Gastric dilatation volvulus (GDV) is a condition that affects large dogs and is characterized by gas accumulation in the stomach leading to bloating and torsion of the stomach. Consequences are life-threatening and include pressure on gastric or blood vessels, pressure on the diaphragm which impedes breathing, or rupture of the stomach wall. Thirty percent of the cases are fatal.
GDV might be associated with intestinal bacteria composition (microbiota). Microbiota composition can be influenced by external and internal factors such as diet, animal breed and genetics of the immune system. A previous study from the group of Dr. Beverley Torok-Storb (Clinical Research Division) established a link between certain genes involved in immune functions and the risk of developing GDV. In a new study, Dr. Michael Harkey, senior staff scientist in the Torok-Storb lab and Dr. Meredith Hullar (Public Health Sciences Division), investigated the roles of the previously identified genes and microbiome composition in the risk of developing GDV in dogs. In their new study recently published in the journal Plos One, the authors demonstrated that mutations in these genes affect microbiome composition and increased the risk for GDV. Dr. Harkey noted, “if GDV is mediated by an altered gut microbiome, and if we can determine which changes are causal to the condition, then we may be able to design a probiotic or dietary protocol to decrease the risk of GDV”.
Among the genes identified, DLA88 and DRB1, components of the canine Major Histocompatibility Complex, regulate host cell expansion against bacteria and avoid autoimmune response, while Toll-like Receptor 5 (TLR5) recognizes pathogen-associated molecular patterns. Dr. Harkey explained, “these genes, and others like them, have been implicated in a variety of autoimmune conditions, such as anchylosing spondylitis and Crohns’. Some of the effect of these genes is probably through the microbiome, but it may also involve other pathways to autoimmunity”. Indeed, all of these genes help regulate the immune response against bacteria and shape the microbiome composition. Consequently, mutations of those genes can result in failure to detect and eliminate certain pathogens that can then become part of the host microbiome.
Great Danes are especially at risk to develop GDV. Hence, client-owned Great Danes that were either healthy (n=38) or previously affected by GDV (n=37) and with similar diets were enrolled into the study. Stool samples were collected 3 months post-surgery for GDV and used for DNA extractions. 16s ribosomal RNA gene sequencing allowed identification of the stool bacterial composition.
Figure provided by Dr. Michael Harkey.
Interestingly, the age but not the diet of the dog had an influence on the microbiota composition. GDV dogs had greater microbial diversity than healthy dogs. The detection of at least one risk allele in the TLR5, DLA88 or DRB1 genes was associated with significantly different microbiota composition relative to the healthy dogs. For example, the Actinobacteria (0.49%) and Firmicutes (38.71%) phyla were significantly more abundant in the GDV dogs relative to the healthy dogs which presented a lower percentage of Actinobacteria (0.14%) and Firmicutes (25.68%). Colinsella, a genera in the Actinobacteria, has previously been associated with autoimmune diseases in humans and humanized mice, and could increase systemic inflammation.
Other studies have shown that mutations in the TLR5 gene can lead to a bloom of the Proteobacteria phyla, such as E. coli. In agreement with previous studies, GDV dogs presented with a Proteobacteria increase (5.84%) relative to the healthy dogs (3.09%). Mutations in the MHC class II DRB1 gene was associated with an increase in the Firmicutes phyla in GVD dogs (38.71%) relative to healthy dogs (25.68%). All together, these data demonstrate the critical importance of these three genes on the bacterial composition which in turn influence both immunity and GDV development.
Figure provided by Dr. Michael Harkey.
Despite these promising advances, there is still a lot of work to do to understand the mechanisms leading to GDV. Dr. Harkey further commented, “the genes we have identified do not account for all cases of GDV. Great Danes that did not carry any of the identified risk alleles had one third the risk of developing GDV as carriers, which is substantial. There are several other immune genes, related to the ones we have studied so far that I would like to address as well.” Dr Hullar added “to develop therapeutic approaches that reduce risk of GDV, we need to move beyond identifying bacterial composition to understanding microbial mechanisms linked to immunity that are involved in GDV.” Of importance, this research can also benefit numerous health issues beyond GDV: “I think that a deeper understanding of the relationship between immune genes (particularly MHC and innate immunity genes), the gut microbiome, and health, is going to have major impact on future medical and veterinary research”, concluded Dr. Harkey.
Funding for this study was provided by Robert and Rebecca Pohlad and from the Van Sloun Foundation and the National Institutes of Health.
Fred Hutch/UW Cancer Consortium faculty members Drs. Johanna Lampe and Beverly Torok-Storb contributed to this research.
Hullar MAJ, Lampe JW, Torok-Storb BJ, Harkey MA. 2018. The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high-risk genetic variants of the immune system. PLoS One, 13(6), e0197686.