The Aging of the Gut Microbiome Contributes to Increased Severity of Sepsis

Sepsis isn't an age-related condition per se, but it is more likely and more dangerous when it occurs in older people. A sizable part of that is thought to arise from the aging of the immune system and its predisposition to chronic inflammation. Researchers here argue that age-related changes in the gut microbiome also conspire to increase the severity of sepsis when it occurs. Gut microbiome aging is likely also connected to the aging of the immune system, as it fails to remove problem microbes as efficiently as it does in youth. There are other contributing factors, however, including lifestyle choices such as diet and exercise.

In the most simplistic terms, sepsis is a severe host-pathogen interaction. However, sepsis definitions (and research investigations) are largely focused on the host response to the pathogen, as opposed to the pathogen itself. Within this framework, the pathogen is often seen as a static, homogeneous infectious insult that triggers the dysregulated host response. Accordingly, exaggerated sepsis severity outcomes in the aging population have been attributed to either an age-associated waning of immune function (i.e., immunosenescence), or an alteration in baseline inflammatory response (i.e., inflammaging). However, therapeutics targeting the host immune response or inflammatory cascade have consistently failed to improve clinical outcomes of septic patients, in any age group. Conversely, therapeutic strategies targeting the pathogen with antimicrobial agents have consistently demonstrated significant decreases in sepsis-associated morbidity and mortality.

Given the importance of the pathogen to sepsis outcomes, we sought to determine if longevity-associated changes in gut microbial virulence contribute to aging-associated sepsis severity. We hypothesized that throughout the lifetime of the host, the gut microbiota accumulate virulence factors that promote host immune evasion. Escape of these age-conditioned pathogens from the intestinal lumen therefore leads to exaggerated sepsis severity. This novel concept - that the gut microbiota also "ages" throughout the lifespan of the host and selects for hypervirulent pathobionts - has the potential to inform targeted therapeutic approaches to mitigate the burden of sepsis in older adults.

We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Our findings highlight a previously unrecognized contributor to the pathophysiology of heightened aging-associated sepsis severity. To date, investigations of the intersection of aging and critical illness have focused on longevity-associated host processes such as waning immune function and alterations in inflammation. However, it is intuitive that the intestinal microbiota simultaneously undergoes genomic and phenotypic changes throughout the lifespan of the host organism. This aging of an enteric bacterial community likely selects for pathobionts with virulence factors that offer a fitness benefit - such as the evasion of host immunity. Our work highlights that pathogen virulence factor genomics, and not simply type of pathogen, is therefore a major mediator of mechanistic sepsis heterogeneity.