Publications by authors named "Sandrine Isaac"

7 Publications

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IL-17 controls central nervous system autoimmunity through the intestinal microbiome.

Sci Immunol 2021 Feb;6(56)

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Interleukin-17A- (IL-17A) and IL-17F-producing CD4 T helper cells (T17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). T17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.aaz6563DOI Listing
February 2021

The Pre-treatment Gut Microbiome is Associated with Lack of Response to Methotrexate in New Onset Rheumatoid Arthritis.

Arthritis Rheumatol 2020 Dec 13. Epub 2020 Dec 13.

Department of Medicine, Division of Rheumatology, New York University School of Medicine and NYU Langone Orthopedic Hospital, New York, NY, USA.

Objectives: Although oral methotrexate (MTX) remains the anchor drug for RA, up to 50% of patients do not achieve a clinically adequate outcome. Concomitantly, there is a lack of prognostic tools for treatment response prior to drug initiation. Here we study whether inter-individual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA (NORA).

Methods: 16S rRNA gene and shotgun metagenomic sequencing were performed on the baseline gut microbiomes of drug-naïve, NORA patients (n=26). Results were validated in an additional independent cohort (n=21). To gain insight into potential microbial mechanisms, ex vivo experiments coupled with metabolomics analysis evaluated the association between microbiome-driven MTX depletion and clinical response.

Results: Our analysis revealed significant associations between the abundance of gut bacterial taxa and their genes with future clinical response, including orthologs related to purine and methotrexate metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicts lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pre-treatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes.

Conclusions: Together, these results provide the first step towards predicting lack of response to oral MTX in NORA patients and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.
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http://dx.doi.org/10.1002/art.41622DOI Listing
December 2020

Gut colonization by a novel Clostridium species is associated with the onset of epizootic rabbit enteropathy.

Vet Res 2018 Dec 20;49(1):123. Epub 2018 Dec 20.

Departamento de Genómica y Salud, Centro Superior de Investigación en Salud Pública - FISABIO, Avenida de Cataluña, 21, 46020, Valencia, Valencia, Spain.

Epizootic rabbit enteropathy (ERE) represents one of the most devastating diseases affecting rabbit farms. Previous studies showing transmissibility of disease symptoms through oral inoculation of intestinal contents from sick animals suggested a bacterial infectious origin for ERE. However, no etiological agent has been identified yet. On the other hand, ERE is associated with major changes in intestinal microbial communities, pinpointing dysbiosis as an alternative cause for the disease. To better understand the role of intestinal bacteria in ERE development, we have performed a prospective longitudinal study in which intestinal samples collected from the same animals before, during and after disease onset were analyzed using high-throughput sequencing. Changes in hundreds of bacterial groups were detected after the initiation of ERE. In contrast, before ERE onset, the microbiota from rabbits that developed ERE did not differ from those that remained healthy. Notably, an expansion of a single novel Clostridium species (Clostridium cuniculi) was detected the day of ERE onset. C. cuniculi encodes several putative toxins and it is phylogenetically related to the two well-characterized pathogens C. botulinum and C. perfringens. Our results are consistent with a bacterial infectious origin of ERE and discard dysbiosis as the initial trigger of the disease. Although experimental validation is required, results derived from sequencing analysis, propose a key role of C. cuniculi in ERE initiation.
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http://dx.doi.org/10.1186/s13567-018-0617-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302431PMC
December 2018

Roles of the intestinal microbiota in pathogen protection.

Clin Transl Immunology 2017 Feb 10;6(2):e128. Epub 2017 Feb 10.

Departamento de Genómica y Salud, Centro Superior de Investigación en Salud Pública - FISABIO , Valencia, Spain.

Hundreds of commensal bacterial species inhabit the gastrointestinal tract. This diverse microbial ecosystem plays a crucial role in the prevention and resolution of infectious diseases. In this review we will describe the major mechanisms by which the intestinal microbiota confers protection against infections, focusing on those caused by intestinal bacterial pathogens. These mechanisms include both non-immune- and immune-cell-mediated pathways, notably through bacterial production of inhibitory molecules and nutrient deprivation by the former and innate lymphoid cell-, myeloid cell- or lymphocyte-dependent stimulation by the latter. Finally, we will discuss novel therapeutic approaches based on commensal microbes and their products, which could potentially be used to combat infections.
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http://dx.doi.org/10.1038/cti.2017.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311919PMC
February 2017

Short- and long-term effects of oral vancomycin on the human intestinal microbiota.

J Antimicrob Chemother 2017 01 5;72(1):128-136. Epub 2016 Oct 5.

Departamento de Genómica y Salud, Centro Superior de Investigación en Salud Pública - FISABIO, Valencia, Spain

Background: Oral vancomycin remains the mainstay of therapy for severe infections produced by Clostridium difficile, the most prevalent cause of healthcare-associated infectious diarrhoea in developed countries. However, its short- and long-term effects on the human intestinal microbiota remain largely unknown.

Methods: We utilized high-throughput sequencing to analyse the effects of vancomycin on the faecal human microbiota up to 22 weeks post-antibiotic cessation. The clinical relevance of the observed microbiota perturbations was studied in mice.

Results: During vancomycin therapy, most intestinal microbiota genera and operational taxonomic units (OTUs) were depleted in all analysed subjects, including all baseline OTUs from the phylum Bacteroidetes. This was accompanied by a vast expansion of genera associated with infections, including Klebsiella and Escherichia/Shigella. Following antibiotic cessation, marked differences in microbiota resilience were observed among subjects. While some individuals recovered a microbiota close to baseline composition, in others, up to 89% of abundant OTUs could no longer be detected. The clinical relevance of the observed microbiota changes was further demonstrated in mice, which developed analogous microbiota alterations. During vancomycin treatment, mice were highly susceptible to intestinal colonization by an antibiotic-resistant pathogen and, upon antibiotic cessation, a less-resilient microbiota allowed higher levels of pathogen colonization.

Conclusions: Oral vancomycin induces drastic and consistent changes in the human intestinal microbiota. Upon vancomycin cessation, the microbiota recovery rate varied considerably among subjects, which could influence, as validated in mice, the level of susceptibility to pathogen intestinal colonization. Our results demonstrate the negative long-term effects of vancomycin, which should be considered as a fundamental aspect of the cost-benefit equation for antibiotic prescription.
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http://dx.doi.org/10.1093/jac/dkw383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161046PMC
January 2017

[Molecular epidemiology studies on the immigrant population in Spain].

Rev Esp Salud Publica 2014 Nov-Dec;88(6):819-28

Background: Molecular epidemiology is a new scientific discipline which allows to integrate information on the genetic variation of infectious pathogens with their diffusion in a population and its subgroups including, for instance, resistance mutations to antibiotics and antiretrovirals. We present the results of an analysis of scientific publications that analyze the health status of the immigrant population in Spain from a molecular epidemiology perspective.

Methods: We reviewed original articles published in 1998-2014 with the keywords "molecular epidemiology", "molecular typing", "sequencing", "immigrant", and "Spain".

Results: From a total of 267 articles identified initially, only 50 passed through the established filters. Most of them (36) analyzed infections by Mycobacterium tuberculosis (3) and HIV (3), followed at a large distance by Staphylococcus aureus and hepatitis B virus. The main goal of these works was the typing of the pathogen and to determine the frequency of resistance mutations.

Conclusion: Is difficult to generalize the conclusions from the analyzed articles because most of them have a purely descriptive and quite restricted scope, considering the type and size of the samples studied. Several studies are focused on the most likely origin for the strains or variants of the pathogen but others also reveal transmissions from the local to the immigrant populations.
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http://dx.doi.org/10.4321/S1135-57272014000600013DOI Listing
April 2015

Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease.

Arthritis Rheumatol 2015 Jan;67(1):128-39

New York University and New York University Hospital for Joint Diseases, New York, New York.

Objective: To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA).

Methods: High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids.

Results: The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis.

Conclusion: Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study.
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http://dx.doi.org/10.1002/art.38892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280348PMC
January 2015