Friendly gut microbes could be our most dangerous enemies

Some studies are interesting and thought-provoking, and some studies are just studies. But this new paper in journal Science is a beauty. One rarely comes across to this type of research.

As many of you many know, we harbor large numbers of friendly microorganisms inside (gut, lung) or outside (skin). In many aspects, these commensal microbes share characteristics, like LPS (endotoxin), with their pathogenic siblings. However, since commensal microbes can live with us in peace, they probably had acquired some properties to make such co-habitation possible. 

Indeed, the authors, led by Andrew Goodman at the Yale University School of Medicine, found that unlike pathogenic microorganisms (E. coli, S. enterica, C. rodentium), major subsets of our commensal microbial world were highly resistant to several cationic anti-microbial peptides (AMP).

The authors determined that this increased resistance of commensals to AMP was relate to a single gene encoding enzyme, LpxF, responsible for removing phosphate group from LPS (component of microbial cell wall). 

In vivo experiments with mono-colonization of LpxF-deficient mutant human commensal microbe, B. thetaiotaomicron, confirmed that unlike LpxF-complemented B. thetaiotaomicron, B. thetaiotaomicron deficient for LpxF was easily displaced by wild-type B. thetaiotaomicron in presence of pathogenic C. rodentium infection or chemical, DSS-induced inflammation. Non-virulent tir mutant C. rodentium or commensal SFB had no impact on LxpF-deficient B. thetaiotaomicron population stability.

Similar results were observed when 14 member of human gut flora were transplanted into germ-free mice and exposed to C. rodentium infection, implying that LxpF played important role in population stability during gut inflammation.

Finally, gut microbes obtained directly from healthy humans displayed similar resistance to AMP.

In summary, these results suggest that human gut microflora acquired resistance to its own host's anti-microbial peptides thus providing additional mechanism responsible for peaceful co-existence and gut ecological stability. 

Of course, such resistance of gut commensals to AMP may pose problem when gut microbes invade inner systems, as during sepsis. So, this is a double-edge sword dilemma for host-microbe mutualism. 

The experiments that are missing, in my opinion: (1) Repeat of experiments with anti-microbial peptide deficient mice models to confirm that population stability is indeed related to resistance to AMPs; (2) It is not clear how presence of LxpF-deficient commensal microbe could affect the severity of inflammation induced by C. rodentium.

David Usharauli

Skin fat cell differentiation program has an immunologically-active phase

Staphylococcus aureus (S. aureus) infection represents a major medical issue. Unlike viral or intra-cellular microbial infections, we still do not know much about how immune system defends against extra-cellular microbes.

This new study in journal Science provided the evidence that white fat cells, adipocytes, may play yet unrecognized role in defense against S. aureus skin infection.

The research group, led by Richard Gallo at UC San Diego School of Medicine, observed that skin infection with S. aureus induced local adipocyte expansion. 

Analysis of mice deficient in fat cell development (Zfp423nur12 mouse) showed that these mice contained  more S. aureus locally in skin wound as well as systematically, in the spleen.

In vitro analysis of adipocyte differentiation revealed that maturation of pre-adipocytes to adipocytes led to selective expression of anti-microbial peptide, cathelicidin (Camp). Camp expression peaked at days 2-4 in adipocyte differentiation program. 

As a result, adipocyte condition medium could inhibit S. aureus growth in vitro.

In addition, up-regulation of Camp in maturing adipocytes was in response to S. aureus infection. As expected, a medium supplemented with adipocyte tissue extract from Camp-KO could not inhibit S. aureus growth.

Finally, adipogenesis deficient Zfp423nur12 mouse did not up-regulate Camp in response to S. aureus.

In summary, these results indicate that S. aureus skin infection activates pre-adipocyte to adipocyte differentiation program and induces Camp, Cathelicidin, anti-microbial peptide expression that inhibits S. aureus growth and prevents it's systemic spread.

The authors suggest that at this early stage of S. aureus skin infection (day 2-7) adipocyte-derived Camp expression dominates the host defense. 

However, in my opinion, to clearly rule out the role of innate immune system (neutrophils, macrophages) it would necessary to repeat these experiments with anti-Gr-1 antibody (neutrophil depletion) or macrophage-deficient mouse models or immune system-specific Camp deficiency (BM chimera).   

David Usharauli