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3 results on '"Marco Constante"'

1. Crohn’s disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice

Author

Alba Santiago, Amber Hann, Marco Constante, Sara Rahmani, Josie Libertucci, Kyle Jackson, Gaston Rueda, Laura Rossi, Rithwik Ramachandran, Wolfram Ruf, Jon Schertzer, Alberto Caminero, Premysl Bercik, Heather Jean Galipeau, and Elena Francisca Verdu

Subjects
Crohn’s disease, proteolytic activity, inflammation, DSS-induced colitis, Proteinase-activated receptor 2 (PAR2), gnotobiotic mice, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

ABSTRACTEmerging evidence implicates microbial proteolytic activity in ulcerative colitis (UC), but whether it also plays a role in Crohn’s disease (CD) remains unclear. We investigated the effects of colonizing adult and neonatal germ-free C57BL/6 mice with CD microbiota, selected based on high (CD-HPA) or low fecal proteolytic activity (CD-LPA), or microbiota from healthy controls with LPA (HC-LPA) or HPA (HC-HPA). We then investigated colitogenic mechanisms in gnotobiotic C57BL/6, and in mice with impaired Nucleotide-binding Oligomerization Domain-2 (NOD2) and Protease-Activated Receptor 2 (PAR2) cleavage resistant mice (Nod2−/−; R38E-PAR2 respectively). At sacrifice, total fecal proteolytic, elastolytic, and mucolytic activity were analyzed. Microbial community and predicted function were assessed by 16S rRNA gene sequencing and PICRUSt2. Immune function and colonic injury were investigated by inflammatory gene expression (NanoString) and histology. Colonization with HC-LPA or CD-LPA lowered baseline fecal proteolytic activity in germ-free mice, which was paralleled by lower acute inflammatory cell infiltrate. CD-HPA further increased proteolytic activity compared with germ-free mice. CD-HPA mice had lower alpha diversity, distinct microbial profiles and higher fecal proteolytic activity compared with CD-LPA. C57BL/6 and Nod2−/− mice, but not R38E-PAR2, colonized with CD-HPA had higher colitis severity than those colonized with CD-LPA. Our results indicate that CD proteolytic microbiota is proinflammatory, increasing colitis severity through a PAR2 pathway.

Published
2023
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2. The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages

Author

Phoenix Toboz, Mehdi Amiri, Negar Tabatabaei, Catherine R. Dufour, Seung Hyeon Kim, Carine Fillebeen, Charles E. Ayemoba, Arkady Khoutorsky, Manfred Nairz, Lijian Shao, Kostandin V. Pajcini, Ki-Wook Kim, Vincent Giguère, Regiana L. Oliveira, Marco Constante, Manuela M. Santos, Carlos R. Morales, Kostas Pantopoulos, Nahum Sonenberg, Sandra Pinho, and Soroush Tahmasebi

Subjects
Mice, Knockout, Erythrocytes, Multidisciplinary, NF-E2-Related Factor 2, Iron, Macrophages, Anemia, Protein Serine-Threonine Kinases, Activating Transcription Factor 4, Hemolysis, Mice, Liver, Cytophagocytosis, Stress, Physiological, Animals, Amino Acids, Hypoxia, Lysosomes, Gene Deletion
Abstract

GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that controls messenger RNA translation in response to amino acid availability and ribosome stalling. Here, we show that GCN2 controls erythrocyte clearance and iron recycling during stress. Our data highlight the importance of liver macrophages as the primary cell type mediating these effects. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia,GCN2knockout (GCN2−/−) mice displayed resistance to anemia compared with wild-type (GCN2+/+) mice.GCN2−/−liver macrophages exhibited defective erythrophagocytosis and lysosome maturation. Molecular analysis ofGCN2−/−cells demonstrated that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating red blood cell clearance and iron recycling.

Published
2022

3. Biogeographic Variation and Functional Pathways of the Gut Microbiota in Celiac Disease

Author

Marco Constante, Josie Libertucci, Heather J. Galipeau, Jake C. Szamosi, Gaston Rueda, Pedro M. Miranda, Maria Ines Pinto-Sanchez, Carolyn M. Southward, Laura Rossi, Michelle E. Fontes, Fernando G. Chirdo, Michael G. Surette, Premysl Bercik, Alberto Caminero, and Elena F. Verdu

Subjects
Mice, Celiac Disease, Hepatology, Glutens, RNA, Ribosomal, 16S, Gastroenterology, Animals, Gastrointestinal Microbiome, Peptide Hydrolases
Abstract

Genes and gluten are necessary but insufficient to cause celiac disease (CeD). Altered gut microbiota has been implicated as an additional risk factor. Variability in sampling site may confound interpretation and mechanistic insight, as CeD primarily affects the small intestine. Thus, we characterized CeD microbiota along the duodenum and in feces and verified functional impact in gnotobiotic mice.We used 16S rRNA gene sequencing (Illumina) and predicted gene function (PICRUSt2) in duodenal biopsies (D1, D2 and D3), aspirates, and stool from patients with active CeD and controls. CeD alleles were determined in consented participants. A subset of duodenal samples stratified according to similar CeD risk genotypes (controls DQ2Microbiota composition and predicted function in CeD was largely determined by intestinal location. In the duodenum, but not stool, there was higher abundance of Escherichia coli (D1), Prevotella salivae (D2), and Neisseria (D3) in CeD vs controls. Predicted bacterial protease and peptidase genes were altered in CeD and impaired gluten degradation was detected only in mice colonized with CeD microbiota.Our results showed luminal and mucosal microbial niches along the gut in CeD. We identified novel microbial proteolytic pathways involved in gluten detoxification that are impaired in CeD but not in controls carrying DQ2, suggesting an association with active duodenal inflammation. Sampling site should be considered a confounding factor in microbiome studies in CeD.

Published
2022

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