Collapse of the Microbiome, Emergence of the Pathobiome, and the Immunopathology of Sepsis

Abstract

The definition of sepsis has been recently modified to accommodate emerging knowledge in the field, while at the same time being recognized as challenging, if not impossible, to define. Here, we seek to clarify the current understanding of sepsis as one that has been typically framed as a disorder of inflammation to one in which the competing interests of the microbiota, pathobiota, and host immune cells lead to loss of resilience and nonresolving organ dysfunction. Here, we challenge the existence of the idea of noninfectious sepsis given that critically ill humans never exist in a germ-free state. Finally, we propose a new vision of the pathophysiology of sepsis that includes the invariable loss of the host's microbiome with the emergence of a pathobiome consisting of both "healthcare-acquired and healthcare-adapted pathobiota." Under this framework, the critically ill patient is viewed as a host colonized by pathobiota dynamically expressing emergent properties which drive, and are driven by, a pathoadaptive immune response.

Figure 1

Mouse sepsis due to cecal ligation and puncture (CLP) can be reversed with proper source control. (A) Experimental design of mouse model of high grade CLP known to result in 100% mortality within 48–72 hrs (75). Following CLP, mice were divided into two groups: (1) no intervention and (2) operative source control, antibiotic treatment, and fluid resuscitation at 6 hours following CLP when first signs of sepsis are noted. (B) Appearance of cecum immediately following CLP. (C) Appearance of cecum 6 hours following CLP. (D) Appearance of cecum following surgical source control, i.e. resection of necrotic cecum and suture ligature of the enterotomy. (E) Mortality is 100% at day 2 following CLP. Source control and supportive therapy result in 0% mortality and all mice recover completely by day 7 (p=0.0023, n=5/group). (F) Appearance of cecum on day 7 following successful operative source control and supportive therapy.