Commensal microorganisms play critical roles in human physiology and diseases. Despite rapidly expanding knowledge of the composition of the human gut microbiota, our understanding of the ecological principles that govern the assembly and resilience of the highly complex and dynamic ecosystemofthegutmicrobiotaisrudimentary.Thisknowledgegapbecomesmoreproblematicasnew approaches to modify the microbiota, such as fecal microbiota transplantation (FMT), are being developed as therapeutic interventions. The overall objective of the proposed studies is to construct an ecologicalframeworktounderstandtheefficacyofFMTintreatingrecurrentC.difficileinfection(rCDI)at the systems level. The central hypothesis is that the functional redundancy of the recipient?s pre-FMT microbiota can be used to predict the extent of donor microbiota engraftment and predict the efficacy of FMT. As a classical concept in ecology, functional redundancy (FR) means that phylogenetically unrelated species perform similar functions in ecosystems so that they can be interchanged with little impact on the overall ecosystem functioning. The rationale for the proposed research is that understandingtheefficacyofFMTintreatingrCDIhasthepotentialtotranslateintobetterunderstanding of its efficacy in treating a variety of other diseases associated with disrupted microbiomes. Guided by strongpreliminarydata,thecentralhypothesiswillbetestedbypursuingthreespecificaims:1)Develop a network-based method to quantify the within-sample FR of human microbiome samples. The applicant?s preliminary results suggest that the FR of a microbiome sample can be calculated from its taxonomicprofileandareferencegenomiccontentnetwork.2)Developanecologicalframeworktostudy therelationshipbetweentheFRofamicrobialcommunityanditsresistancetonewspecies.Theworking hypothesis is that the higher the within-sample FR of a microbial community, the more resistant it is againstspeciesaddition,e.g.,throughFMT.Bothecologicalmodeling/simulationsandrealdataanalysis will be performed to verify this hypothesis. 3) Clinical study to test that FMT has a lower efficacy in treating rCDI patients withhigher FR in their pre-FMT microbiota. Stool samples from the recipients and their respective donors will be collected for metagenomic whole genome shotgun sequencing. Subsequently, the relationships among the FR of the recipients? pre-FMT microbiota, the engraftment of donor-specificspeciesintherecipients?post-FMTmicrobiota,andtheFMTefficacywillbequantitatively analyzed.Theapproachisinnovativebecauseitshiftsfocusfromspecifictaxaorfunctionstoasystems level understanding of the human gut microbiome using network and ecological approaches. The proposedresearchissignificantbecauseitwillimproveourunderstandingontheecologicalprinciplesof FMTforrCDIaswellforotherconditionsassociatedwithdisruptedmicrobiomes.
The proposed research is relevant to public health because revealing the intricate relationship between the functional redundancy of microbial communities and the efficacy of fecal microbiota transplantation areultimatelyexpectedtoincreaseunderstandingoftheefficacyofgeneralmicrobiome-basedtherapies intreatingawiderangeofdiseasesassociatedwithdisruptedmicrobiomes.Thus,theproposedresearch is relevant to the part of NIH?s mission that pertains to developing fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health and reduceillness.