Age-Related Changes in Gut Microbiota Alter Phenotype of Muscularis Macrophages and Disrupt Gastrointestinal Motility.
Ontology highlight
ABSTRACT:
SUBMITTER: Becker L
PROVIDER: S-EPMC6305843 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Age-Related Changes in Gut Microbiota Alter Phenotype of Muscularis Macrophages and Disrupt Gastrointestinal Motility.
Becker Laren L Spear Estelle T ET Sinha Sidhartha R SR Haileselassie Yeneneh Y Habtezion Aida A
Cellular and molecular gastroenterology and hepatology 20180917 1
Similar Datasets
Project description:Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:
| S-EPMC4149228 | biostudies-literature
Project description: Not available
| S-EPMC6477476 | biostudies-literature
Project description:Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNAseq of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later – or not at all – showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early life microbiome in later life dysmotility.
2024-10-15 | GSE241697 | GEO
Project description:Peristaltic movement of the intestine propels food down the length of the gastrointestinal tract to promote nutrient absorption. Interactions between intestinal macrophages and the enteric nervous system regulate gastrointestinal motility, yet we have an incomplete understanding of the molecular mediators of this crosstalk. Here, we identify complement component 1q (C1q) as a macrophage product that regulates gut motility. Macrophages were the predominant source of C1q in the mouse intestine and most extraintestinal tissues. Although C1q mediates the complement-mediated killing of bacteria in the bloodstream, we found that C1q was not essential for the immune defense of the intestine. Instead, C1q-expressing macrophages were located in the intestinal submucosal and myenteric plexuses where they were closely associated with enteric neurons and expressed surface markers characteristic of nerve-adjacent macrophages in other tissues. Mice with a macrophage-specific deletion of C1qa showed changes in enteric neuronal gene expression, increased neurogenic activity of peristalsis, and accelerated intestinal transit. Our findings identify C1q as a key regulator of gastrointestinal motility and provide enhanced insight into the crosstalk between macrophages and the enteric nervous system.
| S-EPMC10185340 | biostudies-literature
Project description:Background and aimsMuscularis macrophages (MMs) are tissue-resident macrophages in the gut muscularis externa which play a supportive role to the enteric nervous system. We have previously shown that age-dependent MM alterations drive low-grade enteric nervous system inflammation, resulting in neuronal loss and disruption of gut motility. The current studies were designed to identify the MM genetic signature involved in these changes, with particular emphasis on comparison to genes in microglia, the central nervous system macrophage population involved in age-dependent cognitive decline.MethodsYoung (3 months) and old (16-24 months) C57BL/6 mice and human tissue were studied. Immune cells from mouse small intestine, colon, and spinal cord and human colon were dissociated, immunophenotyped by flow cytometry, and examined for gene expression by single-cell RNA sequencing and quantitative real-time PCR. Phagocytosis was assessed by in vivo injections of pHrodo beads (Invitrogen). Macrophage counts were performed by immunostaining of muscularis whole mounts.ResultsMMs from young and old mice express homeostatic microglial genes, including Gpr34, C1qc, Trem2, and P2ry12. An MM subpopulation that becomes more abundant with age assumes a geriatric state (GS) phenotype characterized by increased expression of disease-associated microglia genes including Cd9, Clec7a, Itgax (CD11c), Bhlhe40, Lgals3, IL-1β, and Trem2 and diminished phagocytic activity. Acquisition of the GS phenotype is associated with clearance of α-synuclein aggregates. Human MMs demonstrate a similar age-dependent acquisition of the GS phenotype associated with intracellular α-synuclein accumulation.ConclusionMMs demonstrate age-dependent genetic changes that mirror the microglial disease-associated microglia phenotype and result in functional decline.
| S-EPMC10003669 | biostudies-literature
Project description:Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNA sequencing (RNA-seq) of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later-or not at all-showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early-life microbiome in later-life dysmotility.
| S-EPMC11440258 | biostudies-literature
Project description:Regulators of Gut Motility Revealed by a Gnotobiotic Model of Diet-Microbiome Interactions Related to Travel
| PRJEB9169 | ENA
Project description:The association of gut microbiota with gastrointestinal carcinogenesis has been heavily investigated since the recent advance in sequencing technology. Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression. Given by its importance, emerging studies have focussed on targeting microbiota to ameliorate therapeutic effectiveness. It is now clear that the microbial community is closely related to the efficacy of chemotherapy, while the correlation of microbiota with immunotherapy is much less studied. Herein, we review the up-to-date findings on the influence of gut microbiota on three common immunotherapies including adoptive cell transfer, immune checkpoint blockade, and CpG-oligodeoxynucleotide therapy. We then explore three microbiota-targeted strategies that may improve treatment efficacy, involving dietary intervention, probiotics supplementation, and fecal microbiota transplantation.
| S-EPMC7808428 | biostudies-literature
Project description:While fecal microbiota transplantation (FMT) presents an attractive therapeutic strategy, it remains unclear how to choose the microbiota repertoire that most effectively transfers benefit to recipients. We identified a beneficial taxonomic repertoire in a transgenic mouse model (RIP140mϕKD) which resists the development of high fat diet (HFD)-induced metabolic diseases due to enhanced anti-inflammation engineered by lowering receptor interacting protein (RIP140) expression in macrophage. We confirmed using FMT from HFD-fed RIP140mϕKD to wild type (WT) mice that recipient mice acquired the microbiota repertoire of donor mice. Importantly, FMT from RIP140mϕKD to WT not only effectively transferred the beneficial taxonomic repertoire to WT recipients, but also enabled recipient animals acquiring the anti-inflammatory status of RIP140mϕKD donor animals and avoid HFD-induced insulin resistance, which is associated with significantly improved intestinal integrity. We conclude that FMT can transfer not only microbiota but also the donors' intestinal innate immune status and improved intestinal integrity.
| S-EPMC5144013 | biostudies-literature
Project description:The gastrointestinal tract is responsible for food digestion and absorption. The muscularis propria propels the foodstuff through the GI tract and defects in intestine motility may cause obstruction disorders. Our present genetic studies identified non-receptor tyrosine kinase c-Abl as an important regulator of the muscularis propria homeostasis and a risk factor for rectal prolapse. Mouse deficient for c-Abl showed defects in the muscularis propria of gastrointestinal tract and older c-Abl -/- mice developed megaesophagus and rectal prolapse. Inhibition of c-Abl with imatinib mesylate, an anti-CML drug, or ablation of c-Abl using Prx1-Cre, which marks smooth muscle cells, recapitulated most of the muscularis propria phenotypes. The pathogenesis of rectal prolapse was attributable to overproliferation of smooth muscle cells, which was caused by enhanced ERK1/2 activation. Administration of ERK inhibitor U0126 impeded the development of rectal prolapse in c-Abl deficient mice. These results reveal a role for c-Abl-regulated smooth muscle proliferation in the pathogenesis of rectal prolapse, and imply that long-term use of imatinib mesylate may cause gastrointestinal problems in patients while ERK inhibitor may be effective in treating rectal prolapse.
| S-EPMC5472598 | biostudies-literature