Biology subjects

Whistler, C. A.

Publications and source records attributed to Whistler, C. A..

6 recordsLinked to original sources

bioRxiv2025

Dynamic flexibility of the gut microbiota to morphine disturbance enables escape from the stable dysbiosis associated with addiction-like behavior

Although opioids are effective analgesics, they can lead to problematic drug use behaviors that underlie opioid use disorder (OUD). Opioids also drive gut microbiota dysbiosis which is linked to altered opioid responses tied to OUD. To interrogate the role of the gut microbiota in a mouse model of OUD, we used a longitudinal paradigm of voluntary oral morphine self-administration to capture multiple facets of drug seeking and preserve both individual behavioral response and gut microbiota variation to examine associations between these two variables. After prolonged morphine consumption, only a subset of mice transitioned to a state we define statistically as compulsive. In compulsive mice, morphine fragmented the microbiota networks which subsequently reorganized to form robust novel connections. In contrast, the communities of non-compulsive mice also changed but were highly interconnected during morphine disturbance and maintained more continuity post morphine suggesting dynamic flexibility. Compulsive mice displayed a greater loss of functional diversity and a shift towards a new stable state dominated by potential pathobionts, whereas non-compulsive mice better preserved genera associated with gut health and broader functional diversity. These findings highlight how persistent and stable gut microbiota dysbiosis aligns with long-term behavioral changes underlying OUD, potentially contributing to relapse.

microbiology↗

bioRxiv2024

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

systems biology↗

bioRxiv2023

Deletion of arrestin-3 does not alter compulsive morphine-seeking behavior in an oral operant self-administration paradigm

Opioid drugs are potent analgesics that mimic the endogenous opioid peptides, endorphins and enkephalins, by activating the {micro}-opioid receptor. Opioid use is limited by side effects, including significant risk of opioid use disorder. Improvement of the effect/side effect profile of opioid medications is a key pursuit of opioid research, yet there is no consensus on how to achieve this goal. One hypothesis is that the degree of arrestin-3 recruitment to the {micro}-opioid receptor impacts therapeutic utility. However, it is not clear whether increased or decreased interaction of the {micro}-opioid receptor with arrestin-3 would reduce compulsive drug-seeking. To examine this question, we utilized three genotypes of mice with varying abilities to recruit arrestin-3 to the {micro}-opioid receptor in response to morphine in a novel longitudinal operant self-administration model. We demonstrate that arrestin-3 knockout and wild type mice have highly variable drug-seeking behavior with few genotype differences. In contrast, in mice where the {micro}-opioid receptor strongly recruits arrestin-3, drug-seeking behavior is much less varied. We created a quantitative method to define compulsivity in drug-seeking and found that mice lacking arrestin-3 were more likely to meet the criteria for compulsivity whereas mice with enhanced arrestin-3 recruitment did not develop a compulsive phenotype. Our data suggest that opioids that engage both G protein and arrestin-3, recapitulating the endogenous signaling pattern, will reduce abuse liability.

animal behavior and cognition↗

bioRxiv2023

Inoviridae prophage dynamics during diversification, succession and Atlantic invasion of Pacific-native Vibrio parahaemolyticus.

The epidemiology of Vibrio parahaemolyticus, the leading cause of seafood-borne bacterial gastroenteritis of humans world-wide, dramatically changed in the United States following the establishment of a Pacific native lineage called sequence type (ST) 36 in the Atlantic. In this study we used phylogeography based on traceback to environmental source locations and comparative genomics to identify features that promoted evolution, dispersal, and competitive dominance of ST36. The major genomic differentiation and competitive success of ST36 was associated with a striking succession of filamentous prophage in the family Inoviridae (inoviruses), including loss of an inovirus prophage that had been maintained for decades in the endemic north Pacific population. Subsequently, at least five distinct progenitors arising from this diversification translocated from the Pacific into the Atlantic and established four geographically defined clonal subpopulations with remarkably low migration or mixing. Founders of two prevailing Atlantic subpopulations each acquired new stable and diagnostic inoviruses while other subpopulations that apparently declined did not. Broader surveys indicate inoviruses are common and active among the global population of V. parahaemolyticus and though inovirus replacements, such as in ST36, appear to be infrequent, they are notable in pathogenic lineages that dispersed. ImportanceAn understanding of the processes that contribute to emergence of pathogens from environmental reservoirs is critical as changing climate precipitates pathogen evolution and population expansion. Phylogeographic analysis of Vibrio parahaemolyticus hosts combined with analysis of their Inoviridae phage resolved ambiguities of diversification dynamics which preceded successful Atlantic invasion by the epidemiologically predominant ST36 lineage. It has been established experimentally that filamentous phage can limit host recombination, but here we show that phage loss is linked to rapid bacterial host diversification during epidemic spread in natural ecosystems alluding to a potential role for ubiquitous inoviruses in the adaptability of pathogens. This work paves the way for functional analyses to define the contribution of inoviruses in the evolutionary dynamics of environmentally transmitted pathogens.

microbiology↗

bioRxiv2017

Bacterial community profiles and Vibrio parahaemolyticus abundance in individual oysters and their association with estuarine ecology

Oysters naturally harbor the human gastric pathogen Vibrio parahaemolyticus, but the nature of this association is unknown. Because microbial interactions could influence the accumulation of V. parahaemolyticus in oysters, we investigated the composition of the microbiome in water and oysters at two ecologically unique sites in the Great Bay Estuary, New Hampshire using 16s rRNA profiling. We then evaluated correlations between bacteria inhabiting the oyster with V. parahaemolyticus abundance quantified using a most probable number (MPN) analysis. Even though oysters filter-feed, their microbiomes were not a direct snapshot of the bacterial community in overlaying water, suggesting they selectively accumulate some bacterial phyla. The microbiome of individual oysters harvested more centrally in the bay were relatively more similar to each other and had fewer unique phylotypes, but overall more taxonomic and metabolic diversity, than the microbiomes from tributary-harvested oysters that were individually more variable with lower taxonomic and metabolic diversity. Oysters harvested from the same location varied in V. parahaemolyticus abundance, with the highest abundance oysters collected from one location. This study, which to our knowledge is the first of its kind to evaluate associations of V. parahaemolyticus abundance with members of individual oyster microbiomes, implies that sufficient sampling and depth of sequencing may reveal microbiome members that could impact V. parahaemolyticus abundance.

microbiology↗

bioRxiv2017

Parallel evolution of two clades of a major Atlantic endemic Vibrio parahaemolyticus pathogen lineage by independent acquisition of related pathogenicity islands

Shellfish-transmitted Vibrio parahaemolyticus infections have recently increased from locations with historically low disease incidence, such as the Northeast United States (US). This change coincided with a bacterial population shift towards human pathogenic variants occurring in part through the introduction of several Pacific native lineages (ST36, ST43 and ST636) to near-shore areas off the Atlantic coast of the Northeast US. Concomitantly, ST631 emerged as a major endemic pathogen. Phylogenetic trees of clinical and environmental isolates indicated that two clades diverged from a common ST631 ancestor, and in each of these clades, a human pathogenic variant evolved independently through acquisition of distinct Vibrio pathogenicity islands (VPaI). These VPaI differ from each other and bear little resemblance to hemolysin-containing VPaI from isolates of the pandemic clonal complex. Clade I ST631 isolates either harbored no hemolysins, or contained a chromosome I-inserted island we call VPaI{beta} that encodes a type three secretion system (T3SS2{beta}) typical of Trh hemolysin-producers. The more clinically prevalent and clonal ST631 clade II had an island we call VPaI{gamma} that encodes both tdh and trh and that was inserted in chromosome II. VPaI{gamma} was derived from VPaI{beta} but with some additional acquired elements in common with VPaI carried by pandemic isolates, exemplifying the mosaic nature of pathogenicity islands. Genomics comparisons and amplicon assays identified VPaI{gamma}-type islands containing tdh inserted adjacent to the ure cluster in the three introduced Pacific and most other emergent lineages. that collectively cause 67% of Northeast US infections as of 2016.\n\nIMPORTANCEThe availability of three different hemolysin genotypes in the ST631 lineage provided a unique opportunity to employ genome comparisons to further our understanding of the processes underlying pathogen evolution. The fact that two different pathogenic clades arose in parallel from the same potentially benign lineage by independent VPaI acquisition is surprising considering the historically low prevalence of community members harboring VPaI in waters along the Northeast US Coast that could serve as the source of this material. This illustrates a possible predisposition of some lineages to not only acquire foreign DNA but also to become human pathogens. Whereas the underlying cause for the expansion of V. parahaemolyticus lineages harboring VPaI{gamma} along the US Atlantic coast and spread of this element to multiple lineages that underlies disease emergence is not known, this work underscores the need to define the environment factors that favor bacteria harboring VPaI in locations of emergent disease.

evolutionary biology↗