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1.
CRISPR/Cas9: Nature's gift to prokaryotes and an auspicious tool in genome editing.
Khanzadi, MN, Khan, AA
Journal of basic microbiology. 2020;(2):91-102
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR) is a family of DNA direct repeats found in many prokaryotic genomes. It was discovered in bacteria as their (adaptive) immune system against invading viruses. Cas9 is an endonuclease enzyme linked with the CRISPR system in bacteria. Bacteria use the Cas9 enzyme to chop viral DNA sequences by unwinding it and then finding the complementary base pairs to the guide RNA. CRISPR/Cas9 is a modern and powerful molecular biology approach that is widely used in genome engineering (to activate/repress gene expression). It can be used in vivo to cause targeted genome modifications with better efficiency as compared to meganucleases, zinc-finger nucleases and transcription activator-like effector nucleases. CRISPR/Cas9 is a simple, reliable, and rapid method for causing gene alterations that open new horizons of gene editing in a variety of living organisms, including humans, for the treatment of several diseases. In this short review, we explored the basic mechanisms underlying its working principles along with some of its current applications in a number of diverse fields.
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2.
Dietary Gluten as a Conditioning Factor of the Gut Microbiota in Celiac Disease.
Bascuñán, KA, Araya, M, Roncoroni, L, Doneda, L, Elli, L
Advances in nutrition (Bethesda, Md.). 2020;(1):160-174
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Abstract
The gut microbiota plays a relevant role in determining an individual's health status, and the diet is a major factor in modulating the composition and function of gut microbiota. Gluten constitutes an essential dietary component in Western societies and is the environmental trigger of celiac disease. The presence/absence of gluten in the diet can change the diversity and proportions of the microbial communities constituting the gut microbiota. There is an intimate relation between gluten metabolism and celiac disease pathophysiology and gut microbiota; their interrelation defines intestinal health and homeostasis. Environmental factors modify the intestinal microbiota and, in turn, its changes modulate the mucosal and immune responses. Current evidence from studies of young and adult patients with celiac disease increasingly supports that dysbiosis (i.e., compositional and functional alterations of the gut microbiome) is present in celiac disease, but to what extent this is a cause or consequence of the disease and whether the different intestinal diseases (celiac disease, ulcerative colitis, Crohn disease) have specific change patterns is not yet clear. The use of bacterial-origin enzymes that help completion of gluten digestion is of interest because of the potential application as coadjuvant in the current treatment of celiac disease. In this narrative review, we address the current knowledge on the complex interaction between gluten digestion and metabolism, celiac disease, and the intestinal microbiota.
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3.
Evolutionary classification of CRISPR-Cas systems: a burst of class 2 and derived variants.
Makarova, KS, Wolf, YI, Iranzo, J, Shmakov, SA, Alkhnbashi, OS, Brouns, SJJ, Charpentier, E, Cheng, D, Haft, DH, Horvath, P, et al
Nature reviews. Microbiology. 2020;(2):67-83
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Abstract
The number and diversity of known CRISPR-Cas systems have substantially increased in recent years. Here, we provide an updated evolutionary classification of CRISPR-Cas systems and cas genes, with an emphasis on the major developments that have occurred since the publication of the latest classification, in 2015. The new classification includes 2 classes, 6 types and 33 subtypes, compared with 5 types and 16 subtypes in 2015. A key development is the ongoing discovery of multiple, novel class 2 CRISPR-Cas systems, which now include 3 types and 17 subtypes. A second major novelty is the discovery of numerous derived CRISPR-Cas variants, often associated with mobile genetic elements that lack the nucleases required for interference. Some of these variants are involved in RNA-guided transposition, whereas others are predicted to perform functions distinct from adaptive immunity that remain to be characterized experimentally. The third highlight is the discovery of numerous families of ancillary CRISPR-linked genes, often implicated in signal transduction. Together, these findings substantially clarify the functional diversity and evolutionary history of CRISPR-Cas.
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4.
Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells.
Takahashi, D, Hoshina, N, Kabumoto, Y, Maeda, Y, Suzuki, A, Tanabe, H, Isobe, J, Yamada, T, Muroi, K, Yanagisawa, Y, et al
EBioMedicine. 2020;:102913
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (TFR) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating TFR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling TFR cell differentiation remains unknown. METHODS We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5+Bcl-6+Foxp3+ TFR (iTFR) cell culture system and examined whether butyrate promotes the differentiation of iTFR cells. FINDINGS Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting TFR cell differentiation. Butyrate directly induced the differentiation of functional TFR cells in vitro by enhancing histone acetylation in TFR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the TFR-cell marker genes. The adoptive transfer of the butyrate-treated iTFR cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. INTERPRETATION Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. FUNDING This work was supported by AMED-Crest (16gm1010004h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 to KH), the Japan Society for the Promotion of Science (JP17KT0055, JP16H01369, and JP18H04680 to KH; JP17K15734 to DT), Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects (KH), Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT), the SECOM Science and Technology Foundation (KH), the Cell Science Research Foundation (KH), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DT), the Suzuken Memorial Foundation (KH and DT), the Takeda Science Foundation (KH and DT), The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan (KH).
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5.
A Budding Relationship: Bacterial Extracellular Vesicles in the Microbiota-Gut-Brain Axis.
Haas-Neill, S, Forsythe, P
International journal of molecular sciences. 2020;(23)
Abstract
The discovery of the microbiota-gut-brain axis has revolutionized our understanding of systemic influences on brain function and may lead to novel therapeutic approaches to neurodevelopmental and mood disorders. A parallel revolution has occurred in the field of intercellular communication, with the realization that endosomes, and other extracellular vesicles, rival the endocrine system as regulators of distant tissues. These two paradigms shifting developments come together in recent observations that bacterial membrane vesicles contribute to inter-kingdom signaling and may be an integral component of gut microbe communication with the brain. In this short review we address the current understanding of the biogenesis of bacterial membrane vesicles and the roles they play in the survival of microbes and in intra and inter-kingdom communication. We identify recent observations indicating that bacterial membrane vesicles, particularly those derived from probiotic organisms, regulate brain function. We discuss mechanisms by which bacterial membrane vesicles may influence the brain including interaction with the peripheral nervous system, and modulation of immune activity. We also review evidence suggesting that, unlike the parent organism, gut bacteria derived membrane vesicles are able to deliver cargo, including neurotransmitters, directly to the central nervous system and may thus constitute key components of the microbiota-gut-brain axis.
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6.
Iron Acquisition by Bacterial Pathogens: Beyond Tris-Catecholate Complexes.
Zhang, Y, Sen, S, Giedroc, DP
Chembiochem : a European journal of chemical biology. 2020;(14):1955-1967
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Abstract
Sequestration of the essential nutrient iron from bacterial invaders that colonize the vertebrate host is a central feature of nutritional immunity and the "fight over transition metals" at the host-pathogen interface. The iron quota for many bacterial pathogens is large, as iron enzymes often make up a significant share of the metalloproteome. Iron enzymes play critical roles in respiration, energy metabolism, and other cellular processes by catalyzing a wide range of oxidation-reduction, electron transfer, and oxygen activation reactions. In this Concept article, we discuss recent insights into the diverse ways that bacterial pathogens acquire this essential nutrient, beyond the well-characterized tris-catecholate FeIII complexes, in competition and cooperation with significant host efforts to cripple these processes. We also discuss pathogen strategies to adapt their metabolism to less-than-optimal iron concentrations, and briefly speculate on what might be an integrated adaptive response to the concurrent limitation of both iron and zinc in the infected host.
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7.
Multi-metal nutrient restriction and crosstalk in metallostasis systems in microbial pathogens.
Jordan, MR, Wang, J, Capdevila, DA, Giedroc, DP
Current opinion in microbiology. 2020;:17-25
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Abstract
Transition metals from manganese to zinc function as catalytic and structural cofactors for an amazing diversity of proteins and enzymes, and thus are essential for all forms of life. During infection, inflammatory host proteins limit the accessibility of multiple transition metals to invading pathogens in a process termed nutritional immunity. In order to respond to host-mediated metal starvation, bacteria employ both protein and RNA-based mechanisms to sense prevailing transition metal concentrations that collectively regulate systems-level strategies to maintain cellular metallostasis. In this review, we discuss a number of recent advances in our understanding of how bacteria orchestrate the adaptive response to host-mediated multi-metal restriction, highlighting crosstalk among these regulatory systems.
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Modulation of microbially derived short-chain fatty acids on intestinal homeostasis, metabolism, and neuropsychiatric disorder.
Xiao, S, Jiang, S, Qian, D, Duan, J
Applied microbiology and biotechnology. 2020;(2):589-601
Abstract
A diverse range of symbiotic gut bacteria codevelops with the host and is considered a metabolic "organ" that not only facilitates harvesting of nutrients from the dietary components but also produces a class of metabolites. Many metabolites of gut microbes have an important impact on host health. For example, an inventory of metabolic intermediates derived from bacterial protein fermentation may affect host physiology and pathophysiology. Additionally, gut microbiota can convert cholesterol to bile acids and further into secondary bile acids which can conversely modulate microbial community. Moreover, new research identifies that microbes synthesize vitamins for us in the colon. Here, we will review data implicating a major class of bacterial metabolites through breaking down dietary fiber we cannot process, short-chain fatty acids (SCFAs), as crucial executors of alteration of immune mechanisms, regulation of metabolic homeostasis, and neuroprotective effects to combat disease and improve health.
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9.
Probiotics in Medicine: A Long Debate.
Stavropoulou, E, Bezirtzoglou, E
Frontiers in immunology. 2020;:2192
Abstract
During the last years probiotics gained the attention of clinicians for their use in the prevention and treatment of multiple diseases. Probiotics main mechanisms of action include enhanced mucosal barrier function, direct antagonism with pathogens, inhibition of bacterial adherence and invasion capacity in the intestinal epithelium, boosting of the immune system and regulation of the central nervous system. It is accepted that there is a mutual communication between the gut microbiota and the liver, the so-called "microbiota-gut-liver axis" as well as a reciprocal communication between the intestinal microbiota and the central nervous system through the "microbiota-gut-brain axis." Moreover, recently the "gut-lung axis" in bacterial and viral infections is considerably discussed for bacterial and viral infections, as the intestinal microbiota amplifies the alveolar macrophage activity having a protective role in the host defense against pneumonia. The importance of the normal human intestinal microbiota is recognized in the preservation of health. Disease states such as, infections, autoimmune conditions, allergy and other may occur when the intestinal balance is disturbed. Probiotics seem to be a promising approach to prevent and even reduce the symptoms of such clinical states as an adjuvant therapy by preserving the balance of the normal intestinal microbiota and improving the immune system. The present review states globally all different disorders in which probiotics can be given. To date, Stronger data in favor of their clinical use are provided in the prevention of gastrointestinal disorders, antibiotic-associated diarrhea, allergy and respiratory infections. We hereby discuss the role of probiotics in the reduction of the respiratory infection symptoms and we focus on the possibility to use them as an adjuvant to the therapeutic approach of the pandemic COVID-19. Nevertheless, it is accepted by the scientific community that more clinical studies should be undertaken in large samples of diseased populations so that the assessment of their therapeutic potential provide us with strong evidence for their efficacy and safety in clinical use.
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10.
Handling of nutrient copper in the bacterial envelope.
Stewart, LJ, Thaqi, D, Kobe, B, McEwan, AG, Waldron, KJ, Djoko, KY
Metallomics : integrated biometal science. 2019;(1):50-63
Abstract
In bacteria, copper (Cu) is often recognised for its potential toxicity and its antibacterial activity is now considered a key component of the mammalian innate immune system. Cu ions bound in weak sites can catalyse harmful redox reactions while Cu ions in strong but adventitious sites can disrupt protein or enzyme function. For these reasons, the outward transport of Cu from bacteria has received significant attention. Yet, Cu is also a bacterial nutrient, required as a cofactor by enzymes that catalyse electron transfer processes, for instance in aerobic and anaerobic respiration. To date, the inward flow of this metal ion as a nutrient and its insertion into target cuproenzymes remain poorly defined. Here we revisit the available evidence related to bacterial nutrient Cu trafficking and identify gaps in knowledge. Particularly intriguing is the evidence that bacterial cuproenzymes do not always require auxiliary metallochaperones to insert nutrient Cu into their active sites. This review outlines our effort to consolidate the available experimental data using an established energy-driven model for metalation.