Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?

Abstract

A recent report by the National Institutes of Health on sepsis research has implied that there is a trend to move away from mouse models of sepsis. The most commonly used animal model to study the pathogenesis of human sepsis is cecal ligation and puncture (CLP) in mice. The model has been the mainstay of sepsis research for decades and continues to be considered the gold standard to inform novel pathways of sepsis physiology and its therapeutic direction. Although there have been many criticism of the model, particularly regarding its relevance to human disease, how this model might be repurposed to be more reflective of the human condition begs discussion. In this piece, we compare and contrast the mouse microbiome of the CLP model to the emerging science of the microbiome of human sepsis and discuss the relevance for mice to harbor the very pathogens present in the human microbiome during sepsis as well as an underlying disease process to mimic the characteristics of those patients with undesirable outcomes. How to repurpose this model to incorporate these “human factors” is discussed in detail and suggestions offered.

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine

“…Importantly, the model permitted the acquisition of simultaneous multi-organ system temporal data that enabled the tracking of key events of the progression of localized infection to systemic manifestation (Fig 8). This type of model may circumvent many of the challenges and limitations of current rodent models that have failed to widely translate to the human situation, including cecal ligation and puncture in which bacterial species involved are rarely defined, ongoing intestinal ischemia and necrosis is concurrently present, and the mouse microbiota is not the same as in human patients [24,25].…”

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

“…Most previous experiments related to sepsis were induced by CLP or LPS, where researchers used inbred mice under a specific pathogen-free (SPF) experimental environment. These methods do not fully conform to clinical heterogeneity and often do not inform the treatment of sepsis in humans (50,51,101,103,118,121,161,175). In fact, changes in the heterogeneity of Tregs in induced sepsis animal models do not fully reflect clinical sepsis or are even opposite to patients' results (51,75).…”

“…In the CLP model, the cecum of immunocompetent mice is sutured and then punctured to cause spillage of cecal contents into the peritoneum, which creates a life-threatening infection characterized by physical disorders (such as septic shock and acute organ failure) and ultimately death (99,106,161). Unfortunately, the precise composition of cecal contents that participates in the infection process is variable and has not been adequately evaluated in the case of acute organ failure (175). To compensate, some investigators tried to adopt intraperitoneal injection of stool suspension or CS, or endotracheal injection of a predetermined pathogen (such as Klebsiella pneumonia and Staphylococcus aureus, etc.)…”

New Approaches to Identify Sepsis Biomarkers: The Importance of Model and Sample Source for Mass Spectrometry

“…In this context, one could suggest withdrawing preclinical animal models. Nevertheless, it is recognized that, for instance, many of the pathways of acute inflammation have been elucidated by the rodent CLP model, considered as a pertinent polymicrobial model [ 60 ]. In addition, by refining the animal model of sepsis—i.e., by “humanising” animal diet and microbiome, by studying animals of various ages and both sexes in the presence or absence of underlying chronic comorbidities, and incorporating the basic treatment (fluids, antibiotics)—it could be possible to evaluate models of sepsis and septic shock pathological conditions closer to those of human cases with more relevance such as septic cardiomyopathy [ 61 ].…”