Reviewer's report
Title:Involvement of a periodontal pathogen, Porphyromonas gingivalis on the
pathogenesis of non-alcoholic fatty liver disease.
Version: 2Date:27 August 2011
Reviewer: Frank Tacke
Reviewer's report:
This is an interesting manuscript by Wada et al. indicating an association
between periodontal infections by P. gingivalis with NASH/NAFLD.
1. The observations and experiments reported in this paper are interpreted in a
way that they would demonstrate a causal relationship between periodontal
infections and NASH. To my opinion, the data do not allow such a conclusion. It
is possible that the observations are only an epiphenomenon. For instance, it
could be possible that patients with unrecognized (mild) alcoholism have more
frequently periodontal infections, or that patients with a liver-related immune
disturbance (as frequently seen in chronic liver diseases) are predisposed to
develop periodontal infections as well, and so on... This would mean that P.
gingivalis infections do not have a specific disease-promoting effect in NAFLD.
Thus, I feel that this work requires a much more cautious discussion, and the
possibility of an epiphenomenon (which could still be useful for diagnostic
purposes or for estimating prognosis) needs to be mentioned in the abstract as
well.
2. From the cohort study, the authors conclude that periodontal infections might
be an “independent predictor for the development of NASH”. In order to validate
such a hypothesis, it is necessary to perform follow-up examinations on all
patients, which need to show whether patients with P. gingivalis infections have a
higher susceptibility to develop NASH or faster disease progression.
Kaplan-Meier analyses might help to visualize the results.
3. What do the authors conclude from Table 3? I have difficulties to interpret
these findings.
4. The high-fat-diet animal model is apparently a model for steatosis, but not for
steatohepatitis or fibrosis. It is important to show ALT/AST levels of the animals
during HFD and normal diet. Liver triglyceride and free fatty acid measurements
also need to be performed in order to validate the phenotype (the H&E stainings
do not show relevant steatosus in the HFD-treated animals!) and the model.
5. It is unclear to me how the animal model reflects the situation described in
patients. The animals were i.v. injected with bacteria and did not have
periodontal infections. It is well known from work of Schwabe’s group that
bacterial infections / LPS promote liver injury and liver fibrosis (Seki E, Nat Med
2007). To my opinion, two important control groups are missing and need to be
shown, namely LPS-injected HFD animals and HFD animals infected with
different, not periodontal-related bacteria. Only these controls would allow
interpreting to which extent P. gingivalis specifically promotes liver disease
(steatosis) progression.
6. Was antibiotic therapy part of the periodontal treatment (Figure 4)?
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Reviewer's report
Title:Involvement of a periodontal pathogen, Porphyromonas gingivalis on the
pathogenesis of non-alcoholic fatty liver disease.
Version: 2Date:27 August 2011
Reviewer: Frank Tacke
Reviewer's report:
This is an interesting manuscript by Wada et al. indicating an association
between periodontal infections by P. gingivalis with NASH/NAFLD.
1. The observations and experiments reported in this paper are interpreted in a
way that they would demonstrate a causal relationship between periodontal
infections and NASH. To my opinion, the data do not allow such a conclusion. It
is possible that the observations are only an epiphenomenon. For instance, it
could be possible that patients with unrecognized (mild) alcoholism have more
frequently periodontal infections, or that patients with a liver-related immune
disturbance (as frequently seen in chronic liver diseases) are predisposed to
develop periodontal infections as well, and so on... This would mean that P.
gingivalis infections do not have a specific disease-promoting effect in NAFLD.
Thus, I feel that this work requires a much more cautious discussion, and the
possibility of an epiphenomenon (which could still be useful for diagnostic
purposes or for estimating prognosis) needs to be mentioned in the abstract as
well.
2. From the cohort study, the authors conclude that periodontal infections might
be an “independent predictor for the development of NASH”. In order to validate
such a hypothesis, it is necessary to perform follow-up examinations on all
patients, which need to show whether patients with P. gingivalis infections have a
higher susceptibility to develop NASH or faster disease progression.
Kaplan-Meier analyses might help to visualize the results.
3. What do the authors conclude from Table 3? I have difficulties to interpret
these findings.
4. The high-fat-diet animal model is apparently a model for steatosis, but not for
steatohepatitis or fibrosis. It is important to show ALT/AST levels of the animals
during HFD and normal diet. Liver triglyceride and free fatty acid measurements
also need to be performed in order to validate the phenotype (the H&E stainings
do not show relevant steatosus in the HFD-treated animals!) and the model.
5. It is unclear to me how the animal model reflects the situation described in
patients. The animals were i.v. injected with bacteria and did not have
periodontal infections. It is well known from work of Schwabe’s group that
bacterial infections / LPS promote liver injury and liver fibrosis (Seki E, Nat Med
2007). To my opinion, two important control groups are missing and need to be
shown, namely LPS-injected HFD animals and HFD animals infected with
different, not periodontal-related bacteria. Only these controls would allow
interpreting to which extent P. gingivalis specifically promotes liver disease
(steatosis) progression.
6. Was antibiotic therapy part of the periodontal treatment (Figure 4)?
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Please review this paper.
user
Reviewer's report
Title:Involvement of a periodontal pathogen, Porphyromonas gingivalis on the
pathogenesis of non-alcoholic fatty liver disease.
Version: 2Date:27 August 2011
Reviewer: Frank Tacke
Reviewer's report:
This is an interesting manuscript by Wada et al. indicating an association
between periodontal infections by P. gingivalis with NASH/NAFLD.
1. The observations and experiments reported in this paper are interpreted in a
way that they would demonstrate a causal relationship between periodontal
infections and NASH. To my opinion, the data do not allow such a conclusion. It
is possible that the observations are only an epiphenomenon. For instance, it
could be possible that patients with unrecognized (mild) alcoholism have more
frequently periodontal infections, or that patients with a liver-related immune
disturbance (as frequently seen in chronic liver diseases) are predisposed to
develop periodontal infections as well, and so on... This would mean that P.
gingivalis infections do not have a specific disease-promoting effect in NAFLD.
Thus, I feel that this work requires a much more cautious discussion, and the
possibility of an epiphenomenon (which could still be useful for diagnostic
purposes or for estimating prognosis) needs to be mentioned in the abstract as
well.
2. From the cohort study, the authors conclude that periodontal infections might
be an “independent predictor for the development of NASH”. In order to validate
such a hypothesis, it is necessary to perform follow-up examinations on all
patients, which need to show whether patients with P. gingivalis infections have a
higher susceptibility to develop NASH or faster disease progression.
Kaplan-Meier analyses might help to visualize the results.
3. What do the authors conclude from Table 3? I have difficulties to interpret
these findings.
4. The high-fat-diet animal model is apparently a model for steatosis, but not for
steatohepatitis or fibrosis. It is important to show ALT/AST levels of the animals
during HFD and normal diet. Liver triglyceride and free fatty acid measurements
also need to be performed in order to validate the phenotype (the H&E stainings
do not show relevant steatosus in the HFD-treated animals!) and the model.
5. It is unclear to me how the animal model reflects the situation described in
patients. The animals were i.v. injected with bacteria and did not have
periodontal infections. It is well known from work of Schwabe’s group that
bacterial infections / LPS promote liver injury and liver fibrosis (Seki E, Nat Med
2007). To my opinion, two important control groups are missing and need to be
shown, namely LPS-injected HFD animals and HFD animals infected with
different, not periodontal-related bacteria. Only these controls would allow
interpreting to which extent P. gingivalis specifically promotes liver disease
(steatosis) progression.
6. Was antibiotic therapy part of the periodontal treatment (Figure 4)?
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
assistant