Hematopoietic stem and progenitor cells integrate Bacteroides-derived innate immune signals to promote gut tissue repair

Hayashi et al. (BioRxiv) doi: 10.1101/2021.10.05.463122

Keywords

  • Hematopoietic

  • Innate

  • Microbiota

 

Main Findings

The hematopoietic system in critical in maintaining a basal level of lymphopoiesis and myelopoiesis in order to supply sufficient immune cells that can then respond in case of acute infection. In recent studies, accumulating evidence has shown that the human gut microbiota plays a role in regulating hematopoiesis. Additionally, it has recently been demonstrated that hematopoietic cells express TLRs and can respond directly to infectious stimuli. However, it is not known how the hematopoietic system responds to and manages the overwhelming influx of microbial PAMPs and inflammatory cytokines that are found in conditions such as colitis. Furthermore, it is also not known whether there are any differences in the hematopoietic response to acute and chronic colitis. To investigate these questions, Hayashi et al. use an acute DSS colitis mouse model to induce gut inflammation. During acute inflammation, they find that hematopoietic stem and progenitor cells (HSPCs) respond by proliferating and migrating to inflamed mesenteric lymph nodes mesenteric lymph nodes (mLNs) where they differentiate into myeloid cells critical for gut tissue repair. Since there is overwhelming systemic inflammation as well as bacterial infiltration through a compromised mucosal barrier, Hayashi et al. aimed to elucidate the potential role of the gut microbiota in eliciting this effect on HSPCs. Using targeted antibiotics and 16S and metagenomic sequencing, they identified Bacteroides species as essential in inducing HSPC activation and expansion. In addition to acute colitis, Hayashi et al. also tested the effect of chronic gut inflammation on HSPCs. In contrast to acute colitis where HSPCs appear to respond well to manage the inflammation and gut tissue repair response, they find that chronic gut inflammation impairs hematopoietic self-renewal capabilities (tested through serial bone marrow transplantation experiments) and reduces immunoreactivity of HSPCs to infection.

 

Limitations

 

  • Microbiota experiments
    - IP injections of bacterial lysate were intended to recapitulate a systemic infection. However, in their discussion, they claim that there is Bacteroides infiltration upon acute gut injury, which suggests that there is infiltration secondary to colitis. But in this case, I think it would have been maybe more physiologically relevant if they induced colitis and validated that there was microbial infiltration into gut tissue (ie. Through imaging).
    - They also gave no rationale for why they picked the 6 Bacteroides species that they did or delineated which strains of each species were purchased and used in the experiments. There is no way to know if their bacterial lysate consisted of 6 individual strains or more.
    - Because they combined all the Bacteroides into one lysate, there is no way to explore which particular species might be responsible for triggering HSPC activation or to elucidate whether the bacterial themselves or a bacterial product was responsible for these effects.

  • Aging as a model for generalized inflammation. I would have liked to at least see some more discussion about other models of gut inflammation such as the adoptive T cell transfer (TCT) or a colorectal cancer model. I realize that the TCT model relies more on adaptive immune and DSS more on innate, but at least some more discussion to various gut inflammation models was warranted.

  • This point was also brought up in the discussion but perhaps more targeted knockdown of innate immune signaling pathways was warranted.
     

Significance/Novelty

 

What is the novelty of the preprint for the field specific? I think it is very interesting to investigate the role of the microbiota in hematopoiesis and generation of immune cells. Most studies focus on interactions between the microbiota and mature effector cells but if the microbiota plays a role at an earlier developmental stage, that could be a really important area to study, especially in conditions such as chronic colitis where HSPCs may be called upon to repopulate cell lineages that are being used up.
How does the result of the preprint matter for general immunologists and/or patients? I think this matters for increasing our understanding of hematopoietic and immune cell generation and maintenance. Elucidating how these systems and feedback signals function together could help us to eventually manipulate these systems for tissue surveillance/repair.

 

Credit

Reviewed by Alice Chen-Liaw as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow her on Twitter