The gastrointestinal tract of humans is colonized by hundreds of microbial species, - bacteria, archaebacterial, fungi, protozoa and viruses -, collectively named the gut microbiome. The intestinal commensal bacteria have an important role in metabolic processes and contribute to colonization resistance against intestinal pathogens. Fungi are usually considered to be a minor component of the global microbiome. However, the mycobiome (fungal component of the entire microbiome) has been in fact little studied particularly with regards to its relationships with the other components of the microbiome. Fungi could be important players of the microbiome because some fungal species are able to proliferate in response to diet or during dysbiosis due to antibiotic treatment or gut inflammation. The aim of this project is to investigate the effect of specific antibiotics (primarily anti-Gram negative bacteria antibiotic) on the gut mycobiome. More specifically, we will examine the impact of cefotaxime and ceftriaxone, 2 antibiotics with same antimicrobial spectra but different rates of biliary elimination, on the changes in fungal communities.

Bacteria analysis of fecal samples by 16S sequencing has provided a wealth of information for the distribution of bacterial species in both health and disease conditions. When looking at bacterial composition, the focus in generally put on the presence or absence of the most abundant species; yet, even low abundant species may have significant effects on the host when present at even low abundance. To assess the possible contribution of low abundance bacterial species, we aim to undertake a targeted search of publicly available 16S databases for a restricted number of commensals to assess their possible role in the various conditions tested.

Our hypothesis is that gut microbiota could define predictive markers of response and tolerance to biologics. A. Preliminary results: gut bacteria predicting response to TNF blockers. A proof-of-concept study has been performed on 58 patients who were recruited according to the following criteria: active disease despite NSAIDs intake; no history of inflammatory bowel disease; no antibiotics intake within 3 months prior recruitment. Bacterial 16S rRNA gene sequencing region was performed on stools samples before and after TNF-blocker treatment. Diversity metrics and custom LefSe were used to explore the relationship between the composition of the intestinal microbiota and the efficacy of TNF-blockers. A lower alpha diversity at baseline was unexpectedly associated with better treatment response, HLA-B27 genotype and smoking behavior. Meanwhile, beta diversity was associated with smoking behavior and HLA-B27 genotype before and after treatment. Beta diversity at baseline was associated with the BASDAI index after treatment, and the response to the treatment. These results indicate a potential regulatory role for the gut microbiota on the underlying mechanisms involved in the response to TNF-blockers. Moreover, a LefSe-like approach identified 6 bacterial species as potential biomarkers for the treatment response, despite the absence of global changes (beta diversity) in the microbiota composition following a 3-month TNF-blockers intake. B. Current project: ITS2 fungal rDNA sequencing analyses In order to establish a causal link between host-microbe interactions and clinical efficacy of anti-TNF, we expect the following research endpoints from our experimental and translation approach (cohorts/clinical trials): 1. Defining the impact of anti-TNF on fungal microbiota and on the relative representation of fungal/bacterial components 2. Defining correlations between gut fungal composition and clinical outcome, with the aim of identifying stool microbial fingerprint of durable responses and/or primary resistance to anti-TNFα in SpA patients. The analyses will be performed on the same 58 SpA patients that were previously analyzed for their 16S bacterial component. These patients perfectly described regarding their disease characteristics, demographics, ongoing treatments, response to anti-TNF after a 3-month treatment period.

Cepia mass produces two species of Anopheles mosquitoes for research teams studying malaria. The aim of this project is to assess 1) whether or not the compostion of the bacterial microbiota fluctuates over time and if so to what extent ; 2) if there are significant variations can these be correlated with the degree of infectability by plasmodium parasites and/or the fitness of the mosquitoes (measured by their survival rate).

Previous animal models of Primary Antibody Deficiency (PAD) display severe dysbiosis and gut inflammation, which makes them incompatible to study a wide spectrum of PAD (e.g., most IgAD subjects display only mild dysbiosis and are asymptomatic). We would like to evaluate a novel mouse model of PAD and then perform microbiome transplant and IgA supplementation. The first objective is to evaluate the causal role of the microbiome in mediating PAD-associated disease. Our second objective is to apply an IgA supplement to reverse gut dysbiosis in symptomatic PAD and look at the microbiome changes caused by supplementation.