Worm infection tips the balance in favor of Crohn's disease soothing gut flora

This week Science magazine published yet another study that revealed a complex biological inter-species relationship called defensive symbiosis. Here, the authors showed that worm infection of mammalian host favors gut flora species that soothe intestinal inflammation in a T_H2-dependent manner.

Mice deficient in Nod2 develop small intestinal abnormalities that resemble human Crohn's disease (for example, goblet cell defect that compromises intestinal mucus layer). This new study showed that experimental infection of Nod2-deficient mice with the parasitic worm Trichuris muris (T. muris) could restore small intestinal goblet cell numbers and morphology.

Earlier reports showed that intestinal abnormalities in Nod2-deficient mice dependent on gut flora species, Bacteroides vulgatus. Now, the authors showed that T. muris worm infection could reduce Bacteroides vulgatus burden in Nod2-deficient mice in a manner dependent on STAT6 signaling and IL-13 (type II immunity). Similar results were seen with a second worm infection, Heligmosomoides polygyrus.

Finally, the authors showed that worm infection specifically expanded another gut flora species, Clostridiales, that could directly inhibit pro-inflammatory Bacteroides vulgatus.

In summary, this study showed that in Nod2-deficient mice gut species Clostridiales represent defensive symbionts with an antagonistic interaction with another commensal bacteria, Bacteroidales. Worm infection of Nod2-deficient mice tips the balance in favor anti-inflammatory Clostridiales species. This knowledge could be utilized in treatment of Crohn's disease (for example, therapeutic worm infection or application of its derivative that promote type II immunity). 

David Usharauli

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