resolving obesity’s legacy on the cardiovascular system demands more than weight loss. As researchers continue to unravel the epigenetic code governing trained immunity, the prospects for innovative treatments that reconcile metabolic and inflammatory pathways grow ever more promising. Ultimately, this could lead to more effective strategies to protect millions of individuals worldwide from the enduring threats posed by obesity-related cardiovascular disease.
Subject of Research: The long-term impact of metabolic bariatric surgery on innate immune cell phenotype, function, and the persistence of trained immunity related to cardiovascular risk in obese patients.
Article Title: The long-term effect of metabolic bariatric surgery on innate immune cell phenotype and function.
Article References:
van Tuijl, J., Vreeken, D., Broeders, W. et al. The long-term effect of metabolic bariatric surgery on innate immune cell phenotype and function. Int J Obes (2025). https://doi.org/10.1038/s41366-025-01886-3
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