Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease

Potdar, Alka A.; Dube, Shishir; Naito, Takeo; Li, Katherine; Botwin, Gregory J.; Haritunians, Talin; Li, Dalin; Casero, David; Yang, Shaohong; Bilsborough, Janine; Perrigoue, Jacqueline; Denson, Lee A.; Daly, Mark J.; Targan, Stephan R.; Fleshner, Phillip; Braun, Jonathan; Kugathasan, Subra; Stappenbeck, Thaddeus S.; McGovern, Dermot

doi:10.1053/j.gastro.2020.10.041

Cited by 56 publications

(88 citation statements)

References 60 publications

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“…In both mouse models we have found that values of R squared indicated a close correlation between the expression of Ace2 and the pro-inflammatory cytokine Tnf-α. These data are in agreement with the reducing effect on ACE2 expression in the colon of IBD patients exerted by therapy with anti-TNF-α [12, 52]. Confirmation of the direct regulation of ACE2 expression exerted by TNF-α was given by the in vitro experiment on human intestinal epithelial cell line (Caco-2).…”

Section: Discussionsupporting

confidence: 86%

“…The regulatory effects of pelargonidin on the intestinal ACE2 might be of relevance in the context of SARS-CoV2 infection, since high levels of ACE2 are compatible with an increased risk of SARS-CoV2 uptake by the inflamed colon [12]. Importantly, in addition to ACE2 regulation, we have shown that beneficial effects of pelargonidin might extend to a direct regulation of SARS-CoV2/ACE2 interaction.…”

Section: Discussionmentioning

confidence: 89%

“…Recent data suggest that colon inflammation up-regulates the expression of Ace2. Studies of IBD patients have shown that a direct correlation exists between the severity of colon inflammation and the expression of ACE2 [12, 13, 45].…”

Section: Discussionmentioning

confidence: 99%

“…In normal individual, ACE2 mRNA and protein are highly expressed in the gastrointestinal system, in particular in the duodenum, jejunum, ileum, and colon, although the functional role of this peptidase in intestinal epithelial cells remains portly elucidated [11]. Furthermore, similarly to the lung, the intestinal expression of ACE2 is modulated in response to intestinal inflammation in inflammatory bowel disease (IBD) in a phenotype dependent manner [12]. More specifically, while expression of Ace2 is reduced in the ileum of patients with active Crohn disease, an elevated colonic expression of ACE2 mRNA has been reported in ulcerative colitis patients with active inflammation and severe disease [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a AhR flavonoid agonist that counter-regulates ACE2 expression in rodent models of inflammation and attenuates ACE2-SARS-CoV2 interaction in vitro

Biagioli

Marchianò

Roselli

et al. 2021

Preprint

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The severe acute respiratory syndrome (SARS)-CoV-2, a newly emerged coronavirus first identified in 2019, is the pathogenetic agent od Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE) 2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of ACE2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin, a natural flavonoid bind and activates the Aryl hydrocarbon Receptor (AhR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent DSS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of ACE2 mRNA expression. Colon levels of ACE2 mRNA were directly correlated with TNFα mRNA levels. In contrast to ACE2 the angiotensin 1-7 receptor MAS was downregulated in the inflamed tissues. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV2 Spike protein to ACE2 and reduces the SARS-CoV2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of a AhR flavonoid agonist that counter-regulates ACE2 expression in rodent models of inflammation and attenuates ACE2-SARS-CoV2 interaction in vitro

Biagioli

Marchianò

Roselli

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…IBD medications, both biologic and non-biologic, did not significantly impact the expression of both genes in the uninflamed small intestine 5 . However, Potdar et al revealed that within CD, small bowel ACE2 was reduced in patients subsequently developing complicated disease and that its expression was restored in responders to biologic therapy 6 . However, there remain three major gaps in our knowledge not addressed by recent studies reporting on ACE2 expression and its association with clinical IBD.…”

Section: Introductionmentioning

confidence: 99%

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s disease

Toyonaga

Araba

Kennedy

et al. 2020

Preprint

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Background and AimsThe host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn’s disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course.MethodsWe examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients.ResultsColonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037).ConclusionIncreased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

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Bioadhesive Microcarriers Encapsulated with IL‐27 High Expressive MSC Extracellular Vesicles for Inflammatory Bowel Disease Treatment

Nie,

Huang,

Chen

et al. 2023

Advanced Science

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Mesenchymal stem cell (MSC) therapy is a promising candidate for inflammatory bowel disease (IBD) treatment, while overcoming the limitations of naive seeding cells function and realizing efficient intestinal targeting remains a challenge. Here, a bioadhesive microparticle carrying interleukin‐27 (IL‐27) MSC‐derived extracellular vesicles (MSCIL‐27 EVs) is developed to treat IBD. The MSCIL‐27 EVs prepared through lentivirus‐mediated gene transfection technology show ideal anti‐inflammatory and damage repair function. By encapsulating MSCIL‐27 EVs into dopamine methacrylamide‐modified hydrogel, a bioadhesive EVs microcarrier via microfluidic technology is fabricated. The resultant microcarriers exhibit ideal MSCIL‐27 EVs sustained release effect and effective wet adhesion property. Furthermore, the therapeutic potential of MSCIL‐27 EVs‐loaded microcarriers in treating IBD is demonstrated. Through giving IBD rats a rectal administration, it is found that the microcarriers can firmly anchor to the surface of colon, reduce the inflammatory response, and repair the damaged barrier. Therefore, the bioadhesive MSCIL‐27 EVs‐loaded microcarriers provide a promising strategy for the biomedical application of MSC‐derived EVs, and broaden the clinical potential of MSC therapy.

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Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease

Cited by 56 publications

References 60 publications

Discovery of a AhR flavonoid agonist that counter-regulates ACE2 expression in rodent models of inflammation and attenuates ACE2-SARS-CoV2 interaction in vitro

Discovery of a AhR flavonoid agonist that counter-regulates ACE2 expression in rodent models of inflammation and attenuates ACE2-SARS-CoV2 interaction in vitro

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s disease

Bioadhesive Microcarriers Encapsulated with IL‐27 High Expressive MSC Extracellular Vesicles for Inflammatory Bowel Disease Treatment

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