Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling

Reinhardt, Carsten; Bergentall, Mattias; Greiner, Thomas U.; Schaffner, Florence; Östergren‐Lundén, Gunnel; Petersen, Lars C.; Ruf, Wolfram; Bäckhed, Fredrik

doi:10.1038/nature10893

Cited by 221 publications

(158 citation statements)

References 33 publications

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“…Similarly, EPAS1 has been shown to improve insulin sensitivity and fat homeostasis (Shimba et al, 2004) and in this study, EPAS1 was upregulated during the transition period, likely as a response to the negative energy balance described above. F2RL1 and PPAR2 are central signaling genes and originate from the signal clotting cascade in a wide variety of tissues (Reinhardt et al, 2012). In the present study, F2RL1 expression increased likely as a result of MAPK signaling in negative energy balance.…”

Section: Gene Expression and Biological Interactome Analysissupporting

confidence: 50%

Transcriptomic Changes in Ruminal Tissue Induced by the Periparturient Transition in Dairy Cows

Dionissopoulos

AlZahal

Steele

et al. 2014

American Journal of Animal and Veterinary Sciences

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To understand how the capacity for fat metabolism (uptake, synthesis, modification) changes in rumen epithelia immediately before and after onset of lactation in dairy cows, rumen fluid Short Chain Fatty Acid (SCFA) concentrations and mRNA expression profiles of rumen epithelia was determined in twelve Holstein dairy cows at three weeks prior to calving (wk -3, n = 12), one week post calving (week +1, n = 12) and six weeks (week +6, n = 12) after calving. The diet was modified from a dry cow formulation to a lactating cow formulation immediately following parturition and raised the non-fiber carbohydrate level from 34 to 43%. All data was analyzed using the mixed procedure of SAS, with cows blocked by anticipated calving date and week of sampling as the repeated measure. Propionate, butyrate, isovalerate and valerate levels rose significantly following the diet change (p≤0.001), although acetate and isobutyrate levels were unchanged (p>0.05). Mean rumen pH also changed during the transition period (6.38 Vs 5.81 and 5.85±0.08; -3 Vs +1 and +6; p<0.001) as did mean BW (716.00 Vs 635.82 kg and 615.45 kg ±16.20; -3 Vs +1 and +6; p≤0.002). Microarray analysis of total RNA from rumen epithelial biopsies revealed 1476 differentially expressed genes at a false discovery rate of 10%. These results were filtered for genes that were directly related to both the immune system and fat metabolism/homeostasis. Consequently, the expression of the resulting 28 genes was analyzed by quantitative PCR (qRT-PCR) to compare their expression at period -3 versus +6 periods. qRT-PCR analysis revealed that 13 genes were upregulated (p≤0.01), 2 were downregulated (p≤0.01) and 13 were unchanged during the transition period. Pathway and context analysis yielded a unique interactome pathway map which revealed a set of genomic interactions that indicate a link between selected genes from the immune system and those involved in the preparation for lactation.

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Section: Gene Expression and Biological Interactome Analysissupporting

confidence: 50%

Transcriptomic Changes in Ruminal Tissue Induced by the Periparturient Transition in Dairy Cows

Dionissopoulos

AlZahal

Steele

et al. 2014

American Journal of Animal and Veterinary Sciences

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“…The vasculature of the intestine is known to develop postnatally with the influence of the microbiota (38,39). However, the developmental and microbiota-dependent regulation of this process remains poorly understood.…”

Section: Resultsmentioning

confidence: 99%

Analysis of gene–environment interactions in postnatal development of the mammalian intestine

Rakoff-Nahoum

Kong

Kleinstein

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development.

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“…To test whether caspase-8 increasingly binds FADD following IFN treatment, we used PLA (proximity ligation assay) (42)(43)(44). This method detects the proximity of endogenous proteins in individual cells, suggesting either direct or indirect interactions between them.…”

Section: Ifn-induced Apoptosis Is Death Ligand Independentmentioning

confidence: 99%

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

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Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling

Cited by 221 publications

References 33 publications

Transcriptomic Changes in Ruminal Tissue Induced by the Periparturient Transition in Dairy Cows

Transcriptomic Changes in Ruminal Tissue Induced by the Periparturient Transition in Dairy Cows

Analysis of gene–environment interactions in postnatal development of the mammalian intestine

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

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