Proposed model of sox10 mutant intestinal pathology. sox10 mutants have altered intestinal motility and an increased bacterial load. Given the role of the ENS in intestinal function, sox10 mutants likely also experience alterations in epithelial secretion and permeability, although these phenotypes are yet to be examined. sox10 mutants can assemble a microbiota that mirrors WT intestinal microbiota (host population 2) or is dysbiotic (host population 1), characterized by an expansion of the Vibrio lineage and reduction of the Escherichia lineage. We do not yet know what determines which bacterial community assembles in sox10 mutants (dashed lines) but hypothesize that it could be due to the timing or order of exposure to bacterial strains, differences in epithelial permeability or secretion, or differences in other host compensatory mechanisms.
Numerous human diseases, including IBD, diabetes and autism spectrum disorders have been linked to abnormal microbiomes, but an open question is whether these altered microbiomes are drivers of disease. A new study at the University of Oregon, led by postdoctoral fellow Annah Rolig, took aim at that question with experiments in zebrafish to dissect whether changes in the abundance of certain gut bacteria can cause intestinal inflammation.
The study made use of a mutant zebrafish strain that models human Hirschsprung disease, caused by loss of the gut neurons that coordinate gut contractions. Just like Hirschsprung disease patients, who sometimes develop an inflammatory condition called Hirschsprung-associated enterocolitis, a subset of the fish developed intestinal inflammation. They successfully tracked how gut bacterial abundances influenced inflammation. Fish with intestinal inflammation had a larger abundance of a subset of bacteria that appeared to be pro-inflammatory, which they confirmed by dosing the fish with one of these bacteria and finding that it increased the severity of disease symptoms.
They also found a subset of bacteria that was depleted in the inflamed intestines, but present in the mutant fish that remained disease-free. Dosing the fish with a strain of these depleted bacteria ameliorated the disease. Finally, they showed that they could cure the inflammation by transplanting gut neurons from healthy fish into the diseased fish.
Inflamed intestines are rescued by anti-inflammatory bacterial isolates or transplantation of WT ENS into sox10 mutants. (A) Addition of a representative Escherichia isolate, E. coli HS, to CV sox10 mutants reduces intestinal neutrophil accumulation. Monoassociation of sox10 mutants with E. coli HS does not increase neutrophil level over that observed in GF zebrafish. n > 20, from at least three independent experiments. (B) Correlation between absolute abundance of E. coli HS and log10(intestinal neutrophil number + 1) in experiments with added E. coli HS. Linear regression analysis with 95% confidence intervals. For A, B: n > 35, from three to six independent experiments. (C) Representative images of distal intestine from WT, sox10-, and sox10- rescued by WT ENS precursor transplantation. Anti-ElavI1–labeled enteric neurons are white (white arrow); neutrophils are black (black arrow). Scale bar = 100 μm. (D) Quantification of intestinal neutrophil number per 140 μm of distal intestine. n > 6 for all conditions, *p < 0.05, **p < 0.01, ****p < 0.0001, ANOVA with Tukey’s range test.
These studies demonstrate that inflammatory intestinal pathologies, such as Hirschsprung-associated enterocolitis or inflammatory bowel disease, can be explained as an overgrowth of certain pro-inflammatory groups of bacteria or a loss of anti-inflammatory bacteria. “When we started this work, very few people were thinking about how the nervous system and gut bacteria interact,” said Eisen, UO’s Institute of Neuroscience. “Our studies demonstrate how important it is to consider all the interacting cells of an organ, including the microbial cells.”
“Human microbiomes can be overwhelmingly variable due to differences between people’s environments, diets and genetics,” said Guillemin, a biologist and member of the UO’s Institute of Molecular Biology. “The zebrafish model allowed us to control those variables and see how bacterial strains tracked with inflammation. From these patterns, we could show that the drivers of disease can be a very few members of a complex microbial community.”
Identifying the bacteria that drive and protect against disease is the first step toward developing microbial interventions and therapies, said Rolig, UO’s Institute of Molecular Biology. “The fact that we could alleviate inflammation by adding back a single key bacterial strain, suggests that it could be useful as a probiotic for inflammatory diseases,” said Rolig, National Institutes of Health-funded Microbial Ecology and Theory of Animals Center for Systems Biology, known as the META Center, which Guillemin heads. The next steps are to use what they have learned from this zebrafish model of gut inflammation to design better probiotics to treat intestinal inflammation.
https://www.eurekalert.org/pub_releases/2017-02/uoo-obc021517.php
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