Y-ECCO Literature Review: Josh Elias
Josh Elias
Identification of environmental factors that promote intestinal inflammation
Sanmarco LM, Chao CC, Wang YC, et al.
Nature 2022;611:801–9
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Introduction
Patients will often ask, “What causes Inflammatory Bowel Disease?” Frustratingly, we remain unable to answer this seemingly simple question, beyond the often-quoted paradigm that unknown environmental factors trigger inflammation in genetically susceptible individuals. Although our understanding of the immune response in IBD has reached phenomenally detailed levels of resolution, the nature and identity of the initial environmental triggers of IBD have continued to remain a mystery. The strong relationship between socioeconomic development and IBD incidence is tantalising evidence of a definable environmental toxin and various substances such as processed food additives have recently been highlighted as potential suspects [1]. However, searching for the causative agent is like looking for a needle in a haystack as the candidate list includes literally every small molecule in existence!
Methods and key findings
Given the difficulties of unravelling this environmental conundrum, Sanmarco et al. present an exciting new method of screening large numbers of environmental small molecules for their ability to trigger or, more precisely, to aggravate intestinal inflammation. Whenever designing such an experiment, the model selected is always a compromise between scalability and biological insight. For example, although a mouse would provide deeper biological insight than a cultured cell monolayer, the number of mice that would be required to screen large numbers of small molecules makes this approach unfeasible. Addressing this balance, the Sanmarco and colleagues therefore selected the zebrafish as a highly scalable (no pun intended) yet multi-organ model, with the striking feature that the intestine can be assessed in the live fish through the transparent body.
The fish were exposed to individual candidate small molecules dissolved in their water for up to 3 days and at the same time they were treated with a substance (TNBS) which induced a baseline level of intestinal inflammation. This baseline level of inflammation was not enough to kill the fish but was enough to see if the candidate molecule might be making things better or worse.
This model could be used to test any small molecule in existence; however, as proof of principle the authors selected 111 compounds from a database of potentially toxic environmental compounds based on primitive data suggesting potential intestinal toxicity.
When tested, some of the molecules proved fatal, some caused a dose-dependent worsening of intestinal inflammation and, fascinatingly, some ameliorated inflammation. The authors then attempted to use these initial data to train a machine learning algorithm to identify other molecules in the original database which might worsen intestinal inflammation. This second batch of molecules were tested on the zebrafish and showed a similar pattern which was somewhat enriched for pro-inflammatory molecules compared to the first batch.
One of these newly identified pro-inflammatory molecules, propyzamide, was then selected for more in-depth study. Propyzamide is a small molecule found in weed killer and is therefore something we may unknowingly be exposed to. Using very elegant molecular biology experiments, Sanmarco and colleagues discovered that propyzamide aggravated intestinal inflammation by blocking the aryl hydrocarbon receptor, an intracellular aromatic hydrocarbon sensing protein. The aryl hydrocarbon receptor normally suppresses inflammation via transcription of anti-inflammatory genes but its blockage by propyzamide seemingly breaks this homeostatic cycle, leading to production of pro-inflammatory cytokines.
Scientific implications
This study is a valiant attempt to develop a way of narrowing down and screening the enormous list of environmental molecules which may trigger IBD. The zebrafish model seems convincing as a good balance between scalability and biological relevance but the quantity of molecules to be tested remains daunting. Use of machine learning to narrow down this list is an excellent idea; however, this still depends on some information being available on the biological effect of each molecule and the training dataset would need to be much larger for any future potential studies. Although one cannot conclude from the presented data that propyzamide is a trigger of IBD in humans, the study elegantly demonstrates how an environmental small molecule can indeed aggravate intestinal inflammation by perturbing an innate homeostatic cytokine control pathway.
Conclusions
This study by Sanmarco and colleagues provides intriguing insights in the pursuit of specific environmental triggers for IBD. Such studies provide encouragement and hope that such triggers will be identified in the future. Indeed, if environmental triggers were to be successfully identified, this could have enormous implications for patients and potentially allow for targeted preventative strategies. This study and the elegant methods used provide significant optimism for the IBD Community that the challenge of environmental triggers might be solvable and suggest a need to increase efforts and research funding to help address this large area of unmet clinical need.
References
- Maaser C, Langholz E, Gordon H, et al. European Crohn’s and Colitis Organisation topical review on environmental factors in IBD. J Crohns Colitis 2017;11:905–20. doi.org/10.1093/ecco-jcc/jjw223
Josh Elias - Short Biography
Josh Elias is a Clinical Lecturer in Gastroenterology at the University of Cambridge. Alongside his role as postdoctoral researcher, he is currently completing his clinical training in Gastroenterology at Cambridge University Hospitals in the UK. His area of research focus is the pathogenesis underlying PSC and IBD.