The organotin tributyltin (TBT) is a prominent environmental toxin that promotes obesity in vertebrates. The gut microbiota is also known to promote obesity, but it is unknown whether TBT promotes obesity in vivo by influencing the composition of the gut microbiota. Moreover, it remains unknown if TBT-induced alterations of gut microbiota composition are sufficient to alter host adiposity. These gaps in knowledge are important, because without this information, the development of methods to prevent obesity and associated morbidities by mitigating effects of TBT and other obesogens on gut microbiota, is highly unlikely. The overall objective of this application is to exploit the advantages of the zebrafish model system to define the impact of TBT on the assembly and on the obesogenic activity of the gut microbiota. The proposed research will test the central hypothesis that TBT exposures cause compositional alterations to the gut microbiota that are sufficient to increase its obesogenic activity. The rationale for this proposed research is that defining TBT's impact on the assembly and obesogenic activity of the gut microbiota will lead to new approaches for preventing and treating obesity and associated morbidities in humans by reducing TBT-induced modifications to the gut microbiota.
In Specific Aim 1, the working hypothesis to be tested is that exposure to TBT causes alterations in gut microbiota composition and host adiposity. Conventionally raised zebrafish will be chronically exposed to different doses of TBT and then high-throughput 16S rRNA gene sequencing and high-resolution in vivo imaging will be used to evaluate the effects of exposure on gut microbiota composition and adiposity, respectively.
In Specific Aim 2, the working hypothesis to be examined is that TBT-induced alterations in gut microbiota composition confer increased obesogenic activity. Gut microbiotas will be transplanted from TBT-exposed and unexposed conventionally-raised zebrafish donors into unexposed germ-free zebrafish recipients, and then monitor the ability of the transplanted microbiota to promote adiposity in the recipient hosts. The contribution of this work will be significant because it will provide a much-needed vertical advance in our understanding of TBT-microbiota interactions and how those interactions impact host adiposity. The proposed research is innovative because it constitutes the first analysis of the impact of TBT exposures on gut microbiota composition in any animal and the consequences of TBT-induced alterations in gut microbiota composition on its obesogenic potential. The innovation of this research is further enhanced by our use of a vertebrate model that permits high-resolution in vivo analysis of adipose tissue, and the use of gnotobiotic hosts and microbiota transplants to directly test the impact of TBT exposure on the obesogenic potential of the gut microbiota.
The proposed research is relevant to public health because defining the impact of tributyltin (TBT) exposure on intestinal microbiota and its obesogenic potential could lead to new microbe-based strategies for preventing the harmful effects of TBT on human adipose tissues and other physiologic systems. The proposed research is therefore relevant to the aspects of NIH's mission that pertain to developing novel fundamental knowledge on the biological effects of environmental contaminants that will enhance health and reduce the burdens of illness.