Chemically induced mouse models of acute and chronic intestinal inflammation

Wirtz, Stefan; Popp, Vanessa; Kindermann, Markus; Gerlach, Katharina; Weigmann, Benno; Fichtner‐Feigl, Stefan; Neurath, Markus F.

doi:10.1038/nprot.2017.044

Cited by 1,012 publications

(1,026 citation statements)

References 59 publications

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“…This mechanism suggests that the SPXX motif plays a negative regulatory role in multiple proteins. The characteristics of DSS-induced colitis in the mouse model resemble those of human UC (Wirtz et al, 2017). As expected, LIF administration dramatically ameliorated colitis pathology in the mouse model, but only in wild-type mice, not in Stat4 À/À mice.…”

Section: Discussionsupporting

confidence: 71%

STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

et al. 2019

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T helper 17 (Th17)‐cell differentiation triggered by interleukin‐6 (IL‐6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL‐6 family cytokine, restricts inflammation by blocking Th17‐cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C‐terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis‐inducible elements (SIEs) and noncanonical “AGG” elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3‐dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.

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Section: Discussionsupporting

confidence: 71%

STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

et al. 2019

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“…Of note, the latter group employed a very harsh 5% DSS regimen which resulted in >60% mortality in the control group after 14 days. Importantly, established protocols recommend using 2% DSS . Kverka et al .…”

Section: Discussionmentioning

confidence: 99%

Parabacteroides distasonis attenuates toll‐like receptor 4 signaling and Akt activation and blocks colon tumor formation in high‐fat diet‐fed azoxymethane‐treated mice

Koh

Kane

Lee

et al. 2018

Intl Journal of Cancer

100

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Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1β concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week old male A/J mice were fed a low-fat diet (LF), high-fat diet (HF), or HF+ whole freeze-dried Pd (HF+Pd, 0.04% w/w) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane (AOM). PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF+Pd mice (0 of 20) (P = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action. This article is protected by copyright. All rights reserved.

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“…[35] At 4 h after oral delivery, ex vivo imaging showed significantly higher fluorescent signals in colons from colitis mice compared to those of healthy mice ( Figure 3A, the left panel). We first examined the accumulation of AON at the injury sites of the inflamed colon, using AON loaded with Cy7.5-labeled Ac2-26 (abbreviated as Cy7.5-AON).…”

Section: The Distribution Of Orally Delivered Aon In the Inflamed Colonmentioning

confidence: 98%

A Proresolving Peptide Nanotherapy for Site‐Specific Treatment of Inflammatory Bowel Disease by Regulating Proinflammatory Microenvironment and Gut Microbiota

et al. 2019

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The incidence and prevalence of inflammatory bowel disease (IBD) increases steadily worldwide. There is an urgent need for effective and safe IBD therapies. Accelerated resolution of inflammation is a new strategy for the management of inflammatory diseases. For effective and safe IBD treatment, herein a smart nanotherapy (i.e. oxidation‐responsive nanoparticles containing a proresolving annexin A1‐mimetic peptide Ac2‐26, defined as AON) is developed, which can release packaged Ac2‐26, in response to highly expressed reactive oxygen species (ROS) at diseased sites. AON effectively protects Ac2‐26 from degradation in the enzyme‐rich environment of the gastrointestinal tract. By delivering this nanotherapy to the inflamed colons of mice with IBD, site‐specific release and accumulation of Ac2‐26 in response to high levels of ROS at the inflammatory sites are achieved. Mechanistically, the Ac2‐26‐containing, oxidation‐labile nanotherapy AON effectively decreases the expression of proinflammatory mediators, attenuates trafficking and infiltration of inflammatory cells, promotes efferocytosis of apoptotic neutrophils, and increases phenotypic switching of macrophages. Therapeutically, AON reduces symptoms of inflammation, accelerates intestinal mucosal wound healing, reshapes the gut microbiota composition, and increases short‐chain fatty acid production. Additionally, oral delivery of this nanomedicine shows excellent safety profile in a mouse model, conferring the confidence for further development of a targeted precision therapy for IBD and other inflammatory diseases.

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Chemically induced mouse models of acute and chronic intestinal inflammation

Cited by 1,012 publications

References 59 publications

STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

Parabacteroides distasonis attenuates toll‐like receptor 4 signaling and Akt activation and blocks colon tumor formation in high‐fat diet‐fed azoxymethane‐treated mice

A Proresolving Peptide Nanotherapy for Site‐Specific Treatment of Inflammatory Bowel Disease by Regulating Proinflammatory Microenvironment and Gut Microbiota

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