Reviewer's report
Title:Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype
Version: 2Date:20 July 2010
Reviewer: Jonathan Kaunitz
Reviewer's report:
Comment:
The authors have revised the manuscript somewhat by adding some of the
citations suggested by the reviewers. Nevertheless, many of the reviewers'
comments have not yet been answered satisfactorily.
Major Compulsory Revisions
1. As Dr. De Jonge stated in his review, the main intestinal phenotype of CFTR
-/- mice is intestinal obstruction and decreased survival. The phenotypic changes
reported by the authors, such as bacterial overgrowth and delayed intestinal
transit although present, are less well characterized.
2. Although the literature is divided about the mechanism of action of
lubiprostone with regard to intestinal anion secretion, the preponderance of the
data strongly favors lubiprostone acting as a local prostaglandin that activates
CFTR in most cases. I am aware of few in situ data obtained from intact
organisms that support the alternative explanation.
3. The authors make several statements stating that lubiprostone "may" increase
bicarbonate secretion, even this was clearly shown in rats in ref. 20.
4. The authors use rhoadmine dextran to measure intestinal transit. Although the
authors state that it is a "nondigestible, nonabsorbable tracer", dextran is
fermented by colonic flora into butyrate (Olano-Martin E, Mountzouris KC, Gibson
GR, Rastall RA. In vitro fermentability of dextran, oligodextran and maltodextrin
by human gut bacteria. Br J Nutr. 2000 83:247-55). Given the marked differences
of intestinal bacterial colonization between the groups, would the use of this
marker add artifact to the measurements?
5. The authors speculate that some of their findings may be due to changes in
the hydration status of mucus. Yet, mucus in biological systems in considered to
be 99% hydrated. If the authors area aware of intestinal mucus in healthy living
animals that is not fully hydrated, these data should be cited.
6. Since the authors did not measure immune cell function but rather reported
expression changes of immune-function related genes, I reiterate my prior
comment that the data should not be reported as the "innate immune response"
or equivalent. Lacking direct measurements of mast cell migration or actual
measures of immune function, it is exceedingly difficult to interpret expression
changes of this nature.
7. The Discussion is overly long and speculative and would thus benefit from
deletion of many of its sections, despite the authors statements to the contrary.
Minor Essential Revisions
The authors should consider combining Figs. 2 and 3
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
Yes, reserach support from Takeda NA.
Reviewer's report
Title:Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype
Version: 2Date:20 July 2010
Reviewer: Jonathan Kaunitz
Reviewer's report:
Comment:
The authors have revised the manuscript somewhat by adding some of the
citations suggested by the reviewers. Nevertheless, many of the reviewers'
comments have not yet been answered satisfactorily.
Major Compulsory Revisions
1. As Dr. De Jonge stated in his review, the main intestinal phenotype of CFTR
-/- mice is intestinal obstruction and decreased survival. The phenotypic changes
reported by the authors, such as bacterial overgrowth and delayed intestinal
transit although present, are less well characterized.
2. Although the literature is divided about the mechanism of action of
lubiprostone with regard to intestinal anion secretion, the preponderance of the
data strongly favors lubiprostone acting as a local prostaglandin that activates
CFTR in most cases. I am aware of few in situ data obtained from intact
organisms that support the alternative explanation.
3. The authors make several statements stating that lubiprostone "may" increase
bicarbonate secretion, even this was clearly shown in rats in ref. 20.
4. The authors use rhoadmine dextran to measure intestinal transit. Although the
authors state that it is a "nondigestible, nonabsorbable tracer", dextran is
fermented by colonic flora into butyrate (Olano-Martin E, Mountzouris KC, Gibson
GR, Rastall RA. In vitro fermentability of dextran, oligodextran and maltodextrin
by human gut bacteria. Br J Nutr. 2000 83:247-55). Given the marked differences
of intestinal bacterial colonization between the groups, would the use of this
marker add artifact to the measurements?
5. The authors speculate that some of their findings may be due to changes in
the hydration status of mucus. Yet, mucus in biological systems in considered to
be 99% hydrated. If the authors area aware of intestinal mucus in healthy living
animals that is not fully hydrated, these data should be cited.
6. Since the authors did not measure immune cell function but rather reported
expression changes of immune-function related genes, I reiterate my prior
comment that the data should not be reported as the "innate immune response"
or equivalent. Lacking direct measurements of mast cell migration or actual
measures of immune function, it is exceedingly difficult to interpret expression
changes of this nature.
7. The Discussion is overly long and speculative and would thus benefit from
deletion of many of its sections, despite the authors statements to the contrary.
Minor Essential Revisions
The authors should consider combining Figs. 2 and 3
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
Yes, reserach support from Takeda NA.
Please review this paper.
user
Reviewer's report
Title:Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype
Version: 2Date:20 July 2010
Reviewer: Jonathan Kaunitz
Reviewer's report:
Comment:
The authors have revised the manuscript somewhat by adding some of the
citations suggested by the reviewers. Nevertheless, many of the reviewers'
comments have not yet been answered satisfactorily.
Major Compulsory Revisions
1. As Dr. De Jonge stated in his review, the main intestinal phenotype of CFTR
-/- mice is intestinal obstruction and decreased survival. The phenotypic changes
reported by the authors, such as bacterial overgrowth and delayed intestinal
transit although present, are less well characterized.
2. Although the literature is divided about the mechanism of action of
lubiprostone with regard to intestinal anion secretion, the preponderance of the
data strongly favors lubiprostone acting as a local prostaglandin that activates
CFTR in most cases. I am aware of few in situ data obtained from intact
organisms that support the alternative explanation.
3. The authors make several statements stating that lubiprostone "may" increase
bicarbonate secretion, even this was clearly shown in rats in ref. 20.
4. The authors use rhoadmine dextran to measure intestinal transit. Although the
authors state that it is a "nondigestible, nonabsorbable tracer", dextran is
fermented by colonic flora into butyrate (Olano-Martin E, Mountzouris KC, Gibson
GR, Rastall RA. In vitro fermentability of dextran, oligodextran and maltodextrin
by human gut bacteria. Br J Nutr. 2000 83:247-55). Given the marked differences
of intestinal bacterial colonization between the groups, would the use of this
marker add artifact to the measurements?
5. The authors speculate that some of their findings may be due to changes in
the hydration status of mucus. Yet, mucus in biological systems in considered to
be 99% hydrated. If the authors area aware of intestinal mucus in healthy living
animals that is not fully hydrated, these data should be cited.
6. Since the authors did not measure immune cell function but rather reported
expression changes of immune-function related genes, I reiterate my prior
comment that the data should not be reported as the "innate immune response"
or equivalent. Lacking direct measurements of mast cell migration or actual
measures of immune function, it is exceedingly difficult to interpret expression
changes of this nature.
7. The Discussion is overly long and speculative and would thus benefit from
deletion of many of its sections, despite the authors statements to the contrary.
Minor Essential Revisions
The authors should consider combining Figs. 2 and 3
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
Yes, reserach support from Takeda NA.
assistant