The own versus foreign microbiota

It was long known that the absence of the gut microbiota impairs the full functionality of mammalian immune system. However, it appears that the immune system may require the species-specific microbiota not just any microbiota to develop its proper responses as the recent publication indicates. I think that this report has important implications both for the better understanding of principal immune events as well as for predicted and much expected innovative research applications like the advent of experimental animals with humanized microbiota.

The link: http://www.cell.com/abstract/S0092-8674(12)00629-0

In the course of this research authors colonize germ-free mice (it means – without any microbiota) with intestinal bacteria that are derived from several sources. Two main of these sources are murine or human fecal samples. Additionally, some experimental mice are also provided with rat microbiota. Summarizing the applied methodology, the starting fecal material (murine, human or rat) serves to prepare a respective probe that provides the formerly germ-free mice with commensal bacteria which differ by the species origin.  Using such model the publication answers two outstanding questions. The first analyzes how different species microbiotas are accommodated inside the murine intestinal tract by looking what is the difference between the original colonization sample and the established microbiota. The second attempts to find out what could be the influence of incongruent microbiota (in this case human or rat-derived) for the development of murine immune responses that are known to be affected by commensal bacteria.

Obviously, humans and mice harbor different microbiotas and data obtained by investigators reflect this simple fact as species identification among two different experimental microbiotas (murine or human-derived) reveals quite dissimilar results. But what is really interesting involves how, or maybe rather to what extend human-derived commensal bacteria could be maintained inside the murine gastrointestinal tract. It appears that recipients of human microbiota demonstrate a period of instability to their intestinal bacterial community after which a constant state is achieved. However, the final microbiota of such mice differs remarkably from the original sample. This is not the case for animals that received murine microbiota. Thus human intestinal commensals cannot be maintained in mice in their entirety. Additional and important piece of information is that Firmicutes may contain the bulk of bacterial species that are specific to humans and unstable in mice.

What is even more striking – mice colonized with human microbiota resemble germ-free mice in many immune parameters that are normally influenced by the presence of commensal bacteria. Studying such mice investigators document many changes in the immune structures of the small intestine such as smaller number of T cells in the lamina propria, less αβ CD4 T cells in the intraepithelial compartment, smaller Peyer’s patches and less T cells inside Peyer’s patches. The large intestine of mice with human microbiota is also affected but in quite contrasting way since it holds less γδ T cells in the intraepithelium but there are no other changes. Peripheral immune organs like spleen or brachial lymph nodes seem to be not altered by the change in microbiota origin. As an additional argument for the need of species-specific microbiota in the proper development of mucosal immune responses authors provide germ-free mice with rat-derived microbiota and observe similar disfuntionalities of the intestinal immune system as in the case of human microbiome transfer.

When it comes to the mechanism responsible for the impaired accumulation of lymphocytes at intestinal sites in mice with humanized microbiota it looks like it is the proliferation in Peyer’s patches and mesenteric lymph nodes that may be hold accountable. On the other hand the gut homing ability seems to not be affected by the heterologous microbiota transfer. Among other results that this publication contains the observation that the colonization with different species microbiota causes different bias in T cell effector phenotypes compared to the colonization with homologous microbiota definitely merits the further attention. Authors come to such conclusion after performing the detailed transcriptional analysis of CD4 T cells from lamina propria isolated from mice that were given the transfer of either murine or human commensal bacteria.

The commentary that I would like to make concerns the differential ability of murine or human microbiotas to stimulate the proliferation of CD4 T cells at mucosal sites. CD4 T cells proliferate as the response to the antigen stimulation and since they bear anticipatory receptors (the true cornerstone of adaptive immunity) the obvious question that comes to mind is why the origin of microbiota matters that much. I do not have explanation for this unexpected result and authors also do not offer a definitive answer, although they make some intelligent guesses as to the potential reason why heterologous microbiota fail to stimulate CD4 T cells proliferation to the same extend as murine commensals (impaired antigen uptake, decreased ability to penetrate mucus layer). An interesting observation is that the host epithelium seems to be more proficient at detecting host-specific than foreign bacteria. Perhaps the stratification by mucus layer is not as stringent in the case of certain host-specific bacterial species.

My last remark touches more practical thing. I have read recently a number of eloquently written review articles that postulated the need to engineer experimental mice with humanized microbiota as the exciting models to study microbiota-influenced diseases like inflammatory bowel disease or metabolic syndrome. But in the light of data that this publication presents the generation of such models looks more complicated than it was thought before. Obviously it is pertinent now that these findings be revisited by other laboratories. The following studies may confirm, widen or even contradict the conclusion presented in the discussed paper. However, maybe we assumed just too much and did not take into account the deep symbiotic relationship between host and its specific commensal bacteria that may be very difficult to recapitulate in a heterologous model.

Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, Reading NC, Villablanca EJ, Wang S, Mora JR, Umesaki Y, Mathis D, Benoist C, Relman DA, & Kasper DL (2012). Gut immune maturation depends on colonization with a host-specific microbiota. Cell, 149 (7), 1578-93 PMID: 22726443