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 leads to loss of resilience and non-resolving organ dysfunction. Here we challenge the existence of the idea of non-infectious 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.

Abdominal pressure and gastrointestinal function: an inseparable couple?

“…The consequences of a microbiome failure include the reduction in barrier function through a reduction in mucin production and increased permeability (reduction in tight junctions) [93]. Observational data indicate a strong relationship between previous dysbiosis (due to antibiotic exposure) and increased occurrence of subsequent severe sepsis [100].…”

“…Pathogens alone are not responsible for multi-organ failure and death. Animal experiments have revealed that survivors and non-survivors of sepsis are similar in terms of bacterial translocation and dissemination [93]. This has led to the immunocentric model of sepsis with the host response to bacterial infections fea-turing the immune system triggering a cascade of immune reactions that can lead to multi-organ failure and death [93].…”

“…The main causes for dysbiosis in critically ill patients are as follows: 1) critical illness; 2) nutritional changes; 3) the use of antibiotics; d) gut ischemia; and perhaps 4) the presence of abdominal hypertension [93,97,98].…”

“…The intestinal microbiome is considered to function as a virtual organ responsible for upholding important physiological functions, including: 1) immunological functions; 2) intestinal mucus production; 3) upholding permeability (via tight junctions); and 4) digesting complex plant polysaccharides into acetate and butyrate, an important energy source for colonic epithelial cells [93,97].…”

“…The microbiome can be defined as the entirety of microbiological flora including commensal and pathogenic bacteria, viruses, and fungi as well as their genes and their gene products (proteins and metabolites) [93].…”