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1.
Human guanylate binding proteins: nanomachines orchestrating host defense.
Kutsch, M, Coers, J
The FEBS journal. 2021;(20):5826-5849
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Abstract
Disease-causing microorganisms not only breach anatomical barriers and invade tissues but also frequently enter host cells, nutrient-enriched environments amenable to support parasitic microbial growth. Protection from many infectious diseases is therefore reliant on the ability of individual host cells to combat intracellular infections through the execution of cell-autonomous defense programs. Central players in human cell-autonomous immunity are members of the family of dynamin-related guanylate binding proteins (GBPs). The importance of these interferon-inducible GTPases in host defense to viral, bacterial, and protozoan pathogens has been established for some time; only recently, cell biological and biochemical studies that largely focused on the prenylated paralogs GBP1, GBP2, and GBP5 have provided us with robust molecular frameworks for GBP-mediated immunity. Specifically, the recent characterization of GBP1 as a bona fide pattern recognition receptor for bacterial lipopolysaccharide (LPS) disrupting the integrity of bacterial outer membranes through LPS aggregation, the discovery of a link between hydrolysis-induced GMP production by GBP1 and inflammasome activation, and the classification of GBP2 and GBP5 as inhibitors of viral envelope glycoprotein processing via suppression of the host endoprotease furin have paved the way for a vastly improved conceptual understanding of the molecular mechanisms by which GBP nanomachines execute cell-autonomous immunity. The herein discussed models incorporate our current knowledge of the antimicrobial, proinflammatory, and biochemical properties of human GBPs and thereby provide testable hypotheses that will guide future studies into the intricacies of GBP-controlled host defense and their role in human disease.
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Evidence for maternal diet-mediated effects on the offspring microbiome and immunity: implications for public health initiatives.
Mirpuri, J
Pediatric research. 2021;(2):301-306
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Abstract
Diets rich in saturated fats have become a staple globally. Fifty percent of women of childbearing age in the United States are obese or overweight, with diet being a significant contributor. There is increasing evidence of the impact of maternal high-fat diet on the offspring microbiome. Alterations of the neonatal microbiome have been shown to be associated with multiple morbidities, including the development of necrotizing enterocolitis, atopy, asthma, metabolic dysfunction, and hypertension among others. This review provides an overview of the recent studies and mechanisms being examined on how maternal diet can alter the immune response and microbiome in offspring and the implications for directed public health initiatives for women of childbearing age. IMPACT Maternal diet is important in shaping the offspring microbiome and neonatal immune system. Reviews the current literature in the field and suggests potential mechanisms and areas of research to be targeted. Highlights the current scope of our knowledge of ideal nutrition during pregnancy and consideration for enhanced public health initiatives to promote well-being of the future generation.
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Microbiota, Bacterial Carbonic Anhydrases, and Modulators of Their Activity: Links to Human Diseases?
Amedei, A, Capasso, C, Nannini, G, Supuran, CT
Mediators of inflammation. 2021;:6926082
Abstract
The involvement of the human microbiome is crucial for different host functions such as protection, metabolism, reproduction, and especially immunity. However, both endogenous and exogenous factors can affect the balance of the microbiota, creating a state of dysbiosis, which can start various gastrointestinal or systemic diseases. The challenge of future medicine is to remodel the intestinal microbiota to bring it back to healthy equilibrium (eubiosis) and, thus, counteract its negative role in the diseases' onset. The shaping of the microbiota is currently practiced in different ways ranging from diet (or use of prebiotics, probiotics, and synbiotics) to phage therapy and antibiotics, including microbiota fecal transplantation. Furthermore, because microbiota modulation is a capillary process, and because many microbiota bacteria (both beneficial and pathogenic) have carbonic anhydrases (specifically the four classes α, β, γ, and ι), we believe that the use of CA inhibitors and activators can open up new therapeutic strategies for many diseases associated with microbial dysbiosis, such as the various gastrointestinal disorders and the same colorectal cancer.
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Bacterial Responses to Iron Withholding by Calprotectin.
Obisesan, AO, Zygiel, EM, Nolan, EM
Biochemistry. 2021;(45):3337-3346
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Abstract
Iron (Fe) plays important roles in both essential cellular processes and virulence pathways for many bacteria. Consequently, Fe withholding by the human innate immune system is an effective form of defense against bacterial infection. In this Perspective, we review recent studies that have established a foundation for our understanding of the impact of the metal-sequestering host defense protein calprotectin (CP) on bacterial Fe homeostasis. We also discuss two recently uncovered strategies for bacterial adaptation to Fe withholding by CP. Together, these studies provide insight into how Fe sequestration by CP affects bacterial pathogens that include Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus. Overall, recent studies suggest that Fe withholding by CP may have implications for bacterial survival and virulence in the host, and further explorations that directly address this possibility present an important area for discovery.
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Human Milk Microbiota and Oligosaccharides: A Glimpse into Benefits, Diversity, and Correlations.
Moubareck, CA
Nutrients. 2021;(4)
Abstract
Human milk represents a cornerstone for growth and development of infants, with extensive array of benefits. In addition to exceptionally nutritive and bioactive components, human milk encompasses a complex community of signature bacteria that helps establish infant gut microbiota, contributes to maturation of infant immune system, and competitively interferes with pathogens. Among bioactive constituents of milk, human milk oligosaccharides (HMOs) are particularly significant. These are non-digestible carbohydrates forming the third largest solid component in human milk. Valuable effects of HMOs include shaping intestinal microbiota, imparting antimicrobial effects, developing intestinal barrier, and modulating immune response. Moreover, recent investigations suggest correlations between HMOs and milk microbiota, with complex links possibly existing with environmental factors, genetics, geographical location, and other factors. In this review, and from a physiological and health implications perspective, milk benefits for newborns and mothers are highlighted. From a microbiological perspective, a focused insight into milk microbiota, including origins, diversity, benefits, and effect of maternal diet is presented. From a metabolic perspective, biochemical, physiological, and genetic significance of HMOs, and their probable relations to milk microbiota, are addressed. Ongoing research into mechanistic processes through which the rich biological assets of milk promote development, shaping of microbiota, and immunity is tackled.
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Short- and Long-Term Implications of Human Milk Microbiota on Maternal and Child Health.
García-Ricobaraza, M, García-Santos, JA, Escudero-Marín, M, Diéguez, E, Cerdó, T, Campoy, C
International journal of molecular sciences. 2021;(21)
Abstract
Human milk (HM) is considered the most complete food for infants as its nutritional composition is specifically designed to meet infant nutritional requirements during early life. HM also provides numerous biologically active components, such as polyunsaturated fatty acids, milk fat globules, IgA, gangliosides or polyamines, among others; in addition, HM has a "bifidogenic effect", a prebiotic effect, as a result of the low concentration of proteins and phosphates, as well as the presence of lactoferrin, lactose, nucleotides and oligosaccharides. Recently, has been a growing interest in HM as a potential source of probiotics and commensal bacteria to the infant gut, which might, in turn, influence both the gut colonization and maturation of infant immune system. Our review aims to address practical approaches to the detection of microbial communities in human breast milk samples, delving into their origin, composition and functions. Furthermore, we will summarize the current knowledge of how HM microbiota dysbiosis acts as a short- and long-term predictor of maternal and infant health. Finally, we also provide a critical view of the role of breast milk-related bacteria as a novel probiotic strategy in the prevention and treatment of maternal and offspring diseases.
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Emerging role of ferrous iron in bacterial growth and host-pathogen interaction: New tools for chemical (micro)biology and antibacterial therapy.
Gonciarz, RL, Renslo, AR
Current opinion in chemical biology. 2021;:170-178
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Abstract
Chemical tools capable of detecting ferrous iron with oxidation-state specificity have only recently become available. Coincident with this development in chemical biology has been increased study and appreciation for the importance of ferrous iron during infection and more generally in host-pathogen interaction. Some of the recent findings are surprising and challenge long-standing assumptions about bacterial iron homeostasis and the innate immune response to infection. Here, we review these recent developments and their implications for antibacterial therapy.
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The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health.
Nogal, A, Valdes, AM, Menni, C
Gut microbes. 2021;(1):1-24
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Abstract
The gut microbiota plays an important role in cardio-metabolic diseases with diet being among the strongest modulators of gut microbiota composition and function. Resistant dietary carbohydrates are fermented to short-chain fatty acids (SCFAs) by the gut bacteria. Fiber and omega-3 rich diets increase SCFAs production and abundance of SCFA-producing bacteria. Likewise, SCFAs can improve gut barrier integrity, glucose, and lipid metabolism, regulate the immune system, the inflammatory response, and blood pressure. Therefore, targeting the gut microbiota with dietary strategies leading to increased SCFA production may benefit cardio-metabolic health. In this review, we provide an overview of the association between diet, SCFAs produced by the gut microbiota and cardio-metabolic diseases. We first discuss the association between the human gut microbiota and cardio-metabolic diseases, then investigate the role of SCFAs and finally explore the beneficial effects of specific dietary interventions that can improve cardio-metabolic outcomes through boosting the SCFA production.
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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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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).