Biology subjects

Clemente, J. C.

Publications and source records attributed to Clemente, J. C..

14 recordsLinked to original sources

bioRxiv2026

Distinct Hippocampal Cellular Pathologies Influence Cognition Across Diagnostic Categories, also distinguishing Schizophrenia from Affective Psychoses

Introduction: Total and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses cases could be a roadblock if these differ in cellular pathology. Methods: We examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations (1H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis (Psy), including 20 schizophrenia and 13 affective psychoses (aff-P) cases. Results: NP-aff and HC had similar total cognition (46.64{+/-}12.01 vs 41.10{+/-}17.88), both superior to Psy (28.34{+/-} 12.34; p's<0.01). Mean metabolite concentrations were similar across all groups but showed significant within-group associations to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, p's<.05), although no biomarker predicted total cognition in the clinical groups. FFor NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). Opposite NP-aff, reduced myelin/membrane concentrations predicted cognitive deficits in Psy (-.514, p<.05). Separating schizophrenia from aff-P on social cognition showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) ibut higher myelin/membrane turnover and neuronal integrity concentrations in aff-P (.575, .581, p's<.05). Conclusions: Schizophrenia and affective psychosis significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.

pathology↗

bioRxiv2026

Do Symptom Domains Have Similar Cellular Underpinnings Across Psychiatric Diagnoses: Evidence from 3D Hippocampal MR Spectroscopy

Introduction: The NIMH Research Domain Criteria (RDoC) posits similar cellular pathologies for particular symptom domains across diagnostic categories. Conversely, knowledge that these differ could advance treatment discovery, especially for affective and non-affective psychoses, as studies usually intermix them. Methods: We tested this by comparing metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic spectroscopic imaging (1H MRSI) with symptoms from the original and five factor PANSS, and the Hamilton Depression and Young Mania Scales. Participants were 26 healthy controls; 22 non-psychotic affective cases (NP-aff); and 33 with psychosis (including 20 schizophrenia (Scz) and 13 affective psychosis (aff-P) cases). Results: PANSS activation factor was related to reductions in all cellular component biomarkers in Scz, including glia, membrane turnover, neural integrity, glutaminergic neurotransmission, and energy metabolism (p's<.05), but only to energy metabolism in NP-aff (p=.03). Biomarkers for mood symptoms also varied across categories, suggesting gliosis for mania and depression in HC (p's[≤].025), but increased membrane turnover for mania in aff-P (p=.015), and decreased neural integrity and energy metabolism for depression in Scz (p's<.05). In contrast, negative symptoms and autistic preoccupation were related to reduced glia in both NP-aff and aff-P (p's<.05). Autistic preoccupation in Scz was related to both reduced glia and membrane turnover (p's<.05). Only Scz showed a significant finding for positive symptoms, specifically reduced membrane turnover (p=.018). Discussion: These results suggest both distinct and similar cellular pathologies for symptoms across diagnoses, including affective and non-affective psychoses. The differences support categorizing disorders and stratifying different psychoses in research rather than transdiagnostic approaches.

pathology↗

bioRxiv2024

Oral vancomycin treatment alters serum levels of indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes during EAE

Astrocytes play important roles in the central nervous system (CNS) during health and disease. Prior studies have shown that gut commensals derived indole derivatives as well as secondary bile acids modulate astrocyte function during the late stage of EAE (recovery phase). Here we show that administering vancomycin to mice starting during the early stage of EAE improved disease recovery, an effect that is mediated by the gut microbiota. We observed that 6 taxa within the Clostridia vadin BB60 group were enriched in vancomycin treated mice compared to untreated EAE mice. Vancomycin-treated EAE mice also had elevated serum levels of the anti-inflammatory tryptophan derived metabolite, indole-3-lactic acid and decreased levels of deoxycholic acid, a pro-inflammatory secondary bile acid. RNA sequencing revealed altered expression of several genes belonging to the mammalian target of rapamycin (mTOR) pathway in astrocytes obtained during the late stage of EAE from vancomycin treated EAE mice. Furthermore, we observed a link between serum levels of indole derivatives and bile acids and expression of several genes belonging to the mTOR pathway. Interestingly, the mTOR signaling cascades have been implicated in several key biological processes including innate (e.g., astrocyte) immune responses as well as neuronal toxicity/degeneration. In addition, rapamycin, a specific inhibitor of mTOR, has been shown to inhibit the induction and progression of established EAE. Collectively, our findings suggest that the neuroprotective effect of vancomycin is at least partially mediated by indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes. HIGHLIGHTSO_LIVancomycin attenuated established EAE through regulation of the microbiota C_LIO_LIVancomycin induced increased serum levels of indole-3-lactic acid, decreased serum levels of indoxyl-3-sulfate, p-cresol and decreased stool levels of deoxycholic acid C_LIO_LIVancomycin modulated the expression of mTOR pathway genes in astrocytes C_LIO_LILactobacillus reuteri regulated the expression of mTOR pathway genes in astrocytes C_LIO_LISerum levels of indole-3-lactic acid, indoxyl-3-sulfate, p-cresol and deoxycholic acid correlated with expression of mTOR pathway genes in astrocytes C_LI

neuroscience↗

bioRxiv2024

Tobacco Smoke Exposure is Characterized by a Distinct Nasal Rhinotype in a Pediatric Population

BackgroundSecondhand tobacco smoke exposure (TSE) increases susceptibility to respiratory diseases, but the mechanisms of action are poorly understood. ObjectiveTo study the effect of TSE in the nasal microbiome of children, and to evaluate whether such effect is dose-dependent with measured levels of cotinine in saliva and urine. MethodsThe study was performed at the Mount Sinai Kravis Childrens Hospital (New York, NY) and the Johns Hopkins Hospital (Baltimore, MD). We enrolled 236 children between 6 months and 10 years of age, both inpatients and outpatients. We collected swabs to characterize the diversity and composition of the nasal microbiome using 16S rRNA gene sequencing and measured cotinine levels in salivary and urinary samples to quantify TSE. We then determined the relationship between these measures and participant respiratory conditions, demographics and lifestyle factors. ResultsInfants with high cotinine levels had lower nasal microbiome alpha diversity and an enrichment in Moraxella, Dolosigranulum and Corynebacterium, which formed a distinct cluster in network analysis. A Dirichlet Multinomial Mixture model identified the existence of two distinct microbial rhinotypes, the first one characterized by significantly higher cotinine levels, lower alpha diversity, and enrichment of these taxa. ConclusionChildren with higher cotinine levels had reduced alpha diversity and a distinct nasal rhinotype. Our results suggest TSE is associated with alterations of the nasal microbiome and identify a rhinotype as a potential biomarker for TSE.

microbiology↗

bioRxiv2022

Solving Anscombe's Quartet using a Transfer Learning Approach

Analysis of high-dimensional datasets often involves usage of summary statistics, one of which is the correlation coefficient. These values are then used to inform downstream analysis, whether in feature selection or in subsequent construction of networks and heatmaps. Condensing pairwise scatterplots into these singular values however, often results in a loss of information. Originally proposed by F. J. Anscombe in his famous Anscombes Quartet, this phenomenon has been canonically used to demonstrate the importance of plotting and the limitations of summary statistics such as correlation or variance [F.J. Anscombe, (1973) American Statistician. 27 (1), 17-21]. While numerous methods exist for the generation of visually distinct datasets that share similar summary statistics, the converse has not been extensively studied. To address this gap, we propose ICLUST (Image CLUSTering), an image classifier tool that can visually distinguish correlations with similar summary statistics in simulations and identify meaningful clusters in real data. Such a tool can potentially benefit those performing exploratory analysis or feature selection in a complementary fashion by identifying relationships between variables that traditional summary metrics cannot provide. Significance StatementDistilling large-scale, multidimensional datasets via analysis of pairwise relationships often employs a single value to describe the relationship between variables. However, as demonstrated through simulations, such summarization fails to retain the nuances of the data. Characteristics such as the type of relationship (linear versus nonlinear, etc.) and the spread of the data are commonly lost when using correlations. Here we propose a transfer learning framework, borrowing from image clustering and classification software, to visually classify graphs. We apply our method towards separation of scatterplots with similar correlation statistics but visually distinctive patterns in both simulations and real data, demonstrating its broad applicability.

bioinformatics↗

bioRxiv2022

More than Mycobacterium tuberculosis: specific site-of-disease microbial communities, functional capacities, and their distinct clinical profiles in tuberculous lymphadenitis

BackgroundLymphadenitis is the most common extrapulmonary tuberculosis (EPTB) manifestation and a major cause of death. The microbiome is important to human health but uninvestigated in EPTB. We profiled the site-of-disease lymph node microbiome in tuberculosis lymphadenitis (TBL). MethodsFine needle aspiration biopsies (FNABs) were collected from 159 pre-treatment presumptive TBL patients in Cape Town, South Africa. 16S Illumina MiSeq rRNA gene sequencing was done. ResultsWe analysed 89 definite TBLs (dTBLs) and 61 non-TBLs (nTBLs), which had similar -but different {beta}-diversities (p=0.001). Clustering identified five lymphotypes prior to TB status stratification: Mycobacterium-, Prevotella- and Streptococcus-dominant lymphotypes were more frequent in dTBLs whereas a Corynebacterium-dominantlymphotype and a fifth lymphotype (no dominant taxon) were more frequent in nTBLs. When restricted to dTBLs, clustering identified a Mycobacterium-dominant lymphotype with low -diversity and other non-Mycobacterium-dominated lymphotypes (termed Prevotella-Corynebacterium and Prevotella-Streptococcus). The Mycobacterium dTBL lymphotype was associated with HIV-positivity and clinical features characteristic of severe lymphadenitis (e.g., node size). dTBL microbial communities were enriched with potentially proinflammatory microbial short chain fatty acid metabolic pathways (propanoate, butanoate) vs. those in nTBLs. 11% (7/61) of nTBLs had Mycobacterium reads. ConclusionsTBL at the site-of-disease is not microbially homogenous and distinct microbial community clusters exist that are associated with different immunomodulatory potentials and clinical characteristics. Non-Mycobacterium-dominated dTBL lymphotypes, which contain taxa potentially targeted by TB treatment, represent less severe potentially earlier stage disease. These investigations lay foundations for studying the microbiomes role in lymphatic TB and the long-term clinical significance of lymphotypes requires prospective evaluation.

molecular biology↗

bioRxiv2021

Human gut derived Anaerotruncus colihominis ameliorates experimental autoimmune encephalomyelitis

BackgroundThe gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotics effects are not understood. Furthermore, there is no consensus on the gut derived bacterial strains that drive neuroinflammation in multiple sclerosis. ResultsHere we characterized the gut microbiome of untreated and vancomycin treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE and that this protective effect is mediated via the microbiota. Notably, we observed increased abundance of bacteria known to be strong inducers of regulatory T cells, including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE, as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis, a butyrate producer, which had a positive correlation with disease severity. We found that Anaerotruncus colihominis ameliorates EAE and this is associated with induction of ROR{gamma}t+ regulatory T cells in the mesenteric lymph nodes. ConclusionsWe identified vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease.

microbiology↗

bioRxiv2021

Gut IgA Enhances Systemic IgG Responses to Pneumococcal Vaccines Through the Commensal Microbiota

The gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines. However, it is unknown whether this effect involves IgA, a mucosal antibody that coats intestinal microbes. Here we found that gut IgA increased peripheral IgG responses to pneumococcal vaccines, as these responses were profoundly impaired in mice with global or mucosa-restricted IgA deficiency. The positive effect of IgA on vaccine-induced IgG production implicated gut bacteria. Indeed, IgG responses to pneumococcal vaccines were also defective in ex-germ free mice recolonized with gut microbes from mouse or human IgA-deficient donors. IgA exerted this IgG-enhancing effect by constraining the systemic translocation of intestinal commensal antigens, which caused chronic immune activation, including T cell overexpression of programmed death-1. This immune inhibitory receptor hindered vaccine-specific IgG production by eliciting functional B cell unresponsiveness, which was reverted by anti-programmed death-1 treatment. Thus, gut IgA is functionally interconnected with systemic IgG via intestinal microbes.

immunology↗

bioRxiv2020

Quantification of discrete gut bacterial strains following fecal transplantation for recurrent Clostridioides difficile infection demonstrates long-term stable engraftment in non-relapsing recipients

Fecal Microbiota Transplantation (FMT), while successful for the treatment of recurrent Clostridioides difficile (rCDI) infection, lacks a quantitative identification of the discrete bacterial strains that transmit and stably engraft in recipients, and their association with clinical outcomes. Using >1,000 unique bacterial strains isolated and sequenced from a combination of 22 FMT donors and recipients, we develop a statistical approach Strainer to detect and track sequenced bacterial strains from low depth metagenomic sequencing data. On application to 14 FMT interventions, we detect stable and high engraftment of [~]71% of gut microbiota strains in recipients at even 5-years post-transplant, a remarkably durable therapeutic from a single administration. We found differential transmission and engraftment efficacy across bacterial taxonomic groups over short and long-time scales. Although [~]80% of the original pre-FMT recipient strains were eliminated by the FMT, those strains that remain persist even 5 years later, along with newer strains acquired from the environment. The precise quantification of donor bacterial strains in recipients independently explained the clinical outcomes of early and late relapse. Our framework identifies the consistently engrafting discrete bacterial strains for use in Live Biotherapeutic Products (LBP) as a safer, scalable alternative to FMT and enables systematic evaluation of different FMT and LBP study designs.

immunology↗

bioRxiv2019

Defined microbiota transplant restores Th17/RORtγ+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases, where clinical trials of fecal microbiota transplant have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells and a deficit in the tolerogenic ROR{gamma}t+ Treg cell subset. Transplanting healthy donor-derived microbiota into mice colonized with human IBD microbiotas lead to induction of ROR{gamma}t+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohns disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, correlated with a reduction in Th17 cells.

immunology↗

bioRxiv2018

Gut microbiota density influences host physiology and is shaped by host and microbial factors

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohns disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

microbiology↗

bioRxiv2018

Inflammatory bowel disease microbiotas alter gut CD4 T-cell homeostasis and drive colitis in mice

To examine the functional contribution of Inflammatory Bowel Disease (IBD) microbes to immune homeostasis and colitis, we colonized unchallenged and colitis-susceptible germ-free mice with over twenty human intestinal microbiotas from healthy and IBD donors. Compared to healthy microbiotas, IBD microbiotas led to expanded ROR{gamma}t+Th17 cells and reduced ROR{gamma}t+Treg in the gut of unchallenged gnotobiotic mice and increased disease severity in colitis-susceptible mice. The proportions of ROR{gamma}t+Th17 and ROR{gamma}t+Treg induced by each microbiota were highly predictive of the human disease status and strongly correlated with disease severity in colitis-susceptible mice colonized with the same human microbiotas. The transmittable functional potential of IBD microbes suggests a mechanism for a microbial contribution to IBD pathogenesis and a potential route for its treatment and prevention.

immunology↗

bioRxiv2018

Diet Modifies Colonic Microbiota and CD4+ T cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo, we generated a mouse model in which IL-23 was conditionally expressed by CX3CR1+ myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4+ T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag-/- mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4+ T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

immunology↗

bioRxiv2017

Deciphering the combinatorial influence of diet and the microbiota on experimental colitis

Background & AimsThe complex interactions between diet and the microbiota that influence mucosal inflammation and inflammatory bowel disease are poorly understood. Experimental colitis models provide the opportunity to control and systematically perturb diet and the microbiota in parallel to quantify the contributions between multiple dietary ingredients and the microbiota on host physiology and colitis.\n\nMethodsTo examine the interplay of diet and the gut microbiota on host health and colitis, we fed over 40 different diets with varied macronutrient sources and concentrations to specific pathogen free or germ free mice either in the context of healthy, unchallenged animals or colitis models (dextran sodium sulfate (DSS) and T cell transfer).\n\nResultsDiet influenced physiology in both health and colitis across all models, with the concentration of protein and psyllium fiber having the most profound effects. Increasing dietary protein elevated gut microbial density and worsened DSS colitis severity. Depleting gut microbial density by using germ-free animals or antibiotics negated the effect of a high protein diet. Psyllium fiber influenced host physiology and attenuated colitis severity through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary protein and psyllium fiber in parallel explain most variation in gut microbial density, intestinal permeability, and DSS colitis severity, and changes in one ingredient can be offset by changes in the other.\n\nConclusionsOur results demonstrate the importance of examining complex mixtures of nutrients to understand the role of diet in intestinal inflammation.

microbiology↗