Human Experimental Endotoxemia in Modeling the Pathophysiology, Genomics, and Therapeutics of Innate Immunity in Complex Cardiometabolic Diseases

Abstract

Inflammation is a fundamental feature of several complex cardiometabolic diseases. Indeed, obesity, insulin resistance, metabolic dyslipidemia, and atherosclerosis are all closely linked inflammatory states. Increasing evidence suggests that the infectious, biome-related or endogenous activation of the innate immune system may contribute to the development of metabolic syndrome and cardiovascular disease. Here we describe the human experimental endotoxemia model for the specific study of innate immunity in understanding further the pathogenesis of cardiometabolic disease. In a controlled, experimental setting, administration of an intravenous bolus of purified Escherichia coli endotoxin activates innate immunity in healthy human volunteers. During endotoxemia, changes emerge in glucose metabolism, lipoprotein composition, and lipoprotein functions that closely resemble those observed chronically in inflammatory cardiovascular disease risk states. In this review we describe the transient systemic inflammation and specific metabolic consequences that develop during human endotoxemia. Such a model provides a controlled induction of systemic inflammation, eliminates confounding, undermines reverse causation, and possesses unique potential as a starting point for genomic screening and testing of novel therapeutics for treatment of the inflammatory underpinning of cardiometabolic disease.

Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

“…The diverse, multi-system consequences of IV endotoxin administration have recently been comprehensively reviewed and will not be discussed in full here (for full details see [17][18][19]27 ). Instead a brief overview of the range and applicability of the model will be provided alongside primary data pertaining to the classic bolus-dosing regimen (2 ng/kg).…”

“…Administration of 0.06 -0.2 ng/kg via either bolus or infusion induces 2 -10 fold increases in plasma cytokines commensurate with those seen in chronic low-grade inflammatory conditions 32 . Such protocols may have a key role in exploring the contribution of inflammation and the pathways that regulate it to multiple complex cardiometabolic conditions 27 .…”

“…Furthermore, the model may act as a test-bed for therapeutics, not only those against the LPS ligand itself, but LPS-induced signaling pathways and mediators of both the acute and resolution phases of inflammation. This may include agents targeted at restoration of endotoxin tolerance, a hyporesponsive state of the immune system that bears similarities to critical illness-induced immunoparalysis 33,34 Able to replicate key features of both acute 16 and chronic 27 inflammation at not only a physiological/functional level but also a transcriptomic one 35 , IV endotoxin challenge seemingly has a key role to play in the translation of basic scientific breakthroughs to clinical practice. When coupled to directed investigation in appropriate animal models able to more closely replicate the pathophysiological responses of specific disease states (e.g., murine cecal ligation and puncture and sepsis) this investigational paradigm may be especially powerful.…”

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

“…In such studies, additional pharmacological challenges may be required to evoke a measurable and disease-relevant phenotype. The use of evoked endotoxemia (low-dose lipopolysaccharide) as a model of cardiometabolic disease is well documented [279][280][281][282] and has shown great utility as a discovery tool both in omic 283,284 and nutritional contexts. 88,285,286 The combination of nutritional and omic profiling in the context of evoked endotoxemia has great promise for understanding nutritional effects on inflammatory responses.…”

Early markers of phenotypic heterogeneity in the induced model of systemic lupus erythematosus

“…Волчаночный нефрит является од-ним из серьезных проявлений и одним из самых хроническими воспалительными заболеваниями (атеросклероз, диабет, неврологические воспа-ления, метаболический синдром). Реакция на вну-тривенное введение ЛПС, который активирует врожденный иммунитет и вызывает специфиче-ские метаболические последствия, расценивается как интегральный показатель сложных физиоло-гических, молекулярных и генетических взаимо-действий, определяющих воспаление у каждого конкретного индивидуума [5].…”