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I arrived to my shift early, nervous about caring for critically ill patients as a first-year fellow. I sat in the workroom alone, paralyzed, not sure how to preround despite being months into fellowship. The senior fellow appeared minutes before sign-out; fresh, knowledgeable, and calm, despite her busy night and lack of sleep. She asked me how I was doing. With tears in my eyes, my emotions poured out. I explained that I felt lost, unsure of myself, my place, and my knowledge. For the first time, I confessed out loud, “I don’t think I’m supposed to be here. I have no idea what I’m doing.” I could trust her in a way I couldn’t trust others. She was like me: othered by her identity, minoritized by society. Though different from my own, her identity allowed her to understand my own experiences. We were different from one another and we were also the same. Unlike the senior faculty, it was safe to talk to her. And, unlike my other cofellows, there was a kinship between us in our otherness. She looked at me, closed the door, and shared words of strength that I needed to hear. I belonged. I was more than enough. She shared that the pressure I was experiencing was common among systematically minoritized individuals; she too had felt it before. Sitting with her, I was finally seen, supported, and comforted. As a peer mentor from a minoritized background, she provided a sense of security and belonging that had not been provided in my training and was distinct from the support of senior faculty.

Environmental enteric dysfunction (EED)—a chronic inflammatory condition of the intestine—is characterized by villus blunting, compromised intestinal barrier function and reduced nutrient absorption. Here we show that essential genotypic and phenotypic features of EED-associated intestinal injury can be reconstituted in a human intestine-on-a-chip lined by organoid-derived intestinal epithelial cells from patients with EED and cultured in nutrient-deficient medium lacking niacinamide and tryptophan. Exposure of the organ chip to such nutritional deficiencies resulted in congruent changes in six of the top ten upregulated genes that were comparable to changes seen in samples from patients with EED. Chips lined with healthy epithelium or with EED epithelium exposed to nutritional deficiencies resulted in severe villus blunting and barrier dysfunction, and in the impairment of fatty acid uptake and amino acid transport; and the chips with EED epithelium exhibited heightened secretion of inflammatory cytokines. The organ-chip model of EED‐associated intestinal injury may facilitate the analysis of the molecular, genetic and nutritional bases of the disease and the testing of candidate therapeutics for it.

Environmental Enteric Dysfunction (EED) is a chronic inflammatory condition of the intestine characterized by villus blunting, compromised intestinal barrier function, and reduced nutrient absorption. Here, we show that key genotypic and phenotypic features of EED-associated intestinal injury can be reconstituted in a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by organoid-derived intestinal epithelial cells from EED patients and cultured in niacinamide- and tryptophan-deficient (-N/-T) medium. Exposure of EED Intestine Chips to -N/-T deficiencies resulted in transcriptional changes similar to those seen in clinical EED patient samples including congruent changes in six of the top ten upregulated genes. Exposure of EED Intestine Chips or chips lined by healthy intestinal epithelium (healthy Intestine Chips) to -N/-T medium resulted in severe villus blunting and barrier dysfunction, as well as impairment of fatty acid uptake and amino acid transport. EED Intestine Chips exhibited reduced secretion of cytokines at baseline, but their production was significantly upregulated compared to healthy Intestine Chips when exposed to -N/-T deficiencies. The human Intestine Chip model of EED-associated intestinal injury may be useful for analyzing the molecular, genetic, and nutritional basis of this disease and can serve as a preclinical model for testing potential EED therapeutics.

It is impossible to analyze human-specific host-microbiome interactions using animal models and existing in vitro methods fail to support survival of human cells in direct contact with complex living microbiota for extended times. Here we describe a protocol for culturing human organ-on-a-chip (Organ Chip) microfluidic devices lined by human patient-derived primary intestinal epithelium in the presence of a physiologically relevant transluminal hypoxia gradient that enables their coculture with hundreds of different living aerobic and anaerobic bacteria found within the human gut microbiome. This protocol can be adapted to provide different levels of oxygen tension to facilitate coculturing of microbiome from different regions of gastrointestinal tract, and the same system can be applied with any other type of Organ Chip. This method can help to provide further insight into the host-microbiome interactions that contribute to human health and disease, enable discovery of new microbiome-related diagnostics and therapeutics, and provide a novel approach to advanced personalized medicine.

It is impossible to analyze human-specific host-microbiome interactions using animal models and existing in vitro methods fail to support survival of human cells in direct contact with complex living microbiota for extended times. Here we describe a protocol for culturing human organ-on-a-chip (Organ Chip) microfluidic devices lined by human patient-derived primary intestinal epithelium in the presence of a physiologically relevant transluminal hypoxia gradient that enables their coculture with hundreds of different living aerobic and anaerobic bacteria found within the human gut microbiome. This protocol can be adapted to provide different levels of oxygen tension to facilitate coculturing of microbiome from different regions of gastrointestinal tract, and the same system can be applied with any other type of Organ Chip. This method can help to provide further insight into the host-microbiome interactions that contribute to human health and disease, enable discovery of new microbiome-related diagnostics and therapeutics, and provide a novel approach to advanced personalized medicine.

The diverse bacterial populations that comprise the commensal microbiota of the human intestine play a central role in health and disease, yet no method is available to sustain these complex microbial communities in direct contact with living human intestinal cells and their overlying mucus layer in vitro. Here we describe a human Organ-on-a-Chip (Organ Chip) microfluidic platform that permits control and real-time assessment of physiologically-relevant oxygen gradients, and which enables co-culture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota. When compared to aerobic co-culture conditions, establishment of a transluminal hypoxia gradient sustained higher microbial diversity with over 200 unique operational taxonomic units (OTUs) from 11 different genera, and an abundance of obligate anaerobic bacteria with ratios of Firmicutes and Bacteroidetes similar to those observed in human feces, in addition to increasing intestinal barrier function. The ability to culture human intestinal epithelium overlaid by complex human gut microbial communities within microfluidic Intestine Chips may enable investigations of host-microbiome interactions that were not possible previously, and serve as a discovery tool for development of new microbiome-related therapeutics, probiotics, and nutraceuticals.

The diverse bacterial populations that comprise the commensal microbiome of the human intestine play a central role in health and disease. A method that sustains complex microbial communities in direct contact with living human intestinal cells and their overlying mucus layer in vitro would thus enable the investigation of host-microbiome interactions. Here, we show the extended coculture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota, using a microfluidic intestine-on-a-chip that permits the control and real-time assessment of physiologically relevant oxygen gradients. When compared to aerobic coculture conditions, the establishment of a transluminal hypoxia gradient in the chip increased intestinal barrier function and sustained a physiologically relevant level of microbial diversity, consisting of over 200 unique operational taxonomic units from 11 different genera and an abundance of obligate anaerobic bacteria, with ratios of Firmicutes and Bacteroidetes similar to those observed in human faeces. The intestine-on-a-chip may serve as a discovery tool for the development of microbiome-related therapeutics, probiotics and nutraceuticals.

In the version of this Article originally published, the authors mistakenly cited Fig. 5d in the sentence beginning ‘Importantly, the microbiome cultured in these primary Intestine Chips...’; the correct citation is Supplementary Table 2. This has now been amended.