Gut Microbes最新文献

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.

Recent sets of evidence have described profiles of 16S rDNA sequences in host tissues, notably in fat pads that are significantly overrepresented and can serve as signatures of metabolic disease. However, these recent and original observations need to be further detailed and functionally defined. Here, using state-of-the-art targeted DNA sequencing and discriminant predictive approaches, we describe, from the longitudinal FLORINASH cohort of patients who underwent bariatric surgery, visceral, and subcutaneous fat pad-specific bacterial 16SrRNA signatures. The corresponding Porphyromonadaceae, Campylobacteraceae, Prevotellaceae, Actimomycetaceae, Veillonellaceae, Anaerivoracaceae, Fusobacteriaceae, and the Clostridium family XI 16SrRNA DNA segment profiles are signatures of the subcutaneous adipose depot while Pseudomonadaceae and Micrococcacecae, 16SrRNA DNA sequence profiles characterize the visceral adipose depot. In addition, we have further identified that a specific pre-bariatric surgery adipose tissue bacterial DNA signature predicts the efficacy of body weight loss in obese patients 5-10 years after the surgery. 16SrRNA signatures discriminate (ROC ~ 1) the patients who did not maintain bodyweight loss and those who did. Second, from the 16SrRNA sequences we infer potential pathways suggestive of catabolic biochemical activities that could be signatures of subcutaneous adipose depots that predict body weight loss.

In recent years, various strategies have been developed to enable the oral administration of protein-based drugs (biologics) with the aim of overcoming the degradation and inactivation of these drugs that can occur as they traverse the gastrointestinal tract (GIT). In this study, we investigated bacteria as a delivery vehicle for biologics, harnessing their ability to withstand the harsh gastric environment and deliver therapeutic drugs directly to the intestine. Specifically, we explored using the type 5 secretion system (T5SS) to secrete therapeutic cargoes under simulated gut conditions. Our research focused on EspC, a T5SS protein from enteropathogenic Escherichia coli, and its potential to secrete interferon-α (IFNα), a cytokine with immunomodulatory and antiviral properties widely used in the clinic. We demonstrated that EspC can facilitate the secretion of IFNα variant when expressed in nonpathogenic bacteria. Moreover, this EspC-secreted IFN was able to activate the JAK-STAT pathway, upregulate IFN-stimulated genes, and induce a robust antiviral response in cells. Collectively, these findings provide proof of concept supporting the utilization of the EspC protein as a novel delivery platform for protein-based therapeutics.

Microbiota transplant therapy is an emerging therapy for inflammatory bowel disease, but factors influencing its efficacy and mechanism remain poorly understood. In this narrative review, we outline key elements affecting therapeutic outcomes, including donor factors (such as age and patient relationship), recipient factors, control selection, and elements impacting engraftment and its correlation with clinical response. We also examine potential mechanisms through inflammatory bowel disease trials, focusing on the interplay between the microbiota, host, and immune system. Finally, we briefly explore potential future directions for microbiota transplant therapy and promising emerging treatments.

Vornhagen et al. introduced a model combining gut microbiota structure and Klebsiella pneumoniae genotype to assess infection risk in K. pneumoniae-colonized patients. Building on their findings, we investigated the gut microbiota composition and K. pneumoniae genotype in 16 colonized patients, five of whom had bloodstream infections at the time of fecal sampling. Importantly, we did not apply the original machine learning model due to the small sample size of our cohort. Instead, we explored the distribution of key antimicrobial resistance and stress resistance genes and analyzed gut community structure based on amplicon sequence variants (ASVs) of the V3-V4 16S rRNA region. Notably, distinct gene profiles were observed in both infected and non-infected patients, and three patients without bloodstream infections showed no detectable Klebsiella ASVs despite microbiological confirmation of colonization. These findings highlight the need to integrate gut microbiota composition data into infection risk assessment and address limitations in taxonomic resolution and sample size. Future studies should aim to develop streamlined tools for clinical application in K. pneumoniae-colonized patients.

Competition and cooperation are fundamental to the stability and evolution of ecological communities. The human gut microbiota, a dense and complex microbial ecosystem, plays a critical role in the host's health and disease, with competitive interactions being particularly significant. As a dominant and extensively studied group in the human gut, Bacteroidales serves as a successful model system for understanding these intricate dynamic processes. This review summarizes recent advances in our understanding of the intricate antagonism mechanisms among gut Bacteroidales at the biochemical or molecular-genetic levels, focusing on interference and exploitation competition. We also discuss unresolved questions and suggest strategies for studying the competitive mechanisms of Bacteroidales. The review presented here offers valuable insights into the molecular basis of bacterial antagonism in the human gut and may inform strategies for manipulating the microbiome to benefit human health.

Atherosclerosis is the primary cause of cardiovascular and cerebrovascular diseases. However, current anti-atherosclerosis drugs have shown conflicting therapeutic outcomes, thereby spurring the search for novel and effective treatments. Recent research indicates the crucial involvement of oral and gastrointestinal microbiota in atherosclerosis. While gut microbiota metabolites, such as choline derivatives, have been extensively studied and reviewed, emerging evidence suggests that bacterial extracellular vesicles (BEVs), which are membrane-derived lipid bilayers secreted by bacteria, also play a significant role in this process. However, the role of BEVs in host-microbiota interactions remains insufficiently explored. This review aims to elucidate the complex communication mediated by BEVs along the gut-heart axis. In this review, we summarize current knowledge on BEVs, with a specific focus on how pathogen-derived BEVs contribute to the promotion of atherosclerosis, as well as how BEVs from gut symbionts and probiotics may mitigate its progression. We also explore the potential and challenges associated with engineered BEVs in the prevention and treatment of atherosclerosis. Finally, we discuss the benefits and challenges of using BEVs in atherosclerosis diagnosis and treatment, and propose future research directions to address these issues.

Fat mass and obesity-associated protein (FTO) is the key demethylase that reverses the abnormally altered N6-methyladenosine (m6A) modification in eukaryotic cells under environmental pollutants exposure. Arsenic is an environmental metalloid and can cause severe symptoms in human mainly through drinking water. However, there is no specific treatment for its toxic effects due to the uncovered mechanisms. We previously revealed that exposure to arsenic increased the level of m6A via down-regulation of FTO, which might serve as a potential target for intervention against arsenic-related disorders. In this study, our results demonstrated that chronic exposure to arsenic significantly disrupted the intestinal barrier and microenvironment. Also, this administration resulted in the enhancement of m6A modification and the reduction of FTO expression in the intestine. By using both CRISPR/Cas9-based FTO knock-in strategy and adeno-associated virus (AAV)-mediated overexpression of FTO in the intestine, we established for the first time that up-regulation of FTO remarkably ameliorated arsenic-induced disruption of intestinal barriers and altered microenvironment of mice. We also firstly identified a dominant gut microbial species, Desulfovibrio fairfieldensis, which was sharply reduced in arsenic-exposed mice, was able to proceed arsenic-induced neurobehavioral impairments by declining the levels of its major metabolite hydrogen sulfide. Administration of Desulfovibrio fairfieldensis could significantly alleviate the neurotoxicity of arsenic. Intriguingly, the beneficial effects of FTO against arsenic neurotoxicity possibly occurred through a novel gut-brain communication via Desulfovibrio fairfieldensis and its produced hydrogen sulfide. Collectively, these findings will provide new ideas for understanding the mechanisms of arsenic-induced toxic effects from a gut-brain communication perspective, and will assist the development of explicit intervention strategy via regulation of a new potential target FTO for prevention and treatment against arsenic-related both intestinal and neurological disorders.

The development of anxiety during protracted opioid withdrawal heightens the risk of relapse into the cycle of addiction. Understanding the mechanisms driving anxiety during opioid withdrawal could facilitate the development of therapeutics to prevent negative affect and promote continued abstinence. Our lab has previously established the gut microbiome as a driver of various side effects of opioid use, including analgesic tolerance and somatic withdrawal symptoms. We therefore hypothesized that the gut microbiome contributes to the development of anxiety-like behavior during protracted opioid withdrawal. In this study, we first established a mouse model of protracted morphine withdrawal, characterized by anxiety-like behavior and gut microbial dysbiosis. Next, we used fecal microbiota transplantation (FMT) to show that gut dysbiosis alone is sufficient to induce anxiety-like behavior. We further demonstrated that probiotic therapy during morphine withdrawal attenuated the onset of anxiety-like behavior, highlighting its therapeutic potential. Lastly, we examined transcriptional changes in the amygdala of morphine-withdrawn mice treated with probiotics to explore mechanisms by which the gut-brain axis mediates anxiety-like behavior. Our results support the use of probiotics as a promising therapeutic strategy to prevent gut dysbiosis and associated anxiety during opioid withdrawal, with potential implications for improving treatment outcomes in opioid recovery programs.

There is much interest in the development of dietary supplements that selectively promote the growth of beneficial gut bacteria. The selectivity of many candidate prebiotics has, however, not been thoroughly investigated. Here, we evaluated stimulation of the human gut microbiota by the disaccharide lactulose using an ex vivo multimodal activity-based cell sorting approach. Incubation of human donor stool with lactulose resulted in growth or stimulation of a restricted diversity of bacterial genera, most prominently Bifidobacterium, Collinsella, and Lactococcus. Physiological analysis of lactulose-responsive strains isolated by Raman activated cell sorting revealed that most were capable of lactulose degradation. Among these isolates, Lactococcus lactis could not degrade lactulose, but its growth was boosted by co-cultivation with lactulose degraders. This suggests that inter-species facilitation contributes to the lactulose degradation niche. Moreover, we observed that lactulose selectively activates metabolically important taxa, including health-associated genera such as Faecalibacterium and Gemmiger^1,2,3, potentially indicating broader functional effects beyond compositional changes. These results provide novel insights into the physiology and ecology of lactulose utilization by the human gut microbiota and underscore the potential of lactulose as a prebiotic dietary supplement.