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Crohn's Disease Forum » Books, Multimedia, Research & News » ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation


07-27-2012, 06:00 PM   #1
kiny
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ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

(I put the essence in pink if you don't want to read the thing)

http://www.nature.com/nature/journal...ture11228.html

Nature Accepted 14 May 2012 Published online 25 July 2012


ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation


Malnutrition affects up to one billion people in the world and is a major cause of mortality1, 2. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death2. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure3, cardiovascular functions4 and SARS infections5. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.

Tatsuo Hashimoto,Thomas Perlot, Ateequr Rehman,Jean Trichereau,Hiroaki Ishiguro, Magdalena Paolino,Verena Sigl,Toshikatsu Hanada, Reiko nada, Simone Lipinski, Birgit Wild, Simone M. R. Camargo, Dustin Singer, Andreas Richter, Keiji Kuba, Akiyoshi Fukamizu,Stefan Schreiber, Hans Clevers,Francois Verrey,Philip Rosenstiel & Josef M. Penninge
08-05-2012, 10:18 AM   #2
rmoretti49
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Hello,

I haven't yet figured out how to access the full article from my university library. Do you have access to it? If so, would you please elaborate on the key statement that tryptophan can regulate this process. Thanks.
08-05-2012, 11:31 AM   #3
kiny
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Hiya, I go to school at KUL in Belgium (computer science), I am there as a "free university" (vrije universiteit) student now (it is for people who are not consistent student because of sickness or because of their job). I don't know if we have nature magazine, it is sunday now and august is vacation for uni students, I will look, access to nature online I have not, I know that.

If you contact author they can often explain your issues. I contact author or ask someone to ask my questions sometimes, and many gracefully give me access to the study. (if you go to link and click under corresponding author, you can talk to author)
08-05-2012, 09:45 PM   #4
Mark in Seattle
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kiny, is this implying that we should be watching to ensure we have adequate tryptophan intake? That's in turkeys right?
08-05-2012, 09:50 PM   #5
kiny
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Think so, the article isn't directly related to crohn. Amino acid shortage can cause inflammation. I will write author if no one does and ask him a question about it.
08-08-2012, 12:23 PM   #6
kiny
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Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity.

BACKGROUND:

Indoleamine 2,3 dioxygenase-1 (IDO1) is a tryptophan catabolizing enzyme with immunotolerance-promoting functions. We sought to determine if increased gut expression of IDO1 in Crohn's disease (CD) would result in detectable changes in serum levels of tryptophan and the initial IDO1 pathway catabolite, kynurenine.

METHODS:

Individuals were prospectively enrolled through the Washington University Digestive Diseases Research Center. The Montreal Classification was used for disease phenotyping. Disease severity was categorized by the Physician's Global Assessment. Serum tryptophan and kynurenine were measured by high-pressure liquid chromatography. IDO1 immunohistochemical staining was performed on formalin-fixed tissue blocks.

RESULTS:

In all, 25 CD patients and 11 controls were enrolled. Eight CD patients had serum collected at two different timepoints and levels of disease activity compared. Strong IDO1 expression exists in both the lamina propria and epithelium during active CD compared to controls. Suppressed serum tryptophan levels and an elevated kynurenine/tryptophan (K/T) ratio were found in individuals with active CD as compared to those in remission or the control population. K/T ratios correlated positively with disease activity as well as with C-reactive protein and erythrocyte sedimentation rate. In the subgroup of CD patients with two serum measurements, tryptophan levels were elevated while kynurenine levels and the K/T ratio lowered as the disease activity lessened.

CONCLUSIONS:

IDO1 expression in CD is associated with lower serum tryptophan and an elevated K/T ratio. These levels may serve as a reasonable objective marker of gut mucosal immune activation and as a surrogate for CD activity.
08-08-2012, 12:27 PM   #7
kiny
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http://www.ncbi.nlm.nih.gov/pmc/arti...6/?tool=pubmed

Analysis of serum protein levels showed that serum albumin, but not total protein level, was decreased in IBD patients. Interestingly, the concentrations of several plasma AAs (e.g. histidine (His) and tryptophan (Trp)) were significantly decreased, while the levels of others were maintained in IBD patients (Table 2). Therefore, the observed changes in the concentrations of plasma AAs suggested that there is a metabolic alteration that occurs in patients with IBD.
08-08-2012, 03:38 PM   #8
Mark in Seattle
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You're a real sleuth kiny! Now is the metabolic alteration a cause or effect? And can the deficient plasma level(s) be rectified? I wonder if this is why elemental/total parental diet is often helpful.
08-08-2012, 04:01 PM   #9
Mark in Seattle
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..a little snippet from paragraphs 2 & 3 of the "Discussion" section of the latest research article that kiny posted, discussing therapeutic info. about supplementing these amino's in settings of inflammation....


"These observations suggest that the decreased plasma His and Trp in IBD patients may reflect the chronic inflammatory condition, and that supplementation with His and Trp may be a novel therapeutic strategy for IBD. Trp is metabolized into kynurenine by the catabolic enzyme, indoleamine 2,3-dioxygenase (IDO), and Trp metabolism has recently been highlighted as an immunological regulator [13], [14], [15]. It is also reported that plasma kynurenine concentrations and IDO transcription levels are altered in inflamed tissue of IBD patients [16], [17].

Consistent with our observations, plasma His concentrations are decreased in several chronic inflammatory disorders such as rheumatoid arthritis and chronic kidney disease [18], [19], and are inversely correlated with the erythrocyte segmentation ratio (ESR) in rheumatoid arthritis patients [18]. In a clinical trial of rheumatoid arthritis patients, supplementation of 4.5 g L-His for 30 days showed clinical benefits in patients with more active and prolonged disease [20]. In chronic kidney disease, plasma His concentrations are inversely correlated with CRP and hepatocyte growth factor, markers that reflect inflammation [19]. Furthermore, enteral nutrition therapy using an elemental diet, with a His density more than twice that of the recommended WHO/FAO/UN requirement, has shown efficacy in CD [21]. Importantly, we previously reported that orally administered His ameliorates intestinal inflammation in an IL-10-deficient transfer mouse colitis model by inhibiting the production of pro-inflammatory cytokines by activated macrophages through intracellular mechanisms [22]."
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