Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases

Abstract

New models to study the intestine are key to understanding intestinal diseases and developing novel treatments. Intestinal organ-like culture systems (organoids and enteroids) have substantially advanced the study of the human gastrointestinal tract. Stem cell–derived cultures produce self-organizing structures that contain the multiple differentiated intestinal epithelial cell types including enterocytes, goblet, Paneth, and enteroendocrine cells. Understanding host–microbial interactions is one area in which these cultures are expediting major advancements. This review discusses how organoid and enteroid cultures are biologically and physiologically relevant systems to investigate the effects of commensal organisms and study the pathogenesis of human infectious diseases. These cultures can be established from many donors and they retain the genetic and biologic properties of the donors, which can lead to the discovery of host-specific factors that affect susceptibility to infection and result in personalized approaches to treat individuals. The continued development of these cultures to incorporate more facets of the gastrointestinal tract, including neurons, immune cells, and the microbiome, will unravel new mechanisms regulating host–microbial interactions with the long-term goal of translating findings into novel preventive or therapeutic treatments for gastrointestinal infections.

Intestinal in vitro and ex vivo Models to Study Host-Microbiome Interactions and Acute Stressors

“…Dietary tryptophan that is metabolized by both host and bacteria to indole derivatives have been shown to reduce intestinal permeability in T84 cells (Jennis et al, 2018 ). Intestinal organoids have proven to be a good model to examine mechanisms of host-bacterial interactions in a multi-cellular system (Rothschild et al, 2016 ; Blutt et al, 2018 ). Polyphenol metabolites which are biotransformed by the gut microbiota, have also been examined in vitro models (mainly Caco-2) including urolithin A (Gonzalez-Sarrias et al, 2015 ) and tert-butyl hydroperoxide (Deiana et al, 2010 ) and 3,4-dihydroxyphenyl-ethanol (Manna et al, 1997 ).…”

The Significance of the Intestinal Microbiome for Vaccinology: From Correlations to Therapeutic Applications

“…Enteroids can support replication of human rotavirus strains [ 91 ] and have also been successfully used to culture norovirus [ 92 ]. They are also slowly becoming robust enough to survive the addition of simple bacterial cultures or their supernatants [ 93 ]. While missing adaptive immunity, lymphatics, and complex microbiota, the system permits elegant and simplified examination of rotavirus–bacterial–innate immune interactions [ 94 ].…”

Comparative Microbiome Signatures and Short-Chain Fatty Acids in Mouse, Rat, Non-human Primate, and Human Feces

“…The gut microbiome plays a key role in various aspects of human health including nutrient digestion and metabolism, development and maturation of immune system, protection from infections, nervous system development, and has widespread influence beyond the gastrointestinal tract ( Blanton et al, 2016 ; Kho and Lal, 2018 ). Numerous clinical studies have demonstrated the association of gut microbes with a wide array of cardiometabolic and chronic diseases including obesity, type 2 diabetes, atopic diseases, cardiovascular diseases, hypertension, anxiety, depression, bowel diseases, diarrhea, constipation, and brain diseases including Parkinson’s, Alzheimer’s, and others ( Bakhtiar et al, 2013 ; Cojocaru and Chicos, 2014 ; Althani et al, 2016 ; Coit and Sawalha, 2016 ; Scher et al, 2016 ; Davis and Bajaj, 2017 ; Gundogdu and Nalbantoglu, 2017 ; Ipci et al, 2017 ; Ruiz-Rodriguez and Rello, 2017 ; Shivaji, 2017 ; Blutt et al, 2018 ; Davidson and Epperson, 2018 ). However, given the practical and ethical complexity of performing invasive sampling procedures in human subjects, high inter-individual variation in the diets and in the gut microbiomes of humans, and relative ease of using animals with controlled diets for large scale mechanistic and genotypic research studies, different types of animals models including rodents (mice, rats, guinea pigs, and hamsters), rabbits, pigs, zebra fish, and non-human primates (NHPs; e.g., macaques and vervet monkeys) have been developed and are frequently used to investigate the multiple dynamics of host–microbiome interactions ( Gootenberg and Turnbaugh, 2011 ; Tlaskalova-Hogenova et al, 2014 ; Amato et al, 2015 ; National Academies of Sciences et al, 2018 ; Nagpal et al, 2018 ).…”