Biology subjects

Leitman, M.

Publications and source records attributed to Leitman, M..

4 recordsLinked to original sources

bioRxiv2025

A data-driven model of macrophage polarization states reveals an IFN macrophage signature in active Crohn's disease

Macrophages are key innate immune cells responsible for initiating and coordinating immune responses. A major determinant of macrophage function is their tissue-context-dependent polarization state, regulated by the cytokines present in the tissue microenvironment. Yet, the capability of characterizing macrophage polarization states in clinical studies remains limited. Here, we used a defined set of cytokines to polarize human PBMC derived macrophages and determine their transcriptional signatures and stimulus responsiveness. The resultant atlas of transcriptional signatures for human macrophage polarization states was applied to a dataset of intestinal biopsies from Crohns disease patients and healthy controls. Our analysis identified a dominant population of IFN{gamma}-polarized macrophages in areas of active Crohns intestinal inflammation and a loss of wound healing IL-4-, IL-10- and IL-13-polarized macrophages. This study demonstrates that in vitro datasets of macrophages in defined conditions can be leveraged to interpret the functionality of cells transcriptional profiled in clinical studies.

immunology↗

bioRxiv2025

Transitions in human gut viral communities from ancient to industrialized societies

The composition and function of the human gut microbial community (the microbiome) have changed substantially over millennia, with implications for human health. While microbiome research has focused primarily on bacterial dynamics, the long-term history of gut viral communities (the virome) remains largely unexplored, despite their crucial role in shaping bacterial populations. We analyzed gut viromes from 14 pre-modern human coprolites (1301 BCE-1400s CE), as well as 502 non-industrialized and 492 industrialized contemporary human fecal samples. We found that, from pre-modern to contemporary and industrialized populations, human gut viral communities have become more similar in gene content, increasingly dominated by temperate lifestyles, and more supportive of bacterial pathogenicity. These synergistic ecological shifts suggest that long-term changes, especially with industrialization, have fundamentally altered the gut virome, likely affecting human health. These insights into historical shifts in gut viral community and function open potential avenues for ecologically grounded therapeutics to enhance gut microbiome resilience.

microbiology↗

bioRxiv2024

The Association Between Prevotella copri and Advanced Fibrosis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), driven by obesity and metabolic syndrome, is increasingly prevalent and a significant contributor to liver fibrosis, cirrhosis, and liver-related mortality. Emerging research implicates the gut microbiome as a critical player in MASLD progression, yet specific microbial drivers remain poorly understood. Here, we explore the role of Prevotella copri (P. copri) in MASLD progression through both human patient cohorts and a mouse model of diet-induced obesity. Using 16S rRNA sequencing, we identified elevated P. copri abundance in MASLD patients with advanced fibrosis, linked with significant shifts in microbial diversity and bacterial network connectivity. To investigate causality, experimental colonization of P. copri in mice on a high-fat diet worsened MASLD progression, with P. copri-colonized mice showing significant increases in hepatic steatosis, liver triglyceride accumulation, and body weight, independent of caloric intake. At the molecular level, P. copri colonization downregulated key lipid metabolism genes, such as Carnitine Palmitoyltransferase 1, Diacylglycerol Acyltransferase, and Adipose Triglyceride Lipase, and impaired tight intestinal junction integrity through the downregulation of cluadins, occludin, and zonula occludens-1. Collectively, our findings position P. copri as a possible driver of MASLD progression by promoting hepatic steatosis through lipid and triglyceride accumulation and fibrosis through decreased tight junction integrity. These insights suggest a promising therapeutic avenue to target specific microbial signatures like P. copri to curb MASLD progression and mitigate the associated risk of advanced fibrosis.

microbiology↗

bioRxiv2024

Microbial Differences Accurately Identifies Global SERT KO Phenotype in Mice

Altered serotonin signaling is a well-established contributor to depression, with the serotonin transporter gene (SERT) playing a critical role in regulating serotonin reuptake. Mice lacking SERT (SERT -/-) serve as a robust model for depression, exhibiting significant depressive-like behaviors compared to littermate wild-type (SERT +/+) controls. In this study, we aimed to determine the relationship between gut microbiota composition and depressive behaviors in SERT -/- mice. Behavioral assays, including the Forced Swim Test (FST) and Tail Suspension Test (TST), confirmed that SERT -/- mice exhibited significantly increased immobility times compared to SERT +/+ mice (FST: p = 0.004; TST: p = 0.080), consistent with a depressive phenotype. Utilizing littermate controls, shotgun metagenomic sequencing of fecal samples revealed significant differences in alpha diversity between the two groups of mice, as measured by the Shannon entropy index (p = 0.05). Additionally, our bacterial co-occurrence network analysis uncovered distinct structural differences in microbial interactions between SERT -/- and SERT +/+ mice (p = 0.001), suggesting shifts in microbiome stability and functionality between the groups. We created a microbial depression score utilizing the top five bacteria taxa that were differentially abundant between SERT -/- and SERT +/+ mice: Clostridium sp. MD294, Acetatifactor MGBC165152, Desulfovibrio MGBC129232, Oscillibacter MGBC161747, and Schaedlerella MGBC000001. This microbial depression score correlated strongly with immobility times in the FST (r = 0.705, p < 0.0006) and TST (r = 0.401, p < 0.09). A random forest classifier based on these taxa accurately distinguished SERT -/- from SERT +/+ mice (accuracy = 0.82). These findings suggest that gut microbial species composition is highly associated with depressive-like behaviors in SERT -/- mice, likely via alterations in serotonin signaling pathways, and may offer potential targets for microbiome-based interventions in depression.

microbiology↗