Title: Fructose malabsorption and fructan malabsorption are associated in patients with irritable
bowel syndrome
Version: 2 Date: 02 Feb 2024
Reviewer's report:
This original paper relates to a retrospective chart review in a single centre , comparing the
results of hydrogen breath tests with fructose and fructan in patients with IBS. This is novel
and interesting data  and deserves dissemination.  The examination of the relationships of the
different FODMAP intolerances to eachother is a relevant topic.
The paper is clear and succinct. The tabulation of fructose and fructan papers is helpful for
reference. There are a few major and several minor issues. The data are interesting, but the paper
requires a significant reworking, please.
Major issues:
1. Selection of patients. In our own extensive experience with both these breath tests the patient
history already gives us a good indication of the existing intolerance. This means, patients with
a likely intolerance history are more likely to be selected for the respective breath test. Little
is known about the precise selection of  patients for testing in this paper, but this will greatly
influence the results. Evidence for this is seen in the numbers of excluded patients given only
one of the tests. Please give all details you can regarding who was selected for both breath tests.
This limitation should be stated and would normally disqualify the paper, except for the novelty
of the results.
Exactly how was IBS defined? What overlap was there with functional dyspepsia? While the
cohort is too small for subgroup analysis, it appears patients with prominent extra GI complaints
form a different subgroup.
The term 'functional bowel disorder' can now be replaced with disorders of gut-brain interaction
(DGBI).
2. Breath tests. The analysis appears to be different to most, as an absolute threshold of 20ppm
of H2 was used for a positive test, rather then an increase of 20ppm over baseline.  Inclusion
criterion was a baseline of less than 20ppm - this introduces considerable uncertainty relating
to the actual observed increased following the sugar and I suggest baseline-corrected values,
unless baseline values are below 5ppm. In our extensive testing experience, most gas increases
with fructan only begin after 4 hours, which means a measurement cutoff after 3 hours will miss
most positive results. Most symptoms after fructan challenge in our hands occur after 5 hours
and last into at least the next day. This is a serious challenge to the results of this study.  ( I could
not open the supplemental files...).
Another serious challenge is the absence of any symptom reports during the breath tests, as we
know these are more important than the gas results relating to outcomes of dietary modifications
(e.g. low FODMAP) and the clinical symptoms of the patients. This renders the reports results
much weaker and also explains the confusion the authors have with the terms , malabsorption'
and 'intolerance'. You cannot report intolerance without referring to symptoms during the test.
These terms need to be rectified and defined in the paper. A related issue is the  reference
to mechanisms behind fructose intolerance. Several papers have now shown, that fructose
intolerance in IBS is not associated with malabsorption , including your reference 14 and
the GLUT-5 investigations by the same authors.  The mechanism section therefore requires
significant updating, possibly including the issue of chemohypersensitivity and microbiomic
differences.
The Gastrolyzer equipment used for the test has poor reproducibility. It would be useful to have
a measure of the reliability or variability of the machine's measure as a reference.
What was the minimum washout between the two breath tests? Fructan effects can be assumed
to last up to a week. I assume patients and personnel were not blinded to the test substance.
Which fructan/inulin was used for the testing, as results are influenced by the chain length,
please?
Were the same sugar doses used in the paediatric patients - would be unusual, unless they are
older?
Other issues:
Please update references, as several are outdated, e.g. reference 2 - there are much more
comprehensive analyses of the low FODMAP diet published.  It would be useful to include the
recent UEG guidelines on breath testing by Hammer et al.
Do you have any date on lactose intolerance in the same patients, or data on ethnicity?
Were absolute hydrogen levels correlated between fructose and fructan tests and were there
sequence effects?
In the Discussion it would be interesting to dwell on the topic of low-FODMAP
recommendations, as only 22.5% had overlapping elevation in fructan and fructose
(fermentation, cannot be termed intolerance without symptom reporting). This does reflect on
the usefulness of the lumping of FODMAPs.
In the Discussion a more updated mechanistic review of the microbiome's role would be relevant,
as the current focus on malabsorption is very likely incorrect.
Title: Fructose malabsorption and fructan malabsorption are associated in patients with irritable
bowel syndrome
Version: 2 Date: 02 Feb 2024
Reviewer's report:
This original paper relates to a retrospective chart review in a single centre , comparing the
results of hydrogen breath tests with fructose and fructan in patients with IBS. This is novel
and interesting data  and deserves dissemination.  The examination of the relationships of the
different FODMAP intolerances to eachother is a relevant topic.
The paper is clear and succinct. The tabulation of fructose and fructan papers is helpful for
reference. There are a few major and several minor issues. The data are interesting, but the paper
requires a significant reworking, please.
Major issues:
1. Selection of patients. In our own extensive experience with both these breath tests the patient
history already gives us a good indication of the existing intolerance. This means, patients with
a likely intolerance history are more likely to be selected for the respective breath test. Little
is known about the precise selection of  patients for testing in this paper, but this will greatly
influence the results. Evidence for this is seen in the numbers of excluded patients given only
one of the tests. Please give all details you can regarding who was selected for both breath tests.
This limitation should be stated and would normally disqualify the paper, except for the novelty
of the results.
Exactly how was IBS defined? What overlap was there with functional dyspepsia? While the
cohort is too small for subgroup analysis, it appears patients with prominent extra GI complaints
form a different subgroup.
The term 'functional bowel disorder' can now be replaced with disorders of gut-brain interaction
(DGBI).
2. Breath tests. The analysis appears to be different to most, as an absolute threshold of 20ppm
of H2 was used for a positive test, rather then an increase of 20ppm over baseline.  Inclusion
criterion was a baseline of less than 20ppm - this introduces considerable uncertainty relating
to the actual observed increased following the sugar and I suggest baseline-corrected values,
unless baseline values are below 5ppm. In our extensive testing experience, most gas increases
with fructan only begin after 4 hours, which means a measurement cutoff after 3 hours will miss
most positive results. Most symptoms after fructan challenge in our hands occur after 5 hours
and last into at least the next day. This is a serious challenge to the results of this study.  ( I could
not open the supplemental files...).
Another serious challenge is the absence of any symptom reports during the breath tests, as we
know these are more important than the gas results relating to outcomes of dietary modifications
(e.g. low FODMAP) and the clinical symptoms of the patients. This renders the reports results
much weaker and also explains the confusion the authors have with the terms , malabsorption'
and 'intolerance'. You cannot report intolerance without referring to symptoms during the test.
These terms need to be rectified and defined in the paper. A related issue is the  reference
to mechanisms behind fructose intolerance. Several papers have now shown, that fructose
intolerance in IBS is not associated with malabsorption , including your reference 14 and
the GLUT-5 investigations by the same authors.  The mechanism section therefore requires
significant updating, possibly including the issue of chemohypersensitivity and microbiomic
differences.
The Gastrolyzer equipment used for the test has poor reproducibility. It would be useful to have
a measure of the reliability or variability of the machine's measure as a reference.
What was the minimum washout between the two breath tests? Fructan effects can be assumed
to last up to a week. I assume patients and personnel were not blinded to the test substance.
Which fructan/inulin was used for the testing, as results are influenced by the chain length,
please?
Were the same sugar doses used in the paediatric patients - would be unusual, unless they are
older?
Other issues:
Please update references, as several are outdated, e.g. reference 2 - there are much more
comprehensive analyses of the low FODMAP diet published.  It would be useful to include the
recent UEG guidelines on breath testing by Hammer et al.
Do you have any date on lactose intolerance in the same patients, or data on ethnicity?
Were absolute hydrogen levels correlated between fructose and fructan tests and were there
sequence effects?
In the Discussion it would be interesting to dwell on the topic of low-FODMAP
recommendations, as only 22.5% had overlapping elevation in fructan and fructose
(fermentation, cannot be termed intolerance without symptom reporting). This does reflect on
the usefulness of the lumping of FODMAPs.
In the Discussion a more updated mechanistic review of the microbiome's role would be relevant,
as the current focus on malabsorption is very likely incorrect.
Please review this paper.
user
Title: Fructose malabsorption and fructan malabsorption are associated in patients with irritable
bowel syndrome
Version: 2 Date: 02 Feb 2024
Reviewer's report:
This original paper relates to a retrospective chart review in a single centre , comparing the
results of hydrogen breath tests with fructose and fructan in patients with IBS. This is novel
and interesting data  and deserves dissemination.  The examination of the relationships of the
different FODMAP intolerances to eachother is a relevant topic.
The paper is clear and succinct. The tabulation of fructose and fructan papers is helpful for
reference. There are a few major and several minor issues. The data are interesting, but the paper
requires a significant reworking, please.
Major issues:
1. Selection of patients. In our own extensive experience with both these breath tests the patient
history already gives us a good indication of the existing intolerance. This means, patients with
a likely intolerance history are more likely to be selected for the respective breath test. Little
is known about the precise selection of  patients for testing in this paper, but this will greatly
influence the results. Evidence for this is seen in the numbers of excluded patients given only
one of the tests. Please give all details you can regarding who was selected for both breath tests.
This limitation should be stated and would normally disqualify the paper, except for the novelty
of the results.
Exactly how was IBS defined? What overlap was there with functional dyspepsia? While the
cohort is too small for subgroup analysis, it appears patients with prominent extra GI complaints
form a different subgroup.
The term 'functional bowel disorder' can now be replaced with disorders of gut-brain interaction
(DGBI).
2. Breath tests. The analysis appears to be different to most, as an absolute threshold of 20ppm
of H2 was used for a positive test, rather then an increase of 20ppm over baseline.  Inclusion
criterion was a baseline of less than 20ppm - this introduces considerable uncertainty relating
to the actual observed increased following the sugar and I suggest baseline-corrected values,
unless baseline values are below 5ppm. In our extensive testing experience, most gas increases
with fructan only begin after 4 hours, which means a measurement cutoff after 3 hours will miss
most positive results. Most symptoms after fructan challenge in our hands occur after 5 hours
and last into at least the next day. This is a serious challenge to the results of this study.  ( I could
not open the supplemental files...).
Another serious challenge is the absence of any symptom reports during the breath tests, as we
know these are more important than the gas results relating to outcomes of dietary modifications
(e.g. low FODMAP) and the clinical symptoms of the patients. This renders the reports results
much weaker and also explains the confusion the authors have with the terms , malabsorption'
and 'intolerance'. You cannot report intolerance without referring to symptoms during the test.
These terms need to be rectified and defined in the paper. A related issue is the  reference
to mechanisms behind fructose intolerance. Several papers have now shown, that fructose
intolerance in IBS is not associated with malabsorption , including your reference 14 and
the GLUT-5 investigations by the same authors.  The mechanism section therefore requires
significant updating, possibly including the issue of chemohypersensitivity and microbiomic
differences.
The Gastrolyzer equipment used for the test has poor reproducibility. It would be useful to have
a measure of the reliability or variability of the machine's measure as a reference.
What was the minimum washout between the two breath tests? Fructan effects can be assumed
to last up to a week. I assume patients and personnel were not blinded to the test substance.
Which fructan/inulin was used for the testing, as results are influenced by the chain length,
please?
Were the same sugar doses used in the paediatric patients - would be unusual, unless they are
older?
Other issues:
Please update references, as several are outdated, e.g. reference 2 - there are much more
comprehensive analyses of the low FODMAP diet published.  It would be useful to include the
recent UEG guidelines on breath testing by Hammer et al.
Do you have any date on lactose intolerance in the same patients, or data on ethnicity?
Were absolute hydrogen levels correlated between fructose and fructan tests and were there
sequence effects?
In the Discussion it would be interesting to dwell on the topic of low-FODMAP
recommendations, as only 22.5% had overlapping elevation in fructan and fructose
(fermentation, cannot be termed intolerance without symptom reporting). This does reflect on
the usefulness of the lumping of FODMAPs.
In the Discussion a more updated mechanistic review of the microbiome's role would be relevant,
as the current focus on malabsorption is very likely incorrect.
assistant