Defining Microbiome Stability in First-Degree Relatives of Inflammatory Bowel Disease Patients

The microbiome is an emergent area of research focussed on understanding the intricacies of the symbiotic relationship we have with the millions of microbes in and on our bodies. The gut microbiome has been well established as a key modulator of health and disease. Inflammatory bowel disease (IBD) is a chronic inflammatory relapsing condition with no known cure, requiring lifelong medication and often surgical intervention, significantly diminishing quality of life. IBD is intrinsically linked to the gut microbiome with well documented changes in microbial community composition and functional capacity within this niche. IBD risk factors remain elusive with several genetic and environmental risk factors documented but limited establishment of causal associations between these factors and the manifestation and progression of the disease. In first-degree relatives (FDR) of IBD patients risk is notably increased, yet most FDRs don’t progress to develop the condition despite sharing genetic and environmental risk factors. Limited research has sought to characterise the microbiome in this uniquely positioned cohort of FDRs of IBD patients. In this thesis we aimed to define the microbial landscape in FDRs of IBD patients in a novel Australian cohort. Describing the faecal microbiome, faecal metabolome and a novel characterisation of the oral microbiome alongside an array of clinical and demographic assessments. These profiles were compared with matched healthy population controls as wells as their paired IBD relatives available within the Australian IBD microbiome (AIM) study. To further characterise microbial resistance and resilience profiles in FDRs of IBD patients we then applied in vitro modelling techniques to assess gut microbiome responses to dietary, probiotic and antibiotic challenges as well as assessing the influence of autologous faecal microbiota transplant (FMT) for microbial community restoration. The findings provide new insights into microbial community composition and function associated with FDRs. A systematic review of global datasets revealed poor characterisation of the faecal microbiome in FDRs of IBD patients with limited comparisons to healthy benchmarks. Unified bioinformatic reanalysis of global FDR datasets highlighted unique microbial signatures associated with geography and age as well as distinct compositional changes from both HC and IBD comparator groups. To address these knowledge gaps the experimental work in the thesis provides clear integrated analysis of the FDR microbiome. Specifically, we identified significant compositional changes in both the faecal and oral microbiome, alongside distinct metabolic changes. The FDR faecal microbiome aligned closely with HC with no overt changes in diversity or primary genera. Despite this strong similarity was observed between the FDR metabolome and the metabolome of the paediatric IBD patients. Network and predicative analysis tools applied to the faecal microbiome again revealed high alignment between HC and FDR groups however greater discriminatory capacity was present between IBD and FDR microbiomes than FDR and HC. Connectivity of the resulting FDR metabolome again aligned more closely with IBD relatives suggesting dysregulated metabolic function of a ‘healthy’ microbial community. Novel characterisation of the oral microbiome in FDRs of IBD revealed significant deviation from HC profiles, with enrichment of opportunistic pathogenic genera including Capnocytophaga and Phorphyromonas. Oral microbial features in HC and IBD patients shared the highest similarity across the cohort suggesting significant changes are present in the FDR oral microbiome. Across the cohort dietary and health related quality of life metrics correlated strongly with diversity metrics and microbial features. These findings aligned with identified dietary patterns of high fat consumption and high quality of life scores described in the FDR group. To further characterise the FDR microbiome, we selected 3 donors across age (paediatric, adult, senior) alongside a HC and IBD donor of middle age. In vitro modelling of their stool microbial communities revealed unique responses to various environmental triggers. Antibiotic triggers (ciprofloxacin, metronidazole) had the most significant impact on total microbial diversity and composition. We demonstrated effective acceleration of microbial recovery using autologous FMT, however, resulting community structure never completely regained the initial composition. High fat diet was associated with more modest microbial changes but also robust modulation of the resulting metabolome. Across donors, Fusobacterium was strongly associated with high fat diet administration. Probiotic dosing failed to produce consistent modulation of the microbial communities. We observed an increase in Bifidobacterium abundance (probiotic) as a result of probiotic administration, but this effect was only maintained in the paediatric FDR and HC donors with no uptake in the IBD or senior FDR communities. In this thesis we present a comprehensive characterisation of faecal microbial structure and function in FDRs of IBD patients with novel characterisation of oral microbiome. We used in vitro bioreactors to successfully model environmental changes across microbial communities. Responses to triggers were unique and complex across donors, with some shared features. Paediatric and adult FDR communities showed a consistent lack of resistance and resilience with the senior FDR community showing more robust resistance alongside the HC donor. This work contextualises the unique microbial landscape in FDRs of IBD patients reinforcing the need for further characterisation of this unique cohort. We identify key environmental features associated with FDRs holding the capacity for significant microbial modulation. We also reinforce the importance of metabolomic characterisation highlighting that FDRs display conserved microbial profiles riddled with metabolic dysfunction. FDRs are an invaluable resource in bridging the gap between health and disease and continuing to understand the influence of the microbiome. With further research modulating these communities holds great potential in both therapeutic and preventative precision medicine to alleviate the burden of IBD.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2026

Author dc:creator

• Koentgen, Sabrina

• Microbiome
• Inflammatory Bowel Disease
• Metabolome
• Exposome
• Chemostat
• Bioreactor
• Gut Modelling
• anzsrc-for: 310703 Microbial ecology
• anzsrc-for: 3207 Medical microbiology
• anzsrc-for: 320203 Clinical microbiology
• anzsrc-for: 320209 Gastroenterology and hepatology
• anzsrc-for: 3205 Medical biochemistry and metabolomics

Statement dc:rights

• embargoed access
• CC BY 4.0

Licence

• http://purl.org/coar/access_right/c_f1cf
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/32253

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/107729