Antibiotic-associated infection with the bacterial pathogen Clostridium difficile is a major cause of morbidity and increased health care costs. C difficile infection follows disruption of the ...indigenous gut microbiota by antibiotics. Antibiotics create an environment within the intestine that promotes C difficile spore germination, vegetative growth, and toxin production, leading to epithelial damage and colitis. Studies of patients with C difficile infection and animal models have shown that the indigenous microbiota can inhibit expansion and persistence of C difficile . Although the specific mechanisms of these processes are not known, they are likely to interfere with key aspects of the pathogen’s physiology, including spore germination and competitive growth. Increasing our understanding of how the intestinal microbiota manage C difficile could lead to better means of controlling this important nosocomial pathogen.
Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted ...by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H(2) receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases.
Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social ...deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.
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•Treatment with L. reuteri rescues social deficits in several ASD mouse models•L. reuteri reverses social deficits via the vagus nerve•L. reuteri reverses social deficits even in germ-free mice•OXTR inhibition prevents L. reuteri’s effects on social behavior and VTA plasticity
Precision microbial-based therapy rescues social deficits in genetic, environmental, and idiopathic mouse models of ASD. This rescue depends upon the vagus nerve as well as the oxytocinergic and dopaminergic signaling in the brain.
To truly understand the mechanisms through which resveratrol exerts its biological effects, the key direct interactions between resveratrol and its target biomolecules must be identified. With an ...increasing number of biochemical tools to measure and quantify direct physical interactions between biomolecules, there have been around 20 proteins identified as having a specific affinity to resveratrol to date. Resveratrol has been described as a promiscuous molecule, and one would expect it to bind with numerous proteins, which would help explain why resveratrol appears to have so many health benefits and has been shown to act upon various different pathways related to a diverse range of conditions. The aim of this review is to present the direct protein targets of resveratrol that are currently known and highlight the consequences of direct binding and the methods used to identify the nature of these interactions.
Recent advances in our understanding of how the intestinal microbiome contributes to health and disease have generated great interest in developing strategies for modulating the abundance of microbes ...and/or their activity to improve overall human health and prevent pathologies such as osteoporosis. Bone is an organ that the gut has long been known to regulate through absorption of calcium, the key bone mineral. However, it is clear that modulation of the gut and its microbiome can affect bone density and strength in a variety of animal models (zebrafish, rodents, chicken) and humans. This is demonstrated in studies ablating the microbiome through antibiotic treatment or using germ-free mouse conditions as well as in studies modulating the microbiome activity and composition through prebiotic and/or probiotic treatment. This review will discuss recent developments in this new and exciting area.
Vertebrates engage in symbiotic associations with vast and complex microbial communities that colonize their gastrointestinal tracts. Recent advances have provided mechanistic insight into the ...important contributions of the gut microbiome to vertebrate biology, but questions remain about the evolutionary processes that have shaped symbiotic interactions in the gut and the consequences that arise for both the microbes and the host. Here we discuss the biological principles that underlie microbial symbiosis in the vertebrate gut and the potential of the development of mutualism. We then review phylogenetic and experimental studies on the vertebrate symbiont Lactobacillus reuteri that have provided novel insight into the ecological and evolutionary strategy of a gut microbe and its relationship with the host. We argue that a mechanistic understanding of the microbial symbiosis in the vertebrate gut and its evolution will be important to determine how this relationship can go awry, and it may reveal possibilities by which the gut microbiome can be manipulated to support health.
Clostridium difficile infection (CDI) has become one of the most prevalent and costly nosocomial infections. In spite of the importance of CDI, our knowledge of the pathogenesis of this infection is ...still rudimentary. Although previous use of antibiotics is generally considered to be the sine qua non of CDI, the mechanisms by which antibiotics render the host susceptible to C. difficile are not well defined. In this review, we will explore what is known about how the indigenous microbiota acts in concert with the host to prevent colonization and virulence of C. difficile and how antibiotic administration disturbs host–microbiota homeostasis, leading to CDI.
Gut Microbiota and Bone Health Quach, Darin; Britton, Robert A
Advances in experimental medicine and biology,
2017, Volume:
1033
Journal Article
Peer reviewed
The past decade has seen an explosion of research in the area of how the bacteria that inhabit the human body impact health and disease. One of the more surprising concepts to emerge from this work ...is the ability of the intestinal microbiota to impact virtually all systems in the body. Recently, the role of gut bacteria in bone health and disease has received more significant attention. In this chapter, we review what has been learned about how the gut microbiome impacts bone health and discuss possible mechanisms of how the gut-bone axis may be connected. We also discuss the use of therapeutic microbes in the modulation of bone health. Finally, we propose an emerging field of the gut-brain-bone axis, in which the gut drives bone physiology via regulation of key hormones that are originally synthesized in the brain.
1. Predictions of the identities and ecological impacts of invasive alien species are critical for risk assessment, but presently we lack universal and standardized metrics that reliably predict the ...likelihood and degree of impact of such invaders (i.e. measurable changes in populations of affected species). This need is especially pressing for emerging and potential future invaders that have no invasion history. Such a metric would also ideally apply across diverse taxonomic and trophic groups. 2. We derive a new metric of invader ecological impact that blends: (i) the classic Functional Response (FR; consumer per capita effect) and Numerical Response (NR; consumer population response) approaches to determining consumer impact, that is, the Total Response (TR = FR × NR), with; (ii) the Tarker-Lonsdale equation' for invader impact, where Impact = Range × Abundance × Effect (per capita effect), into; (iii) a new metric, Relative Impact Potential (RIP), where RIP = FR × Abundance. The RIP metric is an invader/native ratio, where values > 1 predict that invader ecological impact will occur, and increasing values above 1 indicate increasing impact. In addition, the invader/invader RIP ratio allows comparisons of the ecological impacts of different invaders. 3. Across a diverse range of trophic and taxonomic groups, including predators, herbivores, animals and plants (22 invader/native systems with 47 individual comparisons), high-impact invaders were significantly associated with higher FRs compared to native trophic analogues. However, the RIP metric substantially improves this association, with 100% predictive power of high-impact invaders. 4. Further, RIP scores were significantly and positively correlated with two independent ecological impact scores for invaders, allowing prediction of the degree of impact of invasive alien species with the RIP metric. Finally, invader/invader RIP scores were also successful in identifying and associating with higher impacting invasive alien species. 5. Synthesis and applications. The Relative Impact Potential metric combines the per capita effects of invaders with their abundances, relative to trophically analogous natives, and is successful in predicting the likelihood and degree of ecological impact caused by invasive alien species. As the metric constitutes readily measurable features of individuals, populations and species across abiotic and biotic context-dependencies, even emerging and potential future invasive alien species can be assessed. The Relative Impact Potential metric can be rapidly utilized by scientists and practitioners and could inform policy and management of invasive alien species across diverse taxonomic and trophic groups.
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