On 2014 May 06, Madhusudana Girija Sanal commented:

1) The authors argue that the effects of VSG(vertical sleeve gastrectomy) are mediated through FXR but do not provide this VITAL data in THIS paper on bile acid/salt plasma levels before and after the procedure in wild and FXR-KO animals. Bile salts/acids are FXR ligands. 2) The authors correlate the improvement in glucose tolerance and other beneficial effects to changes in gut microflora especially Roseburia (which is associated with butyrate levels). However, I doubt, the data in Extended Data Table -1 does not support this. The highest level of butyrate is in KO-vertical sleeve gastrectomy (KO-VSG) 29.79 microM/g. 3) Do authors have some hypothesis on butyrate levels and improvement in GTT? 4) Fig-5-G It is not clear how the relative abundance is plotted (X-axis) and if it is significant. Compare, with the data in Extended Data Figure 4<br> 5) Antibiotics were given to the animals during surgery? What effect it had on the gut microbiota? A control for anitbiotics is essential in this experiment. 6) Materials and Methods: It is not clear how the animals were monitored during the entire period and how the data was collected with respect to food preference. I was not able to find the actual data in the paper.<br> 7) What was the eating pattern? What if the KO eats much less food all time-a very basal level so a vertical sleeve surgery do not have much effect on eating? 8) If mediated through FXR, treatment with agonist/antagonist in wild animals would have shown some effect. Can administration of INT-747 –FXR agonist nullify/accentuate the effect of VSG in wild animals? What about DDAH Expression? 9) Explanation for associated with a 24% increase in fasting blood glucose in KO-mice? 10) The authors also ignored the endocrine role of resected gastric mucosa-gastric hormone measurement should have been done.

By and large this paper is description of observations of VSG in FXR-KO mouse rather than elucidation of the mechanisms.

According to the authors, they found the association of VSG and FXR through ‘unbiased’ pathway analysis. However, these is a paper by Mencarelli A1, Renga B, D'Amore C, et al. (2013) which correlates the beneficial effects of bariatric surgeries to the selective activation of intestinal nuclear receptors (FXR,LXR). This key paper (perhaps the first paper correlating bariatric surgery to nuclear receptors) is not cited by the authors in the current paper. There is no doubt that this is an area we are still in dark when it comes to the mechanisms. Research in this area will answer many important questions. For example: Some recent studies found the beneficial effects of bariatric surgery is more than medical management –however it is not clear if bariatric surgery can be recommended for non-obese diabetic. Will an FXR modulator will bestow at least some of the positive effects which are currently provided by painful and risky procedures like VSG?

On 2014 May 06, Madhusudana Girija Sanal commented:

1) The authors argue that the effects of VSG(vertical sleeve gastrectomy) are mediated through FXR but do not provide this VITAL data in THIS paper on bile acid/salt plasma levels before and after the procedure in wild and FXR-KO animals. Bile salts/acids are FXR ligands. 2) The authors correlate the improvement in glucose tolerance and other beneficial effects to changes in gut microflora especially Roseburia (which is associated with butyrate levels). However, I doubt, the data in Extended Data Table -1 does not support this. The highest level of butyrate is in KO-vertical sleeve gastrectomy (KO-VSG) 29.79 microM/g. 3) Do authors have some hypothesis on butyrate levels and improvement in GTT? 4) Fig-5-G It is not clear how the relative abundance is plotted (X-axis) and if it is significant. Compare, with the data in Extended Data Figure 4<br> 5) Antibiotics were given to the animals during surgery? What effect it had on the gut microbiota? A control for anitbiotics is essential in this experiment. 6) Materials and Methods: It is not clear how the animals were monitored during the entire period and how the data was collected with respect to food preference. I was not able to find the actual data in the paper.<br> 7) What was the eating pattern? What if the KO eats much less food all time-a very basal level so a vertical sleeve surgery do not have much effect on eating? 8) If mediated through FXR, treatment with agonist/antagonist in wild animals would have shown some effect. Can administration of INT-747 –FXR agonist nullify/accentuate the effect of VSG in wild animals? What about DDAH Expression? 9) Explanation for associated with a 24% increase in fasting blood glucose in KO-mice? 10) The authors also ignored the endocrine role of resected gastric mucosa-gastric hormone measurement should have been done.

By and large this paper is description of observations of VSG in FXR-KO mouse rather than elucidation of the mechanisms.

According to the authors, they found the association of VSG and FXR through ‘unbiased’ pathway analysis. However, these is a paper by Mencarelli A1, Renga B, D'Amore C, et al. (2013) which correlates the beneficial effects of bariatric surgeries to the selective activation of intestinal nuclear receptors (FXR,LXR). This key paper (perhaps the first paper correlating bariatric surgery to nuclear receptors) is not cited by the authors in the current paper. There is no doubt that this is an area we are still in dark when it comes to the mechanisms. Research in this area will answer many important questions. For example: Some recent studies found the beneficial effects of bariatric surgery is more than medical management –however it is not clear if bariatric surgery can be recommended for non-obese diabetic. Will an FXR modulator will bestow at least some of the positive effects which are currently provided by painful and risky procedures like VSG?