These data do not provide evidence

These data do not provide evidence that the MMP production from macrophages is directly regulated by CBP/β-catenin and that the produced MMPs are involved in fibrosis resolution in our model. The gating strategy for macrophages in analysis of IHL does not exclude monocytes. Moreover, the mechanism by which CBP/β-catenin stimulates the activation of quiescent HSCs and induces the survival of activated HSCs remains unclear. The effects of CBP/β-catenin inhibitors against portal fibroblasts, which represent another type of collagen-producing cells besides HSCs in biliary fibrosis (Wells, 2014), have not yet been investigated. In addition, it is still unclear if the effects of the CBP/β-catenin inhibitor are primarily on HSCs, macrophages, other immune cells, and/or sinusoidal endothelium in vivo. Thus, further studies are needed to resolve these uncertainties.
Conclusions
Conflicts of Interest
Author\'s Contributions The following are the Supplementary data related to this article.
Acknowledgments This work was supported by Grants from the Takeda Science Foundation, the Sagawa Foundation for Promotion of Cancer Research, the JSPS KAKENHI Grant Number 26460965, the Research Program on Hepatitis of Ministry of Health, Labor, and Welfare of Japan, and Clinical Research Fund of Tokyo Metropolitan Government.
Introduction Environmental enteropathy (EE) is a subclinical yet apparently common illness in low income countries that is characterized by small intestine inflammation with shortened villi, intestinal barrier dysfunction, and reduced nutrient Myriocin cost (Korpe and Petri, 2012; Campbell et al., 2003; McKay et al., 2010). EE is associated with poverty and unsanitary living conditions, and hypothesized to be caused by repeated or chronic exposure to enteropathogens and by malnutrition (Korpe and Petri, 2012). EE in turn is suspected to contribute to the development of malnutrition and hinder its treatment, via small intestinal damage and resulting inflammation (Korpe and Petri, 2012; Prendergast and Kelly, 2012). Vaccines against enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in developing countries, particularly in malnourished populations (Haque et al., 2014; Levine, 2010; Grassly et al., 2006; Zaman et al., 2010), suggesting that oral vaccine response could be adversely affected by EE.
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Results
Discussion
Conclusions EE was associated with Rotarix® failure and underperformance of OPV and predicted the development of malnutrition. Understanding the triggers of environmental enteropathy and designing interventions to prevent or treat it are therefore of immense importance. EE is uniquely seen in settings with high exposure to enteric pathogens, malnutrition and poor sanitation (Korpe and Petri, 2012; Prendergast and Kelly, 2012; Keusch et al., 2014; Guerrant et al., 2008). The absence of diarrhea on cluster 2 that contains the EE biomarkers leads us to postulate that asymptomatic enteric infection may contribute to environmental enteropathy. Infants in Dhaka, Bangladesh as young as one month have been found on average to have two enteric pathogens present in stool samples even without overt diarrhea (Taniuchi et al., 2013). It is possible that such subclinical infections could be causing a chronic innate immune activation localized to the gut. Within cluster 2 were also the sanitation markers reporting proximity to an open drain or the availability of a septic tank toilet; as for enteric inflammation biomarkers, it is interesting that these do not cluster with diarrheal burden. This clustering further supports the hypothesis that low-level exposure to pathogens drives enteric inflammation.
Author Contributions
Disclaimer
Acknowledgments The authors wish to thank Raphael Gottardo for consultation on biostatistics, Alex Mentzer for assistance in measures of parenteral vaccine response, and the families of Mirpur for their participation in this study. This work was supported by the Bill & Melinda Gates Foundation and NIH grant 5R01 AI043596. The funders did not have any role in study design, data collection, data analysis, interpretation, or writing of the report.