Research

How host immunity directs form and function of the microbiota to protect from disease

The mammalian immune system must be able to maintain tolerance to commensal organisms while mounting effective immunity to pathogenic species. There are many mechanisms by which the immune system can directly control micro-organisms that include anti-microbials such as defensins, lectins and even complement to directly kill offending microbes. However, these mechanisms rely on the recognition of patterns in microbes that are present in both commensal and pathogenic species. Because mammalian adaptive immune systems possess the ability to use specific antigens to target and kill microbes, we reasoned that this system likely evolved to also recognize and control resident commensal species. Our published findings have identified variations in the MHC loci, as seen in human populations, leads to individualized microbial communities which can dictate susceptibility to infection, demonstrating that antigen specific immunity to the microbiota influences its composition (Nature Communications, 2015). The effector mechanism by which our immune system can shape these microbial communities is through IgA, which is the major antibody type within the gut (Cell Host & Microbe, 2015, Nature Reviews Immunology, 2016).  These studies, along with others published in the field, have led to the idea that IgA targeting of the microbiota in various disease contexts can be harnessed to identify organisms of interest. Using this method, we identified that appropriate IgA targeting of the microbiota can prevent metabolic disease (Science, 2019).  Indeed, disruption of IgA led to outgrowth of a sulfate producer, Desulfovibrio and loss of beneficial Clostridia leading to obesity and type II diabetes. Disease could be rescued by isolation and replacement of these beneficial Clostridia. Interestingly, these microbial changes are similar in humans with obesity and type II diabetes, making our findings relevant to human disease.  Clostridia prevented lipid absorption within the small intestine leading to less fat accumulation.  Based on these published studies, our future work will seek to identify the relevant Clostridia isolates and the mechanisms by which these organisms influence metabolic disease.  

This area involves collaborations with Dr. Sihem Boudina and Dr. Scott Summers at the University of Utah.

Viral dark matter in the gut: bacteriophage mediated effects on gut health

While the microbiota has emerged as a critical component of GI health, the most numerically abundant component of the microbiota, bacteriophages, has remained unexplored. Our published studies have demonstrated that bacteriophages can be used to target organisms that exacerbate colorectal cancer. Additionally, our studies have highlighted that bacteriophages are capable of directly stimulating the host immune response and enhancing inflammatory disease in the intestine.  While these studies have focused on bacteriophages that reside outside of their bacteriophage host, most bacteriophages reside as integrated prophages within bacterial chromosomes. Here bacteriophages can modulate bacterial behavior by conferring novel functions, elicit gene expression changes, expressing novel antigens on the surface of bacterial membrane or becoming part of bacterial biofilms.  In collaboration with bacteriophage biologist Sherwood Casjens, University of Utah and Patrick Secor, University of Montana, we received an NIH R01 to study prophage species and their effects on intestinal disease.  

Additionally, we are exploring whether immune responses against phage species can be detected in humans with intestinal disease. Collaborations with Dr. Randy Longman, Weill Cornel and Dr. Ben Larmen, John’s Hopkins University  and funded by the Helmsley foundation will employ novel technologies to identify phage epitopes that are associated with inflammatory bowel disease.