Review for 10.1186/1471-230X-12-76 (2012)

Reviewer's report
Title:Comparative analysis of inflamed and non-inflamed colon biopsies reveals
strong proteomic inflammation profile in patients with ulcerative colitis
Version: 1Date:28 March 2012
Reviewer: Ryan Stidham
Reviewer's report:
Purpose and significance: This study retrospectively evaluates variation in
mucosal & submucosal proteomic profiles of patients with ulcerative proctitis,
with the intentions of identifying novel biomarkers of disease activity and
elucidating new mechanisms and pathways driving inflammation in inflammatory
bowel disease. There is a need for non-invasive surrogates of mucosal
inflammation and disease activity in ulcerative colitis. I agree that fecal
calprotectin, lactoferrin, C-reactive protein, and imaging do not necessarily reflect
inflammation specific to ulcerative colitis.
Methods: The authors perform paired analysis of endoscopically inflamed and
normal mucosa in those with UC, controlling for individual variation. Sample size
is appropriate given bioinformatics necessary for proteomics. I do have
reservations about the variation in the UC cohort, specifically that 10/20 were
using 5-ASA, 4 were untreated, and two were using renin-angiotensin inhibitors.
Further, the authors state (68-70) that inflammatory biomarkers and pathways of
interest need to be specific to ulcerative colitis and not other causes of colitis
(infectious, neoplastic, medication-induced). An additional comparison group
comprised of non-IBD related inflammation (C. diff colitis mucosal biopsies)
should be included to clarify pathways specific to ulcerative colitis. Ulcerative
proctitis variation in severity impacts histology, cellularity, protein expression, and
likely post-translational protein modification. Histology results, namely grade of
inflammation is not reported and should be to characterize patient characteristics.
Ideally patients would have a consistant grade of inflammation, both
endoscopically and histologically, for more uniform results, especially since fold
change of protein expression is reported. To demonstrate whether normal control
and endoscopically normal UC mucosa are comparable, I would include a direct
comparison of proteomic profiles of control left colon and non-inflamed UC left
colon mucosal biopsies. Further, the variation in control group protein expression
demonstrates the lack of a standard protein profile of colonic mucosal, at least in
this study population. Sound statistical methods used do identify 33 unique
proteins with at least a two fold expression change between inflamed and
non-inflamed mucosa in ulcerative proctitis subjects. These results do highlight
metabolic pathways involved in ulcerative colitis, however nothing specific can be
concluded. Characterizing the consistent elements of mucosal protein profiles
serves an important role for future proteomic investigations in UC, however this
study is very preliminary and few conclusions can be drawn.
This study reports unique mucosal proteins differentially expressed in inflamed
mucosa compared to normal mucosal in patients with ulcerative proctitis. There
is value within the field of suggesting novel metabolic pathways potentially driving
inflammation in ulcerative colitis, especially as proteomics becomes more
accessible. The results from this study, remain far from having clinical impact.
The variance reported, even in glycerol-3-phosphate-dehydrogenase, is small. In
addition, it is unclear if any of these markers can be used as a biomarker, as
there were no comparisons to stool or serum detection of high-variance
compounds by ELISA or other high-throughput assays. A biomarker that
non-invasively better correlates to histology or endoscopic appearance of
mucosa or predicts response to specific therapies, would be clinically useful.
To strengthen this manuscript I would recommend:
Major Revision
1. Clearly state in the abstract and background that the purpose of this work is to
describe the proteomic profile in ulcerative colitis, not the express discovery of
new biomarkers.
2. Narrow the UC cohort to identical medical therapy (all 5-ASA, all treatment
naïve, etc) including non-IBD medications and reanalyze the data. This should be
possible given the small number of patients necessary to enroll.
3. Add a non-IBD inflammation control group (i.e. C diff colitis distal colon
biopsies) for comparison and clarification of proteins unique to IBD related
inflammation.
Minor Revision
4. Please provide histology inflammation grading for UC cohort.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests.