Research in the Round lab employs an inter-disciplinary approach that incorporates immunology, microbiology, ecology and bioinformatics to understand how host-commensal interactions influence disease. We have five major areas of investigation described below.
1) 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 it’s 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.
2) Commensal fungal effects on intestinal disease
Most studies involving the microbiota focus on the bacterial population of organisms within the gut, however mammals are home to a vast collection of fungi as well. Fungi are larger and more complex than bacteria and thus could have important impacts on mammalian biology. Moreover, antibodies against fungi have long been used as a diagnostic test to distinguish between ulcerative colitis and Crohn’s disease in humans. Our published studies have now identified that the most commonly found fungi in the gut, Saccharomyces cerevisiae, exacerbates intestinal colitis via induction of purine metabolism. We have just received an NIH R01 to identify the mechanism by which S. cerevisiae can induce purine metabolism in the mammalian host and how it worsens disease through host receptors in collaboration with biochemist Eric Schmidt, fungal biologist, Jessica Brown and mucosal immunologist Ken Cadwell.
In addition, we interested in how fungal organisms are influenced by host IgA. In collaboration with Suzanne Noble at UCSF and Teresa O’Meara at University of Michigan we are combining fungal genomics and immunology to better understand how this interaction influences gut homeostasis.
Effects of the microbiota on neurological disorders
Neurodegenerative diseases, such as multiple sclerosis (MS), and neurodevelopmental diseases, such as autism, are prevalent disorders of the western world, yet little is known about their etiology. A strong genetic component has been identified, however epidemiological and twin studies suggest that these are acquired rather than inherited. While no clear pathogenic agent has been found to be the root cause of neurological disease, micro-organisms have long been suspected. It has been reported that the microbiota can influence neurological disorders, however much remains to be explored. In collaboration with Tom Lane at University of Irvine we have recently published that gut microbes can protect from virally induced paralysis via microglia intrinsic TLR4 signaling (Brown, eLIFE, 2019) . These data suggest that possession of microbiota that provides TLR4 stimulation could protect from the neurological sequelae that follow viral infection within the brain. Questions that arise from these studies and will be pursued in the lab are: Do individuals with MS (or other neurological disease have microbiotas that have differential TLR4 stimulating capacity? What are the organisms that provide this stimulus? Can they be added to prevent neurologic symptoms? How are these signals transmitted from the gut to the brain? Humankind will continue to endure deadly viral infections, thus understanding mechanisms, like the microbiota, that can prevent or boost immune responses toward these infections might reveal novel therapeutic interventions. Using human samples we have identified several bacterial species that influence positively impact immune responses within the CNS. Future studies from the lab will identify the mechanistic basis for these beneficial microbe-immune interactions on diseases of the CNS. These studies are in collaboration with Dr. Marco Bortolato 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.
Microbiota and Cancer
My laboratory recently moved to the Huntsman Cancer Institute (HCI) which is a NIH comprehensive cancer center with access to many human samples and an extensively collaborative faculty. In the last four years we have begun projects in pancreatic development and cancer in collaboration with Dr. Charles Murtaugh and colorectal cancer (CRC) in collaboration with Dr. Neli Ulrich. Both of these projects will capitalize on the use of human stool samples from individuals with CRC or pancreatic cancer to colonize germfree animal models of CRC and pancreatic cancer. The most developed of these projects is the one involving CRC. We received 5 stool samples from healthy donors and 5 samples from individuals with CRC. We used these samples to colonize germfree mice and induced CRC using the AOM-DSS CRC model. In 4/5 paired samples we found that the sample from the individual with CRC drove worsened cancer formation, providing us a platform to identify specific microbes that protect or are associated with disease. We have now identified two species that appear to be protective during CRC and enhance immune-therapy in animal models.
- Klag K, Round JL (2020). Immunology: How the Microbiota Digests Bile to Protect against Viral Infection. Curr Biol, 30(20), R1271-R1272.
- Sanchez JMS, Doty DJ, DePaula-Silva AB, Brown DG, Bell R, Klag KA, Truong A, Libbey JE, Round JL, Fujinami RS (2020). Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system. J Neuroinflammation, 17(1), 291.
- Yeung F, Chen YH, Lin JD, Leung JM, McCauley C, Devlin JC, Hansen C, Cronkite A, Stephens Z, Drake-Dunn C, Fulmer Y, Shopsin B, Ruggles KV, Round JL, Loke P, Graham AL, Cadwell K (2020). Altered Immunity of Laboratory Mice in the Natural Environment Is Associated with Fungal Colonization. Cell Host Microbe, 27(5), 809-822.e6.
- Petersen C, Bell R, Klag KA, Lee SH, Soto R, Ghazaryan A, Buhrke K, Ekiz HA, Ost KS, Boudina S, OConnell RM, Cox JE, Villanueva CJ, Stephens WZ, Round JL (2018). T cell-mediated regulation of the microbiota protects against obesity. Science, 365(6451).
- Brown DG, Soto R, Yandamuri S, Stone C, Dickey L, Gomes-Neto JC, Pastuzyn ED, Bell R, Petersen C, Buhrke K, Fujinami RS, OConnell RM, Stephens WZ, Shepherd JD, Lane TE, Round JL (2019). The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling. eLife, 8.
- Gogokhia L, Buhrke K, Bell R, Hoffman B, Brown DG, Hanke-Gogokhia C, Ajami NJ, Wong MC, Ghazaryan A, Valentine JF, Porter N, Martens E, OConnell R, Jacob V, Scherl E, Crawford C, Stephens WZ, Casjens SR, Longman RS, Round JL (2018). Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis. Cell Host Microbe, 25(2), 285-299.e8.
- Ost K and Round JL (2018). Communication between the microbiota and mammalian immunity. [Review]. Annu Rev Microbiol, 72, 399-422.
- Round JL and Noah Palm (2018). Casual effects of the microbiota on immune-mediated disease. 9(3), 20.
- Soto R, Petersen C, Novis CL, Kubinak JL, Bell R, Stephens WZ, Lane TE, Fujinami RS, Bosque A, OConnell RM, Round JL (2017). Microbiota promotes systemic T-cell survival through suppression of an apoptotic factor. Proc Natl Acad Sci U S A, 114(21), 5497-5502.
- Chiaro TR, Soto R, Zac Stephens W, Kubinak JL, Petersen C, Gogokhia L, Bell R, Delgado JC, Cox J, Voth W, Brown J, Stillman DJ, OConnell RM, Tebo AE, Round JL (2017). A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice. Sci Transl Med, 9(380).
- Ost K and Round JL (2017). A Few Good Commensals: Gut microbes use IFN-? to Fight Salmonella. 46(6), 977-979.
- Brown DG, and Round JL (2017). Friends in low places: Intestinal commensals limit colitis through molecular mimcry. 171(3), 503-505.
- Kubinak J, and Round JL (2016). Do antibodies select a healthy microbiota? [Review]. Nat Rev Immunol, 16, 767-774.
- Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, Bell R, Ajami NJ, Petrosino JF, Morrison L, Potts WK, Jensen PE, OConnell RM, Round JL (2015). MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun, 6, 8642.
- Kubinak JL, Petersen C, Stephens WZ, Soto R, Bake E, OConnell RM, Round JL (2015). MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe, 17(2), 153-63.
- Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (2011). The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science, 332(6032), 974-7.
- Round JL, Mazmanian SK (2010). Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A, 107(27), 12204-9.
- Mazmanian SK, Round JL, Kasper DL (2008). A microbial symbiosis factor prevents intestinal inflammatory disease. Nature, 453(7195), 620-5.