Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids

Abstract

Association between the microbiome, IBD and liver diseases are known, yet cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver and circulating Treg/Th17 cells, we modeled progression of ulcerative colitis (UC) ex vivo. We show that microbiome-derived short-chain fatty acids (SCFA) may either improve or worsen disease severity, depending on the activation state of CD4 T cells. Employing multiomics, we found SCFA reduced innate activation of the UC gut and increased hepatic metabolism. However, during acute T cell-mediated inflammation, SCFA exacerbate CD4 T cell effector function leading to gut barrier disruption and liver damage. These paradoxical findings underscore the emerging utility of human physiomimetic technology to study causality and temporal facets of gut-liver axis related diseases where animal models leave ambiguity.

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune-Prone Mice

“…Unexpectedly, these differences were more apparent in males rather than females, and treatment related effects were only observed in males except for GM-CSF, where treatment related decreases were observed in both sexes. A decrease in gut cytokines is consistent with what would be expected with a decrease in microbial abundance, which may be due in part to the propensity of microbes to produce short-chain fatty acids which can markedly reduce innate immune activation in the gut ( Trapecar et al, 2020 ). It is not clear why females had fewer Firmicutes than males to begin with, yet showed a greater increase in this population with TCE exposure.…”

Menstruation: science and society

“…Integrated systems allow the investigation of systemic effects, including hormonal and other factors that might influence menstruation. An enabling technology for such integration is a nowcommercialized onboard microfluidic pump, first used to drive long-term culture of 3D liver tissue 336,337 and adapted to study gut-liver interactions 338,339 and ultimately an integrated platform supporting 10 different interconnected MPSs communicating in a common culture medium for a month, 340 including a 3D endometrium. 328 This platform pumping technology was also adapted to build a model of interconnected 3D units of ovarian, fallopian, uterine, cervical, and liver tissues integrated into a single communicating fluidic system, 341 allowing the assessment of up to 5 different types of tissues at a time over a menstrual cycle mimic.…”

Instrumented Microphysiological Systems for Real-Time Measurement and Manipulation of Cellular Electrochemical Processes

“…The ‘physiome-on-a-chip’ utilizes interconnected Transwells to recapitulate up to 10 different organ systems, while monitoring gut TEER values (Edington et al., 2018). Further, this platform has been leveraged to study the role of inflammation and products of the microbiome in gut-liver-related diseases such as ulcerative colitis (Trapecar et al., 2019). Miller and Shuler have developed a pumpless, non PDMS MPS that recapitulates 13 organs (Miller and Shuler, 2016).…”