Humanized Mice as a Tool to Study Sepsis—More Than Meets the Eye

Abstract

(1) Background. Repetitive animal studies that have disappointed upon translation into clinical therapies have led to an increased appreciation of humanized mice as a remedy to the shortcomings of rodent-based models. However, their limitations have to be understood in depth. (2) Methods. This is a narrative, comprehensive review of humanized mice and sepsis literature to understand the model’s benefits and shortcomings. (3) Results: Studies involving humanized models of sepsis include bacterial, viral, and protozoan etiology. Humanized mice provided several unique insights into the etiology and natural history of sepsis and are particularly useful in studying Ebola, and certain viral and protozoan infections. However, studies are relatively sparse and based on several different models of sepsis and humanized animals. (4) Conclusions. The utilization of humanized mice as a model for sepsis presents complex limitations that, once surpassed, hold some potential for the advancement of sepsis etiology and treatment.

Sepsis Disrupts Mitochondrial Function and Diaphragm Morphology

“…Water and chow (standard diet AIN93) were available ad libitum . CLP is the gold standard murine sepsis model ( Laudanski, 2021 ). Sepsis was induced in the experimental group by CLP; control animals were sham-operated as described previously ( Rittirsch et al, 2009 ; Bloise et al, 2020 ).…”

The Multifaceted Biology of PCSK9

“…Indeed, mice and rats have a significantly higher resistance to sepsis than humans. However, recently humanized mouse models of sepsis were reported to mitigate somewhat this restriction ( 231 ). Nevertheless, although PCSK9 inhibitors may increase survival of adult patients, they may not be beneficial for young children with sepsis, as LOF of PCSK9 was associated with decreased survival in juvenile mice (14 day old) and young children (1-6 years old) ( 232 ).…”

The leaky gut and the gut microbiome in sepsis – targets in research and treatment

“…fungi that can produce some molecules against several harmful factors (some organisms and toxic substances) [ 15 ]. The differences in sepsis conditions between humans and mice [ 140 , 141 ] raise the possibility that gut fungi in patients with sepsis might be enhanced by several factors that differ from those in mice, such as the duration of sepsis (human patients survive longer than mice), antibiotic use (more potent in human conditions), intensive care unit (ICU) environment (nosocomial infections are likelier in patients in ICUs than in mice in controlled animal facilities) and naturally higher Candida levels in human faeces and underlying diseases (such as altered gut fungi in Type 2 diabetes) [ 142–144 ]. Based on the well-established increase in gut fungi in patients with IBD and alcohol ingestion [ 56–58 ], intestinal inflammation and reduced mucosal immunity might be important exacerbating factors for the enhancement of gut fungi associated with sepsis (systemic cytokine-induced intestinal barrier defects and apoptosis of immune cells) [ 65 , 118 ].…”