The gut microbiota in immune-mediated disorders

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Das, Mrinmoy
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University College Cork
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The human gut microbiota is a diverse community of microbes residing in the intestine. Evidence from various animal models and human studies have highlighted its potential role in health, metabolic and immune-associated conditions such as osteoporosis, inflammatory arthritis, inflammatory bowel disease (IBD) and multiple sclerosis. This thesis provides further understanding of the changes in the gut microbiota dynamics in these disorders which is important for establishing a necessary knowledge base for potential microbiota-based diagnostic/therapeutic options. The studies undertaken in this thesis provides a baseline observation and identify the directionality of changes that occurs in the gut microbiota throughout disease progression and treatment. The thesis investigates alterations in the microbiota due to biologics treatment and differences associated with health and disease status. Amplicon and metagenomic whole genome shotgun (mWGS) sequencing were employed along with extensive meta-data analyses. Using robust and rigorous statistical approaches on the amplicon dataset, I identified a set of key taxa that are differentially abundant in osteoporosis. The microbiota diversity is associated with various covariates; however, the key taxa retain association with bone measures after accounting for the covariates. The gut microbiota of different arthritis and IBD samples were profiled at different time-points using mWGS before and during biologics treatment. This demonstrated that the long-term biologics treated samples show the presence of taxa observed in healthy controls which are absent or reduced in treatment naive arthritic subjects. This signature is reflected in β-diversity and in the differentially abundant taxa. The strength of this signature varies in different arthritic diseases. In MS, I identified different taxonomic and functional signatures of the gut microbiota associated with different MS phenotype which is distinct from both young and elderly healthy population using mWGS profiles. For better inference of functional potential from amplicon data, I developed a novel methodology IPCO, a flexible R library. It outperforms other tools both in terms of sample and features profiles correlation by retaining most of the observed biological signal determined from paired mWGS and metabolites profile data. In conclusion, an altered microbiota composition was found to be associated with bone mineral density in osteoporosis, different phenotypes of MS as well as with biologics-mediated disease remission in different forms of arthritis. These noted alterations will contribute to a better understanding of the relationship between the gut microbiota and immune disorders. This can be useful to identify potential diagnostic or therapeutic targets in at-risk individuals. Lastly, I demonstrated that IPCO generated reliable prediction of the functional potential from 16S data in contrast to established tools.
Microbiome , Inflammation , Arthritis , Co-variance , Osteoporosis , Multiple sclerosis
Das, M. 2020.The gut microbiota in immune-mediated disorders Title. PhD Thesis, University College Cork.