Studies using a novel human “gut-inflammation-on-a-chip” suggest that probiotic bacteria may not always be a benefit to our health. Woojung Shin, Ph.D. student, and Hyun Jun Kim, Ph.D., assistant professor in the department of biomedical engineering at the University of Austin at Texas, used the chip to demonstrate how gut inflammation starts when the integrity of the intestinal epithelium is compromised, and sets in motion events that lead to the production of inflammatory cytokines and recruitment of immune cells. The results also indicated that while probiotic bacteria can be of benefit to gut health when the intestinal epithelium is intact, they may cause more harm than good when the gut barrier is already compromised.
“Once the gut barrier has been damaged, probiotics can be harmful just like any other bacteria that escapes into the human body through a damaged intestinal barrier,” says co-author Shin. “When the gut barrier is healthy, probiotics are beneficial. When it is compromised, however, they can cause more harm than good. Essentially, ‘good fences make good neighbors.’”
The researchers report their results in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “Intestinal barrier dysfunction orchestrates the onset of inflammatory host–microbiome cross-talk in a human gut inflammation-on-a-chip.”
Human intestinal inflammation involves complex processes that include mucosal injury, impaired barrier function, and the recruitment and infiltration of immune cells, leading to inflammatory responses that include the secretion of inflammatory cytokines, the authors write. Studies in humans and animal models also indicate that dysfunctional interaction between gut epithelium, microbiome, and immune components represents a key contributing factor in inflammatory pathogenesis.
However, identifying what goes wrong in this cross-talk, and which factors act to trigger gut inflammation hasn’t been easy, because it’s not possible to manipulate these complex interactions in existing models. “Thus, identification of the key modulator that orchestrates the onset of inflammatory responses in the gut is of great importance because this identification would support the development of clinical and therapeutic options that target the prime initiator of the whole inflammatory cascades,” the authors note.
The team’s new human gut inflammation-on-a-chip effectively mimics the interaction between intestinal luminal cells, immune cells, and the microbiome, and allows scientists to trigger and monitor the onset and development of intestinal inflammation, in this case mimicking the development of inflammation in a well-studied murine model, which can be caused by the chemical dextran sodium sulfate (DSS). The microchip also represents the first such diseased organ-on-a-chip, they suggest. Until now, organ chip technology has been used to model how organs function in a controlled environment, but the new device enables scientists to fine-tune the system by adding and removing key factors.
“By making it possible to customize specific conditions in the gut, we could establish the original catalyst, or onset initiator, for the disease,” says Dr. Kim, who led the study. “If we can determine the root cause, we can more accurately determine the most appropriate treatment.”
The researchers’ studies using the new microchip showed that DSS treatment impaired epithelial barrier integrity, the structure of gut villi, and mucus production, without causing cytotoxic damage. The effects of DSS were reversible. The findings indicated that interaction between the DSS-sensitized epithelium and immune cells increased oxidative stress, causing gut microbiota to produce inflammatory cytokines, and leading to immune cell recruitment. Importantly, the studies showed that disruption to epithelial barrier integrity and function was the most critical factor in triggering inflammation. And while treatment using probiotics can effectively reduce oxidative stress, probiotic bacteria couldn’t repair epithelial barrier dysfunction and proinflammatory responses when administered after DSS-induced barrier disruption.
“By utilizing our pathomimetic gut inflammation-on-a-chip, we discovered that barrier dysfunction is one of the most critical triggers that initiates the onset of intestinal inflammation,” the authors conclude. “Maintaining the integrity of the epithelial barrier is necessary and sufficient to suppress mucosal oxidative stress and the subsequent proinflammatory cascades mediated by the aberrant intercellular host–microbiome cross-talk.”
The researchers say the findings indicate that individuals with so-called ‘leaky gut’ may be more vulnerable to microbial attack and heightened immune infiltration, leading to chronic inflammation that occurs when homeostatic tolerance is disrupted. “Our mechanistic study also suggests that targeting the restoration of barrier dysfunction may be a compelling therapeutic approach to effectively control the local inflammation …” they suggest.
The researchers plan to build on their chip technology and develop more customized human intestinal disease models, such as for inflammatory bowel disease or colorectal cancer, so they can identify how the gut microbiome controls inflammation, cancer metastasis and microbiome impact on the efficacy of cancer immunotherapy.