Biology subjects

Silverman, M. A.

Publications and source records attributed to Silverman, M. A..

6 recordsLinked to original sources

bioRxiv2025

Development of charged nanobubble-containing media and their effects on iPSC-derived cell cultures

Nanobubbles (NBs) are gas-filled spherical structures less than 1 {micro}m in diameter, characterized by high surface charge, long-term stability, and the ability to generate bactericidal hydroxyl radicals upon collapse. Although these unique properties enable their extensive applications, including wastewater treatment, their cell biological applications at neutral pH remain limited by difficulties in maintaining stability and surface charge. Here, we succeeded in generating both positively and negatively charged NBs, achieving high zeta potentials in human iPSC-derived neural progenitor cell (NPC) and neuron culture media (pH 7.4). Similar to their bactericidal effects, NBs induced cell death in iPSC-derived cells, with positively charged NBs showing stronger cytotoxicity than negatively charged ones. This may be because the cell membrane carries a negative charge, making positively charged NBs more likely to approach and interact with the membrane, or because positively charged nanobubbles exhibit stronger radical generation. In future, we aim to elucidate the molecular biological mechanisms underlying NB-induced cell death and to contribute to the potential application of nanobubbles in regenerative medicine. This study will serve as an initial step toward that goal.

bioengineering↗

bioRxiv2025

Microbial succession at weaning is guided by microbial metabolism of host glycans.

The weaning transition from a milk-based to a solid-food diet supports critical developmental changes to the intestinal microbiome and immune system. However, the specific microbial and host features that influence microbial succession at weaning are not well understood. Here, we developed a simple approach to investigate the complex dynamics of microbial succession during weaning by co-housing gnotobiotic mice colonized with the defined pre-weaning community PedsCom and the adult-derived consortium OMM12. As expected, co-housing PedsCom mice with OMM12 recapitulated microbial succession at weaning and induced immune system maturation in PedsCom mice. Unexpectedly, we found that the OMM12 microbes with the highest host glycan utilization profiles were the most adept colonizers of PedsCom mice. Genomic analysis confirmed that PedsCom is deficient in the carbohydrate-active enzymes responsible for degrading host-derived glycans, including mucins, compared to adult-derived consortia. We validated a role for glycan utilization in vivo by demonstrating that the mucus-degrading commensal microbe Akkermansia muciniphila critically depends on the metabolism of mucin glycans for colonization of PedsCom mice. These findings highlight the importance of host-derived glycans in shaping microbial communities during the weaning transition and suggest host glycans as novel targets to modulate intestinal microbial populations, introduce beneficial probiotics, and enhance immune system development during weaning.

microbiology↗

bioRxiv2024

Comparison of gnotobiotic communities reveals unexpected amino acid metabolism by the pre-weaning microbiome.

The intestinal microbiome during infancy and childhood has distinct compositions and metabolic functions to that of adults. We recently published a gnotobiotic mouse model of the pre-weaning microbiome (PedsCom), which retains a pre-weaning configuration during the transition from a milk-based diet to solid foods and leads to a stunted immune system and susceptibility to enteric infection. Here we compared the phylogenetic and metabolic relationship of the PedsCom consortium to the adult-derived gnotobiotic communities, Altered Schaedler Flora and Oligo-MM12. We find that PedsCom contains several unique functions relative to adult-derived mouse consortia. In particular, amino acid degradation metabolic modules are more prevalent among PedsCom isolates, which is in line with the ready availability of these nutrients in milk. Indeed, metabolomic analysis showed significantly lower levels of free amino acids in the intestinal contents of adult PedsCom colonized mice versus Oligo-MM12 controls. Thus, enhanced amino acid metabolism is a prominent feature of the pre-weaning microbiome that may facilitate design of early life microbiome interventions.

microbiology↗

bioRxiv2024

Early-life exposures to specific commensal microbes prevent type 1 diabetes.

Early-life disruptions of the gut microbiome have long-lasting impacts on the risk of developing autoimmune diseases. How the composition of the early-life microbiota contributes to autoimmunity and whether manipulating it can prove therapeutically beneficial remains largely unexplored. Here we demonstrate that a simple consortium of nine early-life commensal bacteria (PedsCom) prevents type 1 diabetes (T1D) in diabetes-susceptible NOD mice. Remarkably, we find that this protection is completely dependent upon early-life colonization. During this critical time window of early-life colonization and immune development, specific microbes unexpectedly translocate from the gut to peripheral tissues and induce the tolerogenic responses required for T1D protection. These findings highlight how the timing and localization of microbial interactions during a pivotal stage of immune development contribute to protection from T1D. Altogether, these findings suggest an opportunity to develop microbial therapies for human infants to prevent autoimmune diseases. One sentence summaryA defined consortium of early-life microbes shapes immune development and prevents type 1 diabetes.

immunology↗

bioRxiv2022

Modulation of adaptive immune responses by Akkermansia muciniphila is restricted to an early life window in NOD mice

Early life microbiota drive immune system development and influence risk for immune dysfunction later in life, including the development of type 1 diabetes (T1D). Which specific early-life microbes modulate diabetes risk and the timing of these critical interactions are not well understood. To address this gap in knowledge, we screened for microbes that induce systemic IgG1 responses in young NOD mice. We isolated a strain of Akkermansia muciniphila that potently induces systemic IgG1 antibodies and peripheral regulatory T cells (pTregs). Since this mucus-degrading commensal protects NOD mice from T1D and is associated with lower risk of developing T1D in children, we investigated how A. muciniphila impacts early-life host-commensal interactions using gnotobiotic NOD mice colonized with a defined 9-member bacterial consortium that models the early life microbiome. We find that A. muciniphila potently induces pTregs and enhances antibody responses to other commensal microbes. Remarkably, these effects only occur when A. muciniphila colonizes NOD mice prior to weaning, establishing that the specific window of exposure to A. muciniphila shapes adaptive immune system development in diabetes-susceptible NOD mice. This time dependence provides important evidence that early-life exposure may enhance microbiota-based therapies to prevent T1D. One Sentence SummaryAkkermansia muciniphila induces peripheral Tregs and enhances antibody responses to itself and other commensals during an early life window.

immunology↗

bioRxiv2022

Arresting microbiome development limits immune system maturation and resistance to infection.

Disruptions to the intestinal microbiome during weaning lead to long-term negative effects on host immune function. However, the critical host-microbe interactions occurring during weaning required for healthy immune system development remain poorly understood. We find that restricting microbiome maturation during weaning leads to stunted immune system development and increased susceptibility to enteric infection. We developed a gnotobiotic mouse model of the early-life microbiome designated as Pediatric Community (PedsCom). This nine-member consortium of microbes derived from intestinal microbiomes of preweaning mice stably colonized germfree adult mice and was efficiently transmitted to offspring for multiple generations. Unexpectedly, the relative abundance of PedsCom microbes were largely unaffected by the transition from a milk-based to a fiber rich solid food diet. PedsCom mice developed less peripheral regulatory T cells and Immunoglobulin A, hallmarks of microbiota-driven immune system development. Consistent with defects in maturation, adult PedsCom mice retain high susceptibility to salmonella infection characteristic of young mice and humans. Altogether, our work illustrates how the post-weaning transition in intestinal microbiome composition contributes to normal immune maturation and protection from enteric infection. Accurate modelling of the pre-weaning microbiome provides a window into the microbial requirements of healthy immune development and suggests an opportunity to design microbial interventions at weaning to improve immune system development in human infants. One Sentence SummaryArresting microbiome development stunts immune ontogeny

immunology↗