Characterising intestinal microbiome disruption in healthcare settings: towards therapeutic intervention to prevent infection

Author: Lito Papanicolas

Papanicolas, Lito, 2022 Characterising intestinal microbiome disruption in healthcare settings: towards therapeutic intervention to prevent infection, Flinders University, College of Medicine and Public Health

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It is increasingly recognised that microbes residing in our intestinal tract significantly influence our physiology and susceptibility to disease. Disruption of resident gut microbiota promotes pathogen colonisation and expansion thereby increasing the risk of infection. However, little is known about how medical therapies contribute to gut microbiome disruption and whether faecal microbiome transplantation (FMT) can be optimised for use as a therapeutic to restore damaged microbiomes. In order to examine these knowledge gaps this doctorate is divided into two sections: the first investigates microbiome disruption in populations at high risk of infection, and the second investigates the effects of FMT processing on bacterial viability and function.

To better understand the role of medical therapy in driving microbiome disruption two distinct cohorts of patients were studied: those receiving myelosuppressive chemotherapy and critically ill patients receiving intensive care. Faecal samples collected longitudinally underwent 16S rRNA gene amplicon sequencing to determine the within-patient changes to microbiome characteristics occurring during medical intervention. In the second part of this doctorate a propidium monoazide (PMA) based method was optimised for use in determining bacterial viability in faecal samples. This methodology was then applied to study the viability of commensal donor microbiota used in a clinical trial investigating the role of FMT in preventing recurrent urinary tract infection.

The results of the first observational study indicate that chemotherapy treatment promotes gut microbiome instability and increases the relative abundance of gram-negative commensal bacteria at the expense of gram-positive Firmicutes during periods of predicted myelosuppression. However, the microbiome disruption experienced by this cohort was minor compared to the vast shifts in microbiome diversity and composition experienced by critically ill patients. Results from the second section of this doctorate demonstrate that PMA in combination with molecular assays can be used to accurately define the viability of bacteria in donor faecal slurries and that processing FMT material in aerobic conditions significantly impairs the viability of important beneficial commensals.

Together these findings suggest medical interventions are important drivers of microbiome disruption. In both cohorts, but particularly in the critically ill, the changes observed are likely to contribute to the risk of infection developing. Continuation of these studies will shed further light on which markers of microbiome disruption are linked to infection risk. Although FMT is a promising therapy for reconstituting disrupted microbiomes, it is critical that transplants are prepared in a manner that preserves beneficial microbes. Ultimately, further research, including randomised controlled trials such as the one developed as part of this doctorate, are required to determine the role of microbiome reconstitution as an intervention to prevent infection.

Keywords: microbiome, faecal microbiota transplant, infection,sepsis, chemotherapy

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2022
School: College of Medicine and Public Health
Supervisor: Professor Geraint Rogers