The Effects of Obesity on Outcome in Preclinical Animal Models of Infection and Sepsis: A Systematic Review and Meta-Analysis

Abstract

Background. Clinical studies suggest obesity paradoxically increases survival during bacterial infection and sepsis but decreases it with influenza, but these studies are observational. By contrast, animal studies of obesity in infection can prospectively compare obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity’s survival effect in infection and sepsis. Methods. Databases were searched for studies comparing survival in obese versus nonobese animals following bacteria, lipopolysaccharide, or influenza virus challenges. Results. Twenty-one studies (761 obese and 603 control animals) met the inclusion criteria. Obesity reduced survival in 19 studies (11 significantly) and the odds ratio (95% CI) of survival (0.21(0.13, 0.35); I2 = 64%, p<0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I2 = 31%, p=0.20 and n = 5, 0.22(0.13, 0.36); I2 = 0%, p=0.59, respectively), (2) not significantly with cecal ligation and puncture (n = 4, 0.72(0.08, 6.23); I2 = 75%, p<0.01), and (3) significantly with influenza but with high heterogeneity (n = 6, 0.12(0.04, 0.34); I2 = 73%, p<0.01). Obesity’s survival effects did not differ significantly comparing the four challenge types (p=0.49). Animal models did not include antimicrobials or glycemic control and study quality was low. Conclusions. Preclinical and clinical studies together emphasize the need for prospective studies in patients accurately assessing obesity’s impact on survival during severe infection.

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

“…Despite obesity being protective in terms of survival, HFD-fed mice experienced greater incidence of kidney injury, as evidenced by increased expression of renal NGAL and elevated plasma creatinine. These results are in line with murine and clinical data (9,44). IL-17A, which is the only inflammatory cytokine having significantly higher levels in the septic HFD-fed mice in our study, has been shown to contribute to kidney injury in CLP-induced sepsis, as knockout of IL-17A improved functional and morphological measures of AKI, and exogenous administration of IL-17A aggravated AKI (45).…”

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

“…However, blockage of CXCR2 did not prevent neutrophil accumulation in liver sinusoids of obese animals. The receptor ligands in mice are CXCL1 (KC) and CXCL2 (MIP-2), known to regulate neutrophil chemotaxis [ 59 ], and their levels are also elevated in obesity [ 31 , 45 ]. CXCR2 works in tandem with CXCR1 and they share numerous ligands, however, some of them are unique to the former, including KC and MIP-2 [ 60 , 61 ].…”

“…This is despite the fact that obese individuals are at greater risk of comorbidities such as diabetes, cardiovascular diseases, or liver abnormalities associated with shortened life expectancy [ 30 ]. However, not all studies confirm the very existence of such a paradox nor empirical studies minimizing bias and confounding factors were performed thus far [ 31 , 32 ].…”

Possible Role of Adipose Tissue and the Endocannabinoid System in Coronavirus Disease 2019 Pathogenesis: Can Rimonabant Return?

“…Although inflammation accompanying obesity appears as a low‐grade chronic inflammatory state, one can question whether the huge numbers of immune cells present in adipose tissue of patients with obesity might not represent a kind of time bomb contributing to the cytokine storm observed in COVID‐19. Despite perturbing data suggesting a paradoxical protection of obesity against bacterial sepsis (4), the opposite has been observed for influenza, pneumonia (4), and COVID‐19 (1).…”