Project description:A comparison of rectal mucosal RNA transcriptome findings between transgender women using feminizing hormone therapy, men who have sex with men engaging in receptive anal intercourse, and males who had never engaged in anal intercourse demonstrates differential gene expression involving pathways critical for mucosal inflammation, suggesting the urgent need for further exploration into the immunologic effects of cross-sex hormone therapy in the rectal mucosa and the potential impact on HIV transmission risk at this site.
Project description:Pouchitis is a common complication for ulcerative colitis (UC) patients with ileal pouch-anal anastomosis (IPAA) surgery. Similarly to IBD, both innate host factors such as genetics, and environmental stimuli including the tissue-associated microbiome have been implicated in the pathogenesis. In this study, we make use of the IPAA model of inflammatory bowel disease (IBD) to carry out a study associating mucosal host gene expression with the microbiome and corresponding clinical outcomes.
Project description:Pouchitis is a common complication for ulcerative colitis (UC) patients with ileal pouch-anal anastomosis (IPAA) surgery. Similarly to IBD, both innate host factors such as genetics, and environmental stimuli including the tissue-associated microbiome have been implicated in the pathogenesis. In this study, we make use of the IPAA model of inflammatory bowel disease (IBD) to carry out a study associating mucosal host gene expression with the microbiome and corresponding clinical outcomes. In order to determine how host gene expression might influence, or be influenced by the tissue associated microbiome, we analyzed 205 IPAA patients with biopsies collected from the pouch and afferent limb for host transcriptomics and 16S rDNA gene sequencing. Metadata included antibiotic use, inflammation score, and clinical classification. To achieve power for a genome-wide microbiome-transcriptome association study, we used principal component analysis to reduce OTUs and host transcripts to eigengenes and eigenclades explaining 50% of observed variance. These were subsequently tested for significant covariation with one another and/or outcome using multivariate linear modeling.
Project description:Leber2015 - Mucosal immunity and gut
microbiome interaction during C. difficile infection
This model is described in the article:
Systems Modeling of
Interactions between Mucosal Immunity and the Gut Microbiome
during Clostridium difficile Infection.
Leber A, Viladomiu M, Hontecillas R,
Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera
J.
PLoS ONE 2015; 10(7): e0134849
Abstract:
Clostridium difficile infections are associated with the use
of broad-spectrum antibiotics and result in an exuberant
inflammatory response, leading to nosocomial diarrhea, colitis
and even death. To better understand the dynamics of mucosal
immunity during C. difficile infection from initiation through
expansion to resolution, we built a computational model of the
mucosal immune response to the bacterium. The model was
calibrated using data from a mouse model of C. difficile
infection. The model demonstrates a crucial role of T helper 17
(Th17) effector responses in the colonic lamina propria and
luminal commensal bacteria populations in the clearance of C.
difficile and colonic pathology, whereas regulatory T (Treg)
cells responses are associated with the recovery phase. In
addition, the production of anti-microbial peptides by inflamed
epithelial cells and activated neutrophils in response to C.
difficile infection inhibit the re-growth of beneficial
commensal bacterial species. Computational simulations suggest
that the removal of neutrophil and epithelial cell derived
anti-microbial inhibitions, separately and together, on
commensal bacterial regrowth promote recovery and minimize
colonic inflammatory pathology. Simulation results predict a
decrease in colonic inflammatory markers, such as neutrophilic
influx and Th17 cells in the colonic lamina propria, and length
of infection with accelerated commensal bacteria re-growth
through altered anti-microbial inhibition. Computational
modeling provides novel insights on the therapeutic value of
repopulating the colonic microbiome and inducing regulatory
mucosal immune responses during C. difficile infection. Thus,
modeling mucosal immunity-gut microbiota interactions has the
potential to guide the development of targeted fecal
transplantation therapies in the context of precision medicine
interventions.
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and identified by:
BIOMD0000000583.
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To the extent possible under law, all copyright and related or
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Project description:Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). The clinical results were reported here https://www.ncbi.nlm.nih.gov/pubmed/27986684. For the gene expression study, rectal biopsies were obtained from a subset of participants (n = 36) in the United States (Pittsburgh) and Thailand (Bangkok). Biopsies were provided at baseline and after each study period.
Project description:Genomic response of C. elegans after infection with Microbacterium nematophilum.<br><br>The interaction between the nematode Caenorhabditis elegans and a Gram-positive bacterial pathogen, Microbacterium nematophilum, provides a model for an innate immune response in nematodes. This pathogen adheres to the rectal and post-anal cuticle of the worm, causing slowed growth, constipation, and a defensive swelling response of rectal hypodermal cells. To explore the genomic responses that the worm activates after pathogenic attack we used microarray analysis of transcriptional changes induced after 6 hr infection, comparing virulent with avirulent infection.
Project description:A total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is considered the surgery of choice for definitive management of familial adenomatous polyposis (FAP) and selected patients with ulcerative colitis (UC). However, this surgical treatment often associates with a long-term complication, pouchitis, which occurs mostly in UC patients. To better define the molecular background of pouchitis, the microarray-based survey was performed using pouch mucosal samples collected from 28 and 8 patients operated for UC and FAP, respectively. A number of 4771 genes was significantly differentiating uninflamed from inflamed mucosal samples, and their functional features were represented mostly by alerted metabolic and cell proliferation pathways. In contrast, functional analyses of aberrantly expressed probe sets between UC and FAP samples, irrespectively of mucosal inflammation status, revealed multiple pathways and terms which were linked to changes in immune response. Noteworthy, the comparison of uninflamed UC and FAP samples distinguished a set of 26 altered mRNAs including inflammation-related transcript encoding a Charcot-Leyden crystal (CLC) protein. The most discrete changes in gene expression profiles differentiating uninflamed UC and FAP mucosal samples were attributed to a Gene Ontology category innate immune response. Our study confirmed alterations of the immune responses as dominant in UC pouchitis which were earlier found in the studies using analyses of singular molecular elements. This observation may be important when managing IPAA patients. Each sample represents three biopsies taken from single patient, from the same areas of the lower part of the pouch mucosa (above the rectal cuff) during endoscopic examination. 28 patients underwent surgery for UC and 8 patients for FAP.
Project description:To seek effects of inflammatory status and 5-aminosalicylic acid (5-ASA, mesalazine) exposure ex vivo on mRNA levels within rectal mucosal biopsies from patients with ulcerative colitis.
Project description:The rectal mucosal transcriptome of men who have sex with men (MSM) engaging in condomless receptive anal intercourse (CRAI) compared with men who have never engaged in anal intercourse (controls)
Project description:Persistent mucosal inflammation and microbial infection are characteristic of Chronic Rhinosinusitis (CRS). Though mucosal microbiota dysbiosis is a characteristic feature of other chronic inflammatory diseases, the relationship between sinus microbiota composition and CRS is unknown. Here we demonstrate, using comparative microbiome profiling of a cohort of CRS patients and healthy subjects, that the sinus microbiota of CRS patients exhibit significantly reduced bacterial diversity. Characteristic of this community collapse is the depletion of multiple, phylogenetically distinct, Lactic Acid Bacteria and the concomitant increase in relative abundance of a single species, Corynebacterium tuberculostearicum. Recapitulating the conditions observed in our human cohort in a murine model confirmed the pathogenic potential of C. tuberculostearicum and the critical necessity for a replete mucosal microbiota to protect against this species. Moreover, we provide evidence that Lactobacillus sakei, identified from our comparative microbiome analyses as a potentially protective species, affords defense against C. tuberculostearicum sinus infection, even in the context of a depleted sinus bacterial community. These studies demonstrate that sinus mucosal health is highly dependent on the composition of the resident microbiota, and identifies a new sino-pathogen and a strong bacterial candidate for therapeutic intervention. A total of 14 samples were profiled for microbiome composition: 7 from non-sinusitis patients, and 7 from patients with clinically diagnosed chronic sinusitis.