Summary: Organ-on-a-chip models reveal how different tissues and the immune system interact to influence inflammatory diseases, including ulcerative colitis.

Source: MIT

MIT Engineers Build Multi-Tissue Organ-on-a-Chip to Study Immune Interactions

MIT biological engineers have developed a multi-tissue microfluidic platform seeded with human cells that enables controlled study of organ-to-organ and immune interactions.

Using so-called organ-on-a-chip or physiome-on-a-chip technology, the research team investigated how circulating immune cells shape inflammatory processes in ulcerative colitis (UC) and related liver diseases. Their experiments also highlighted a key role for short-chain fatty acids (SCFAs)—metabolic byproducts produced by gut bacteria—under inflammatory conditions.

“We’ve shown that you can begin to address chronic inflammatory diseases by designing experiments in organs-on-chips,” says Linda Griffith, School of Engineering Professor of Teaching Innovation, professor of biological and mechanical engineering, and senior author of the study.

The study, published in Cell Systems, demonstrates how microphysiological systems (MPS) can be used to vary and control disease complexity to better understand multi-organ and immune-driven disorders.

Creating a Complex, Connected Model

Griffith’s lab has been developing human organ models for nearly two decades, beginning with a liver chip used for drug-toxicity testing. More recently they expanded this approach to interconnected microphysiological systems that can model interactions across multiple organs. These platforms are particularly useful for diseases that involve multiple tissues, immune responses, or complex metabolic regulation—cases where single-gene models fall short.

In the current work, the team focused on the gut-liver axis. They built a connected system using colon tissue taken from patients with ulcerative colitis and healthy human liver tissue. The platform also allows introduction of specific immune cells to simulate adaptive immune responses. When gut and liver tissues were linked, their behavior changed markedly versus when they were cultured separately: inflammation in the UC gut tissue decreased in the presence of healthy liver tissue, while metabolic and immune-related gene pathways increased activity in both organs.

Introducing T Cells and Recreating Disease Features

To probe immune effects, researchers added two types of CD4+ T cells: regulatory T cells (Treg), which typically suppress immune responses, and Th17 cells, which drive inflammation. Adding these T cells to the connected gut-liver model rapidly increased inflammatory responses and reproduced characteristics associated with inflammatory bowel disease and autoimmune liver disorders. This demonstrates how circulating adaptive immune cells can reshape tissue physiology across organs.

Gut tissue in organ-on-a-chip model — MIT engineers devised a multi-tissue organ-on-a-chip approach to study complex inflammatory diseases such as ulcerative colitis. Image credit: Linda Griffith et al.

Short-Chain Fatty Acids: Friend or Foe?

The team then examined the role of short-chain fatty acids (SCFAs)—including butyrate, propionate, and acetate—that gut microbes produce when fermenting dietary fiber. SCFAs are abundant, contribute meaningfully to human energy needs, and are generally associated with anti-inflammatory effects. However, the MIT model revealed a more nuanced picture.

SCFAs reduced innate inflammation in UC gut tissue when adaptive T cell involvement was minimal. In contrast, when effector CD4+ T cells were present, SCFAs markedly exacerbated inflammatory responses across both gut and liver tissues. The findings suggest SCFAs can either attenuate or amplify inflammation depending on the state of adaptive immunity: protective in early or innate-driven inflammation, but potentially harmful when many effector T cells are recruited—an effect that may accelerate autoimmune pathology.

“Our hypothesis, based on these experiments, is that the impact of short-chain fatty acids depends on the extent of adaptive immune engagement,” says lead author Martin Trapecar, an MIT postdoc. The study links SCFAs to metabolic reprogramming in tissues, showing increased ketone production, glycolysis, and lipogenesis under certain conditions, as well as changes in innate immune activation.

Extending the Model to Brain Disorders and Beyond

The research grew from broader efforts to model multi-organ interactions, including the gut, liver, and brain. Prior animal studies have implicated microbial metabolites like SCFAs in neurodegenerative disease progression, motivating the lab to explore connections to disorders such as Parkinson’s disease. Griffith’s group plans to use the MPS platform to investigate these links and to study other complex diseases in a controlled, human-relevant setting.

“Complex human diseases demand complex models,” Griffith says. “Animal models can generate hypotheses, but physiomimetic human systems help identify drug targets and guide development more directly from patient-derived samples.”

Funding and Publication

Funding for the research came from the U.S. Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health (NIH), the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Environmental Health Sciences, the Koch Institute Support Grant from the National Cancer Institute, and the Pew-Stewart Trust Foundation.

Publication: The study is reported in Cell Systems under the title “Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids.” The work was led by Martin Trapecar and Linda Griffith with collaborators including Catherine Communal, Jason Velazquez, and others.

Abstract Highlights

Developed a human gut-liver axis model that incorporates adaptive immune cells.
Gut-liver interactions increased metabolic activity while reducing innate inflammation in isolated conditions.
SCFAs reduced innate inflammation in ulcerative colitis gut tissue when Treg and Th17 cells were absent.
In the presence of acute CD4+ T cell-mediated inflammation, SCFAs exacerbated effector T cell activity and promoted barrier disruption and liver injury.

These findings highlight the value of human microphysiological systems combined with systems immunology to study causality and the interplay of immunity, metabolism, and tissue homeostasis in complex, multi-organ diseases.