A mouse model of ileocolic resection and the changes in microbiome and bile acid physiology

Bile acids (BAs) and the gastrointestinal microbiota share an intimate relationship, recently termed the BA-microbiome axis. In health, 95% of BAs produced by the liver are reabsorbed at the ileum as part of the enterohepatic circulation (EHC). The remainder of BAs which travel through to the colon are subject to a diverse range of metabolic reactions, performed exclusively by the resident microbes, converting these BAs into chemically and physiologically diverse bioactive molecules. Recently, it has been demonstrated that alterations in this delicate ecosystem is implicated in a range of illnesses, including inflammatory bowel disease, colon cancer and metabolic syndrome.

Ileocolic resection (ICR), commonly performed for Crohn’s disease or caecal cancer, disrupts BA homeostasis and the microbial ecology by interrupting the EHC. Despite this, a detailed characterisation of how ICR fits in the context of the BA-microbiome axis has been poorly characterised. This gap in a mechanistic understanding of the effects of surgical procedure was the overarching theme of this thesis. It was hypothesised that the increase in BA influx into the colon following ICR would drive large-scale alterations in the microbial community, leading to shifts in microbial metabolism that would be reflected in the composition of the BA pool. Furthermore, signatures in BA and microbiota may be correlated with post-operative outcomes, such as survival.

The aim of chapter 2 was to to perform a systematic review investigating the effects of ileal surgery on the BA-microbiome axis. This highlighted that the current literature was limited to a handful of observational human studies and that a mechanistic understanding of the BA-microbiome axis in relation to ICR was still lacking.

In chapter 4 and 5, a mouse model of ICR was used to create a BA-overloaded state in the colon through interruption of the EHC by surgical resection of the terminal ileum. The taxonomic and functional changes in the microbiome was characterised using shotgun metagenomic sequencing. Liquid chromatography mass spectrometry was used to define the BA composition in the colon in these mice.

Chapter 4 aimed to perform an in-depth characterisation of the impact of ICR on the BA composition in the colon and the taxonomic and functional changes in microbiome. It was found the mice who underwent ICR had a characteristically “dysbiotic” colonic microbial signature, characterised by decreased alpha diversity, loss of beneficial species and enrichment of pathogens, particularly Escherichia coli. Further functional genomic annotation revealed that the gene expression of bile salt hydrolase (BSH) and several other BA metabolism enzymes were reduced in the microbiomes of ICR mice. In line with this, the BA signature was characterised by an increase in conjugated BAs, such as taurocholic acid and taurochenodeoxycholic acid, but a decrease in secondary BAs.

In chapter 5, the aim was to explore the effect of BA sequestration on the microbiota within the BA-overloaded state. Additionally, BA-microbiome signatures were correlated with postoperative outcomes, such as post-operative wellness and anastomotic healing in mice. It was found that whilst the drastic changes in microbiota were ameliorated in these mice, this did not translate to improved post-operative recovery. Furthermore, certain microbial species and BAs were associated with the post-operative recovery and survival.

In conclusion, this thesis provides novel insights into the changes in microbial community and metabolism of BAs following ICR. These preclinical findings contribute to a broader understanding of intestinal physiology by illustrating how the microbiome and metabolites, such as BAs can influence host recovery. Ultimately, this work lays the foundation for future hypothesis-driven research into leveraging microbial therapies to improve post-surgical outcomes.