The human gut microbiome is a major factor in sepsis development, yet a dearth of human studies means limited new therapies that utilize the microbiome as a method of treating bacterial sepsis effectively, according to a review published in The Journal of Infectious Diseases.

The authors noted that most research of sepsis in humans has focused on the host’s dysregulated immune response, while research implicating the gut microbiome as a key factor in sepsis risk is only well documented in animals. A disrupted gut microbiome may play a role in organ dysfunction across multiple systems, a hallmark of severe sepsis.

On the molecular level, microbiota interact with components of the hosts’ immune system via a “microbiota-immune crosstalk” that constantly evolves. Microbiota use contact-dependent mechanisms to influence local barrier function at the site of colonization, hematopoiesis, T cell differentiation and activation, cytokine production, antibody production, and phagocytosis.

Bacteroides and Firmicutes, the most abundant bacterial phyla in the intestines, are important producers of short-chain fatty acids, which can regulate gene expression in regulatory T cells and alter how macrophages kill bacteria.


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A healthy gut microbiome, dominated by obligate anaerobes Bacteroidetes and Firmicutes, establishes resistance to colonization of normally low-level, highly pathogenic species in the intestinal tract, such as Enterococcus faecium and Klebsiella pneumoniae.

However, within minutes or hours of stress introduction to the gut such as tissue injury or infection, there is a loss of the obligate anaerobes. Artificial nutrition and antibiotics, hallmarks of sepsis management, further disrupt the intestinal microbiome, leading to sepsis.

The authors therefore emphasize that sepsis treatment should be guided by the connection between the microbiota and sepsis outcomes.

First, clinicians should follow society guidelines on antibiotic stewardship because antibiotics are necessary to treat sepsis despite their impact on the gut microbiome. Additionally, oral scavenger compounds should be used to limit antibiotic disruption of the gut microbiota while maintaining systemic therapeutic levels. The authors acknowledge that more clinical studies on oral scavengers are needed.

Second, artificial nutrition should include more fiber to support a healthy microbiome. Artificial nutrition usually consists of a casein-based, sterile, chemically defined diet lacking any dietary fiber, and studies have shown that patients fed an animal-protein-based, low-fiber diet develop intestinal conditions that inhibit the growth of Firmicutes and Bacteroidetes.

Finally, the authors highlighted prebiotics, fermentable fiber additives for those receiving enteral nutrition, and FMT as alternative treatments. Yet they pointed out that “at the present time, therapies targeting the microbiome remain largely investigational, and judicious use of antibiotics and a rethinking of current nutritional formulations remain the only therapeutic interventions that can be recommended on the basis of current evidence.”

Reference

Miller WD, Keskey R, Alverdy J. Sepsis and the microbiome: a vicious cycle. J Infect Dis. Published online December 17, 2020. doi:10.1093/infdis/jiaa682