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1.
Cell Host Microbe ; 32(6): 887-899.e6, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38806059

RESUMO

Inflammation boosts the availability of electron acceptors in the intestinal lumen, creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection increases intestinal levels of the amino acid aspartate. S. Tm used aspartate-ammonia lyase (aspA)-dependent fumarate respiration for growth in the murine gut only during inflammation. AspA-dependent growth advantage was abolished in the gut of germ-free mice and restored in gnotobiotic mice colonized with members of the classes Bacteroidia and Clostridia. Reactive oxygen species (ROS) produced during the host response caused lysis of commensal microbes, resulting in the release of microbiota-derived aspartate that was used by S. Tm, in concert with nitrate-dependent anaerobic respiration, to outcompete commensal Enterobacteriaceae. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent S. Tm expansion during colitis.


Assuntos
Ácido Aspártico , Microbioma Gastrointestinal , Espécies Reativas de Oxigênio , Salmonella typhimurium , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ácido Aspártico/metabolismo , Colite/microbiologia , Colite/metabolismo , Camundongos Endogâmicos C57BL , Enterobacteriaceae/metabolismo , Vida Livre de Germes , Inflamação/microbiologia , Inflamação/metabolismo , Infecções por Salmonella/microbiologia , Infecções por Salmonella/imunologia
2.
Cell Host Microbe ; 31(10): 1604-1619.e10, 2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37794592

RESUMO

The mechanisms by which the early-life microbiota protects against environmental factors that promote childhood obesity remain largely unknown. Using a mouse model in which young mice are simultaneously exposed to antibiotics and a high-fat (HF) diet, we show that Lactobacillus species, predominant members of the small intestine (SI) microbiota, regulate intestinal epithelial cells (IECs) to limit diet-induced obesity during early life. A Lactobacillus-derived metabolite, phenyllactic acid (PLA), protects against metabolic dysfunction caused by early-life exposure to antibiotics and a HF diet by increasing the abundance of peroxisome proliferator-activated receptor γ (PPAR-γ) in SI IECs. Therefore, PLA is a microbiota-derived metabolite that activates protective pathways in the small intestinal epithelium to regulate intestinal lipid metabolism and prevent antibiotic-associated obesity during early life.


Assuntos
Microbiota , Obesidade Infantil , Humanos , Criança , Animais , Camundongos , Metabolismo dos Lipídeos , Dieta Hiperlipídica/efeitos adversos , Antibacterianos , Poliésteres , Camundongos Endogâmicos C57BL
3.
Cell Host Microbe ; 31(10): 1639-1654.e10, 2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37776864

RESUMO

During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients, such as iron. Pathogens scavenge iron using siderophores, including enterobactin; however, this strategy is counteracted by host protein lipocalin-2, which sequesters iron-laden enterobactin. Although this iron competition occurs in the presence of gut bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron and sustains its resilience in the inflamed gut by utilizing siderophores produced by other bacteria, including Salmonella, via a secreted siderophore-binding lipoprotein XusB. Notably, XusB-bound enterobactin is less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella, allowing the pathogen to evade nutritional immunity. Because the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the host-pathogen interactions and nutritional immunity.


Assuntos
Infecções por Salmonella , Sideróforos , Humanos , Lipocalina-2/metabolismo , Sideróforos/metabolismo , Enterobactina/metabolismo , Bactérias/metabolismo , Ferro/metabolismo
4.
bioRxiv ; 2023 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-37425782

RESUMO

During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella , allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.

5.
Cell Mol Gastroenterol Hepatol ; 14(4): 731-750, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35835390

RESUMO

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is characterized by severe gastrointestinal inflammation, but many patients experience extra-intestinal disease. Bone loss is one common extra-intestinal manifestation of IBD that occurs through dysregulated interactions between osteoclasts and osteoblasts. Systemic inflammation has been postulated to contribute to bone loss, but the specific pathologic mechanisms have not yet been fully elucidated. We hypothesized that intestinal inflammation leads to bone loss through increased abundance and altered function of osteoclast progenitors. METHODS: We used chemical, T cell driven, and infectious models of intestinal inflammation to determine the impact of intestinal inflammation on bone volume, the skeletal cytokine environment, and the cellular changes to pre-osteoclast populations within bone marrow. Additionally, we evaluated the potential for monoclonal antibody treatment against an inflammation-induced osteoclast co-receptor, myeloid DNAX activation protein 12-associating lectin-1 (MDL-1) to reduce bone loss during colitis. RESULTS: We observed significant bone loss across all models of intestinal inflammation. Bone loss was associated with an increase in pro-osteoclastogenic cytokines within the bone and an expansion of a specific Cd11b-/loLy6Chi osteoclast precursor (OCP) population. Intestinal inflammation led to altered OCP expression of surface receptors involved in osteoclast differentiation and function, including the pro-osteoclastogenic co-receptor MDL-1. OCPs isolated from mice with intestinal inflammation demonstrated enhanced osteoclast differentiation ex vivo compared to controls, which was abrogated by anti-MDL-1 antibody treatment. Importantly, in vivo anti-MDL-1 antibody treatment ameliorated bone loss during intestinal inflammation. CONCLUSIONS: Collectively, these data implicate the pathologic expansion and altered function of OCPs expressing MDL-1 in bone loss during IBD.


Assuntos
Reabsorção Óssea , Doenças Inflamatórias Intestinais , Lectinas Tipo C , Osteoclastos , Osteogênese , Receptores de Superfície Celular , Animais , Anticorpos Monoclonais/metabolismo , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/fisiologia , Citocinas/metabolismo , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Intestinos/metabolismo , Lectinas/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Camundongos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Osteogênese/fisiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
6.
Cell Rep ; 38(1): 110180, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34986344

RESUMO

The gut microbiota benefits the host by limiting enteric pathogen expansion (colonization resistance), partially via the production of inhibitory metabolites. Propionate, a short-chain fatty acid produced by microbiota members, is proposed to mediate colonization resistance against Salmonella enterica serovar Typhimurium (S. Tm). Here, we show that S. Tm overcomes the inhibitory effects of propionate by using it as a carbon source for anaerobic respiration. We determine that propionate metabolism provides an inflammation-dependent colonization advantage to S. Tm during infection. Such benefit is abolished in the intestinal lumen of Salmonella-infected germ-free mice. Interestingly, S. Tm propionate-mediated intestinal expansion is restored when germ-free mice are monocolonized with Bacteroides thetaiotaomicron (B. theta), a prominent propionate producer in the gut, but not when mice are monocolonized with a propionate-production-deficient B. theta strain. Taken together, our results reveal a strategy used by S. Tm to mitigate colonization resistance by metabolizing microbiota-derived propionate.


Assuntos
Anaerobiose/fisiologia , Propionatos/metabolismo , Salmonelose Animal/patologia , Salmonella typhimurium/crescimento & desenvolvimento , Salmonella typhimurium/metabolismo , Animais , Antibiose/fisiologia , Bacteroides thetaiotaomicron/genética , Bacteroides thetaiotaomicron/metabolismo , Feminino , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Nitratos/metabolismo
7.
Science ; 373(6556): 813-818, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34385401

RESUMO

A Western-style, high-fat diet promotes cardiovascular disease, in part because it is rich in choline, which is converted to trimethylamine (TMA) by the gut microbiota. However, whether diet-induced changes in intestinal physiology can alter the metabolic capacity of the microbiota remains unknown. Using a mouse model of diet-induced obesity, we show that chronic exposure to a high-fat diet escalates Escherichia coli choline catabolism by altering intestinal epithelial physiology. A high-fat diet impaired the bioenergetics of mitochondria in the colonic epithelium to increase the luminal bioavailability of oxygen and nitrate, thereby intensifying respiration-dependent choline catabolism of E. coli In turn, E. coli choline catabolism increased levels of circulating trimethlamine N-oxide, which is a potentially harmful metabolite generated by gut microbiota.


Assuntos
Colo/fisiologia , Dieta Hiperlipídica , Escherichia coli/metabolismo , Mucosa Intestinal/fisiologia , Metilaminas/metabolismo , Animais , Hipóxia Celular , Colina/administração & dosagem , Colina/metabolismo , Colo/citologia , Metabolismo Energético , Células Epiteliais/fisiologia , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Fezes/microbiologia , Microbioma Gastrointestinal , Inflamação , Mucosa Intestinal/metabolismo , Masculino , Metilaminas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Nitratos/metabolismo , Obesidade , Consumo de Oxigênio
8.
Science ; 357(6351): 570-575, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28798125

RESUMO

Perturbation of the gut-associated microbial community may underlie many human illnesses, but the mechanisms that maintain homeostasis are poorly understood. We found that the depletion of butyrate-producing microbes by antibiotic treatment reduced epithelial signaling through the intracellular butyrate sensor peroxisome proliferator-activated receptor γ (PPAR-γ). Nitrate levels increased in the colonic lumen because epithelial expression of Nos2, the gene encoding inducible nitric oxide synthase, was elevated in the absence of PPAR-γ signaling. Microbiota-induced PPAR-γ signaling also limits the luminal bioavailability of oxygen by driving the energy metabolism of colonic epithelial cells (colonocytes) toward ß-oxidation. Therefore, microbiota-activated PPAR-γ signaling is a homeostatic pathway that prevents a dysbiotic expansion of potentially pathogenic Escherichia and Salmonella by reducing the bioavailability of respiratory electron acceptors to Enterobacteriaceae in the lumen of the colon.


Assuntos
Disbiose/metabolismo , Disbiose/microbiologia , Enterobacteriaceae/patogenicidade , Microbioma Gastrointestinal , Óxido Nítrico Sintase Tipo II/metabolismo , PPAR gama/metabolismo , Proteína 4 Semelhante a Angiopoietina/genética , Anilidas/farmacologia , Animais , Antibacterianos/farmacologia , Butiratos/metabolismo , Células CACO-2 , Clostridium/efeitos dos fármacos , Clostridium/metabolismo , Colite/metabolismo , Colite/microbiologia , Colo/metabolismo , Colo/microbiologia , Disbiose/induzido quimicamente , Disbiose/genética , Enterobacteriaceae/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Feminino , Expressão Gênica , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Oxirredução , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Transdução de Sinais , Estreptomicina/farmacologia
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