The gut microbiota has wide-ranging effects on host physiology and is an important determinant of health and disease. As we have learned over the past two decades, these effects are not limited to the gastrointestinal tract, but can influence host functions throughout the body. A great deal of research has focused on understanding the mechanisms by which microbes influence host function and immunity, and gnotobiotic models have been instrumental in this line of research. The effects of the microbiota on immunity and metabolism have been well characterized, but the basic understanding of how microbes influence the overall structure and function of the intestinal barrier is not well understood.
The intestinal barrier is the first line of defense against pathogens and antigens in the gut and it encompasses both physical and chemical properties. Its function is critical for maintaining health, and a dysfunctional intestinal barrier has been implicated in many inflammatory diseases. However, little is known about how barrier function is influenced by the microbiota under healthy conditions or in physiological states.
A new study at McMaster University by Hayes et al. investigated the dynamics of host-microbe interactions on intestinal barrier structure and permeability in mice. The authors first demonstrated that the presence of a commensal microbiota was critical for the maturation of colonic structure and permeability. Compared to conventionally raised mice that harbour a murine commensal microbiota, germ-free mice had lower permeability to a paracellular probe (51Cr-EDTA) that coincided with changes in the expression of proteins that determine paracellular permeability.
The authors then went on to study how the colonic barrier adapts to microbes by colonizing germ-free mice with a healthy human microbiota. One week following colonization, paracellular permeability increased, and was maintained at three weeks following colonization. Again, these changes in paracellular permeability coincided with changes in proteins (claudin-1, occludin) that help regulate passage of molecules between epithelial cells. Importantly, this increased “leakiness” after colonization of germ-free mice was not considered pathological, because it reached the “normal” levels observed in a conventionally raised mouse. Moreover, no structural gut damage was observed following colonization, suggesting that physiological paracellular permeability is determined by the microbiota.
In addition to functional changes, structural adaptions of the colonic barrier were also observed within one week of colonization. A thin and patchy mucus layer that allowed direct microbe-epithelial cell interaction was observed at day one following colonization. However, after one week of adaptation to the microbiota a thicker mucus layer excluded bacteria from direct epithelial cell contact. These functional and structural adaptations to the presence of a microbiota were critical for maintaining intestinal homeostasis. Mice colonized for shorter periods of time with human-derived microbiota were more susceptible to inflammation than mice colonized for longer periods of time.
The results suggest that structural and functional aspects of the colonic barrier very rapidly reach a physiological state. “It is key to understand how normal interactions are established between the microbiota and the intestinal barrier, because this helps us understand how and why things go wrong during inflammation or disease”, says Dr. Elena Verdu from the Farncombe Institute at McMaster University and senior author of the study. “In this sense, basic studies like this one are crucial to generate questions that will then be validated in clinical trials and may translate into therapeutic targets”, explained Verdu.
Hayes CL, Dong J, Galipeau HJ, et al. Commensal microbiota induces colonic barrier structure and functions that contribute to homeostasis. Sci Rep. 2018; 8(1):14184. doi: 10.1038/s41598-018-32366-6.
Tlaskalova-Hogenova H, Kverka M, Verdu EF, et al. Chapter 8 – Gnotobiology and the Study of Complex Interactions between the Intestinal Microbiota, Probiotics, and the Host. Mucosal Immunology. 2015; 1:109-33. doi: 10.1016/B978-0-12-415847-4.00008-2.
Natividad JM, Verdu EF. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol Res. 2013; 69(1):42-51. doi: 10.1016/j.phrs.2012.10.007.