John R. Kirby

Background: Cerebrovascular dysfunction contributes to mild cognitive impairment (MCI), but the complementary value of arterial spin labeling (ASL)‐derived cerebral blood flow (CBF) and breath‐hold cerebrovascular reactivity (CVR) for multivariate MRI classification remains unclear. Purpose/Hypothesis: To determine whether combining CBF and CVR improves multivariate classification of clinically defined MCI compared with either metric alone and whether classifier‐derived scores relate to cognitive performance. Study Type: Retrospective case–control study. Population/Subjects: Eighty‐five older adults, including 37 participants with clinically defined MCI (73.8 ± 5.1 years; 21 male) and 48 cognitively unimpaired (CU) controls (69.2 ± 7.1 years; 14 male). Field Strength/Sequence: 3 T MRI; 3D pseudo‐continuous arterial spin labeling (pCASL), multiband multi‐echo (MBME) echo planar imaging (EPI) blood oxygenation level dependent (BOLD) functional MRI breath‐hold CVR imaging, 3D T1‐weighted magnetization‐prepared rapid gradient‐echo, and 3D T2‐weighted fast spin‐echo (FSE). Assessment: Whole‐brain searchlight multivariate pattern analysis using a linear logistic regression classifier evaluated MCI versus CU subjects from CBF‐only, CVR‐only, and combined CBF + CVR features. Regional performance was summarized using the 400‐region Schaefer atlas. Decision scores from the combined model were correlated with delayed recall and Trail Making Test (TMT) Part A and B performance. Statistical Tests: Permutation testing assessed classifier significance. Linear regression evaluated cognitive associations. False discovery rate correction was applied for multiple comparisons. Statistical significance was defined as p < 0.05. Results: Mean regional AUC values across the 10 highest‐performing regions ranged from 0.740 to 0.766 for CBF, 0.753 to 0.805 for CVR, and 0.816 to 0.830 for the combined CBF + CVR model. Compared with the better‐performing single‐metric model, the combined model improved regional classification performance by ΔAUC = 0.020–0.062. Five regions showed nominal paired‐permutation significance, although none remained significant after false discovery rate correction. Higher decision scores were associated with poorer delayed recall (partial r = −0.353 to −0.422) and poorer TMT Parts A and B performance (partial r = −0.243 to −0.390). Data Conclusion: Combining CBF and CVR improved multivariate discrimination of clinically defined MCI relative to either metric alone and identified clinically relevant posterior cortical neurovascular patterns associated with memory and executive dysfunction. Evidence Level: 3. Technical Efficacy: Stage 2.

We propose that the metabolic benefits of sleeve gastrectomy are initiated by decreased liver transcription of cyp8b1 and slc10a1. A notable downstream effect includes changes in systemic bile acid composition and circulation, including increased LCA. An altered gut microbiome after surgery includes increases in Ligilactobacillus that was shown to express a bile salt hydrolase, which could be a contributor to the post-sleeve gastrectomy gut microbiome changes.

The role of the gut microbiota in influencing physiological processes has become increasingly evident over the past several decades. One such process, thermogenesis, has become a topic of interest in recent years owing to the threat of climate change as well as the ongoing obesity epidemic. Here, we offer an overview of current knowledge regarding the contributions of the gut microbiota to thermogenesis in ecological and biomedical contexts. We first describe how the metabolic and behavioral changes associated with the gut microbiota can lead to changes in energy balance, allowing animals to adapt to environmental stressors. We then discuss how changes in the gut microbial community composition, such as through antibiotic use, can lead to dysfunctional thermoregulation and, ultimately, disease states. Finally, we consider how microbes can be exploited to improve energy balance and propose some future directions worthy of additional study.

The gut microbial community represents a thermogenic biomass. The composition of the microbial community dictates energy expenditure of the microbial biomass and is altered by xenobiotics and bacterial metabolites. This study demonstrates that treatment with reutericyclin positively modulates anaerobic energy expenditure and may represent a novel therapeutic in the treatment of obesity.

Background/Objectives: The interplay between the gut microbiome (GMB) and neurovascular function in neurodegeneration is unclear. The goal of this proof-of-concept, cross-sectional study is to identify relationships between the GMB, neurovascular functioning, and cognition in amnestic mild cognitive impairment (aMCI), the prototypical prodromal symptomatic stage of Alzheimer’s disease (AD). Methods: Participants (n = 14 aMCI and 10 controls) provided fecal samples for GMB sequencing (16S and shotgun metagenomics), underwent MRI, and completed cognitive testing. Cerebral vascular reactivity (CVR), cerebral blood flow (CBF), and arterial transit time (ATT) were assessed. Statistical analyses evaluated the relationships between discriminatory taxa, cerebrovascular metrics, and cognition. Results: Sequencing revealed differentially abundant bacterial and viral taxa distinguishing aMCI from controls. Spearman correlations revealed that bacteria known to induce inflammation were negatively associated with CVR, CBF, and cognition, and positively associated with ATT. A reciprocal pattern emerged for the association of taxa with gut health. Conclusions: Our results provide preliminary evidence that pro-inflammatory gut bacterial and viral taxa are associated with neurovascular dysfunction and cognitive impairment in prodromal AD, highlighting their potential as candidate microbial biomarkers and targets for early intervention.

The role of xenobiotic disruption of microbiota, corresponding dysbiosis, and potential links to host metabolic diseases are of critical importance. In this study, we used a widely prescribed antipsychotic drug, risperidone, known to influence weight gain in humans, to induce weight gain in C57BL/6J female mice. We hypothesized that microbes essential for maintaining gut homeostasis and energy balance would be depleted following treatment with risperidone, leading to enhanced weight gain relative to controls. Thus, we performed metagenomic analyses on stool samples to identify microbes that were excluded in risperidone-treated animals but remained present in controls. We identified multiple taxa including Limosilactobacillus reuteri as a candidate for further study. Oral supplementation with L. reuteri protected against risperidone-induced weight gain (RIWG) and was dependent on cellular production of a specialized metabolite, reutericyclin. Further, synthetic reutericyclin was sufficient to mitigate RIWG. Both synthetic reutericyclin and L. reuteri restored energy balance in the presence of risperidone to mitigate excess weight gain and induce shifts in the microbiome associated with leanness. In total, our results identify reutericyclin production by L. reuteri as a potential probiotic to restore energy balance induced by risperidone and to promote leanness.

The soil-dwelling delta-proteobacterium Myxococcus xanthus is a model organism to study predation and competition. M. xanthus preys on a broad range of bacteria mediated by lytic enzymes, exopolysaccharides, Type-IV pilus-based motility, and specialized metabolites. Competition between M. xanthus and prey bacterial strains with various specialized metabolite profiles indicates a range of fitness, suggesting that specialized metabolites contribute to prey survival. To expand our understanding of how specialized metabolites affect predator–prey dynamics, we assessed interspecies interactions between M. xanthus and two strains of Bacillus cereus. While strain ATCC 14579 resisted predation, strain T was found to be highly sensitive to M. xanthus predation. The interaction between B. cereus ATCC 14579 and M. xanthus appears to be competitive, resulting in population loss for both predator and prey. Genome analysis revealed that ATCC 14579 belongs to a clade that possesses the biosynthetic gene cluster for production of thiocillins, whereas B. cereus strain T lacks those genes. Further, purified thiocillin protects B. cereus strains unable to produce this specialized metabolite, strengthening the finding that thiocillin protects against predation and contributes to the ecological fitness of B. cereus ATCC 14579. Lastly, strains that produce thiocillin appear to confer some level of protection to their own antibiotic by encoding an additional copy of the L11 ribosomal protein, a known target for thiopeptides. This work highlights the importance of specialized metabolites affecting predator–prey dynamics in soil microenvironments.

With obesity and type 2 diabetes (T2D) at epidemic levels, we need to understand the complex nature of these diseases to design better therapeutics. The underlying causes of both obesity and T2D are complex, but both are thought to develop, in part, based on contributions from the gut microbiota.

Evidence supports various roles for microbial metabolites in the control of multiple aspects of host energy flux including feeding behaviors, digestive efficiency, and energy expenditure, but few studies have quantified the energy utilization of the biomass of the gut microbiota itself. Because gut microbiota exist in an anoxic environment, energy flux is expected to be anaerobic; unfortunately, commonly utilized O₂/CO₂ respirometry-based approaches are unable to detect anaerobic energy flux. To quantify the contribution of the gut microbial biomass to whole-animal energy flux, we examined the effect of surgical reduction of gut biomass in C57BL/6J mice via cecectomy and assessed energy expenditure using methods sensitive to anaerobic flux, including bomb and direct calorimetry. First, we determined that cecectomy caused an acceleration of weight gain over several months due to a reduction in combined total host plus microbial energy expenditure, as reflected by an increase in energy efficiency (ie, weight gained per calorie absorbed). Second, we determined that under general anesthesia, cecectomy caused immediate changes in heat dissipation that were significantly modified by short-term pretreatment with dietary or pharmaceutical interventions known to modify the microbiome, and confirmed that these effects were undetectable by respirometry. We conclude that while the cecum only contributes approximately 1% of body mass in the mouse, this organ contributes roughly 8% of total resting energy expenditure, that this contribution is predominantly anaerobic, and that the composition and abundance of the cecal microbial contents can significantly alter its contribution to energy flux.

Two-component signaling systems (TCS) regulate bacterial responses to environmental signals through the process of protein phosphorylation. Specifically, sensor histidine kinases (SK) recognize signals and propagate the response via phosphorylation of a cognate response regulator (RR) that functions to initiate transcription of specific genes. Signaling within a single TCS is remarkably specific and cross-talk between TCS is limited. However, regulation of the flow of information through complex signaling networks that include closely related TCS remains largely unknown. Additionally, many bacteria utilize multi-component signaling networks which provide additional genetic and biochemical interactions that must be regulated for signaling fidelity, input and output specificity, and phosphorylation kinetics. Here we describe the characterization of an NtrC-like RR that participates in regulation of Type-IV pilus-dependent motility of Myxococcus xanthus and is thus named NmpR, NtrC Modulator of Pili Regulator. A complex multi-component signaling system including NmpR was revealed by suppressor mutations that restored motility to cells lacking PilR, an evolutionarily conserved RR required for expression of pilA encoding the major Type-IV pilus monomer found in many bacterial species. The system contains at least four signaling proteins: a SK with a protoglobin sensor domain (NmpU), a hybrid SK (NmpS), a phospho-sink protein (NmpT), and an NtrC-like RR (NmpR). We demonstrate that ΔpilR bypass suppressor mutations affect regulation of the NmpRSTU multi-component system, such that NmpR activation is capable of restoring expression of pilA in the absence of PilR. Our findings indicate that pilus gene expression in M. xanthus is regulated by an extended network of TCS which interact to refine control of pilus function. Sensing and responding to the environment are critical for bacterial survival and adaptation. Many bacteria sense environmental signals through biological machinery referred to as two-component signaling systems. These signaling systems are composed of a sensor histidine kinase and a cognate response regulator and serve to regulate gene expression in response to environmental cues. Due to their importance for survival, many bacterial genomes encode multiple two-component systems, some of which arose from gene duplication events. However, the mechanisms by which two-component systems integrate multiple inputs within larger networks remains poorly defined. In this study, we demonstrate that suppressor mutations within a Myxococcus xanthus signaling system of previously unknown function restore Type-IV pilus-dependent motility to cells lacking PilR, a response regulator typically required for production of the pilin monomer PilA. Suppressor mutations in ΔpilR cells led to activation of a related signaling system, resulting in expression of pilA and the corresponding production of PilA to restore motility. Thus, both PilSR and NmpSR coordinately regulate motility in M. xanthus. Collectively, our results expand our understanding of the activation of response regulators via phosphorylation and the mechanisms controlling multi-component signal transduction systems.