Search

Background: Parkinson's disease (PD) has been consistently linked to alterations within the gut microbiome. Objective: Our goal was to identify microbial features associated with PD incidence and progression. Methods: Metagenomic sequencing was used to characterize taxonomic and functional changes to the PD microbiome and to explore their relation to bacterial metabolites and disease progression. Motor and non‐motor symptoms were tracked using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) and levodopa equivalent dose across ≤5 yearly study visits. Stool samples were collected at baseline for metagenomic sequencing (176 PD, 100 controls). Results: PD‐derived stool samples had reduced intermicrobial connectivity and seven differentially abundant species compared to controls. A suite of bacterial functions differed between PD and controls, including depletion of carbohydrate degradation pathways and enrichment of ribosomal genes. Faecalibacterium prausnitzii‐specific reads contributed significantly to more than half of all differentially abundant functional terms. A subset of disease‐associated functional terms correlated with faster progression of MDS‐UPDRS part IV and separated those with slow and fast progression with moderate accuracy within a random forest model (area under curve = 0.70). Most PD‐associated microbial trends were stronger in those with symmetric motor symptoms. Conclusion: We provide further evidence that the PD microbiome is characterized by reduced intermicrobial communication and a shift to proteolytic metabolism in lieu of short‐chain fatty acid production, and suggest that these microbial alterations may be relevant to disease progression. We also describe how our results support the existence of gut‐first versus brain‐first PD subtypes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Enteric pathogens navigate distinct regional microenvironments within the intestine that cue important adaptive behaviors. We investigated the response of Citrobacter rodentium, a model of human pathogenic Escherichia coli infection in mice, to regional gastrointestinal pH. We found that small intestinal pH (4.4–4.8) triggered virulence gene expression and altered cell morphology, supporting initial intestinal attachment, while higher pH, representative of C. rodentium's replicative niches further along the murine intestine, supported pathogen growth. Gastric pH, a key barrier to intestinal colonization, caused significant accumulation of intra-bacterial reactive oxygen species (ROS), inhibiting growth of C. rodentium and related human pathogens. Within-host adaptation increased gastric acid survival, which may be due to a robust acid tolerance response (ATR) induced at colonic pH. However, the intestinal environment changes throughout the course of infection. We found that murine gastric pH decreases postinfection, corresponding to increased serum gastrin levels and altered host expression of acid secretion-related genes. Similar responses following Salmonella infection may indicate a protective host response to limit further pathogen ingestion. Together, we highlight interlinked bacterial and host adaptive pH responses as an important component of host–pathogen coevolution. Enteric pathogens navigate distinct regional micro-environments along the intestinal tract. This study shows that intraluminal intestinal pH is an important spatial driver of virulence and adaptive behavior during C. rodentium infection, and is manipulated by the host in response to pathogen invasion. [ABSTRACT FROM AUTHOR]

With the global prevalence of allergic disease continuing to rise at an alarming rate, the need for effective and safe therapeutics is paramount. Given the critical role of the early-life microbiota on immune development, emerging research suggests the potential use of live biotherapeutic products (LBP) for the prevention and treatment of childhood allergy. However, findings are limited and inconsistent. Therefore, the present review critically evaluates the current animal and human data on the therapeutic value of LBPs in allergy, the underlying immunological mechanisms by which LBPs may mediate allergy susceptibility, limitations of the current research that need to be addressed, and future research directions. Accordingly, LBPs may protect against allergic disease through several immunological and physiological mechanisms during early-life, including regulation of Th1/Th2 balance, SCFA-induced activation of GPR41/43 and HDAC inhibition, and maturation of epithelial barrier integrity. Taken together, current findings indicate powerful immunomodulatory properties of LBPs on allergic immune response, with LBPs offering exciting potential as a novel therapeutic tool for childhood allergy. However, the efficacy of LBPs in allergy is complex and influenced by many population and methodological factors, resulting in varied therapeutic benefits. While research thus far has focused on traditional probiotic strains, greater investigation into microbial consortiums selected from the microbiota of non-allergic infants may provide greater promise as a therapeutic tool for allergic disease. Further investigation, particularly into long-term efficacy, strain-specific effects, optimal supplementation regimes, and use of multi-strain consortiums, is necessary before findings can be translated into clinical applications to tackle childhood allergic disease. [ABSTRACT FROM AUTHOR]

Background: Bacterial virulence-associated type III secretion system (T3SS) assembly requires a dedicated enzyme to penetrate peptidoglycan (PG).Results: We structurally characterized a T3SS PG-lytic enzyme, identified catalytically important residues, and characterized its activity.Conclusion: The active site is similar to lysozymes and lytic transglycosylases and interaction with the T3SS enhances activity.Significance: Structural information is critical for development of drugs targeting T3SS PG-lytic enzymes.The Gram-negative bacterium enteropathogenic Escherichia coli uses a syringe-like type III secretion system (T3SS) to inject virulence or “effector” proteins into the cytoplasm of host intestinal epithelial cells. To assemble, the T3SS must traverse both bacterial membranes, as well as the peptidoglycan layer. Peptidoglycan is made of repeating N-acetylmuramic acid and N-acetylglucosamine disaccharides cross-linked by pentapeptides to form a tight mesh barrier. Assembly of many macromolecular machines requires a dedicated peptidoglycan lytic enzyme (PG-lytic enzyme) to locally clear peptidoglycan. Here we have solved the first structure of a T3SS-associated PG-lytic enzyme, EtgA from enteropathogenic E. coli. Unexpectedly, the active site of EtgA has features in common with both lytic transglycosylases and hen egg white lysozyme. Most notably, the β-hairpin region resembles that of lysozyme and contains an aspartate that aligns with lysozyme Asp-52 (a residue critical for catalysis), a conservation not observed in other previously characterized lytic transglycosylase families to which the conserved T3SS enzymes had been presumed to belong. Mutation of the EtgA catalytic glutamate, Glu-42, conserved across lytic transglycosylases and hen egg white lysozyme, and this differentiating aspartate diminishes type III secretion in vivo, supporting its essential role in clearing the peptidoglycan for T3SS assembly. Finally, we show that EtgA forms a 1:1 complex with the building block of the polymerized T3SS inner rod component, EscI, and that this interaction enhances PG-lytic activity of EtgA in vitro, collectively providing the necessary strict localization and regulation of the lytic activity to prevent overall cell lysis.

Background: The microbiome has a pivotal role in intestinal health, and nutrition has a major role shaping its structure. Enteral deprivation, in which no oral/enteral nutrition is administered, is common in hospitalized/gastrointestinal patients. The dynamics that enteral deprivation exerts on the microbial community, specifically in the small intestine, are not well understood. Methods: Enteral deprivation was modeled with exclusive parenteral nutrition (EPN) mice. Mice were allocated to receive either EPN or saline and chow (control) and euthanized after 0, 2, 4, or 6 days. DNA was extracted from jejunum, ileum, and colon content. 16S sequencing was used to compare changes in microbial communities between groups. Functional pathways were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. Results: EPN‐treated mice showed community changes throughout the intestine. Beta diversity in colon showed clear separation between the groups (Bray‐Curtis, P < 0.001). Time‐dependent dynamics were seen in ileal but not jejunal samples. Alpha diversity was lower in the colon of EPN mice compared with control/baseline mice (Chao1, P < 0.01) but not in ileum/jejunum. Progressive loss of single‐taxon domination was seen, most notably in the small intestine. This was accompanied by increases/decreases in specific taxa. A clear separation was seen in the functional capacity of the community between fed and enterally deprived mice at the ileum and colon, which was observed early on. Conclusions: Enteral deprivation disturbs the microbial community in a spatial and dynamic manner. There should be further focus on studying the effect of these changes on the host. [ABSTRACT FROM AUTHOR]