The major advances in fundamental immunology for the past 25 years have to do with major advances in artificial manipulations of gene expressions (knock-out, knock-in, conditional knock-out, CRISPR-Cas9, etc).
Until recently very little attention was given to the extra-genomic influence of such gene manipulation. The scientists rarely bothered and still many don't to study gene effects in homozygous offspring derived from heterozygous parents to balance for exrta-genomic influence.
For example, it is conceivable that homozygous gene effect are influenced wholly or in part by extra-genomic factors such as microbiota. This is exactly what a new study in journal Nature suggests.
In this study, the authors made initial observation that two colonies of genetically identical B6 mice kept in two different research facilities differed in their gut derived fecal IgA level (IgAhigh and IgAlow). Interestingly two colonies did not differ in serum IgA level. The authors found that fecal IgA phenotype was vertically transmittable from parents to progeny.
Surprisingly, co-housing experiments revealed that IgAlow phenotype was dominant. This dominance of IgAlow phenotype was reversed when fecal materials were passed through 0.45 micron filter before transplantation into IgAhigh hosts.
In addition, the authors found that pre-treatment of IgAlow mice with broad-spectrum antibiotics or ampicillin could reverse IgAlow phenotype as well, indicating that presence of ampicillin sensitive large microbes were responsible for this microbiota effect.
The authors found that IgAlow mice intestine were more sensitive to chemical injury compared to IgAhigh mice.
However, intestinal sensitivity to DSS were independent of microbiota and dependent of intestinal IgA secretion.
To understand the mechanism behind IgAlow phenotype the authors tested components of fecal IgA complexes. These experiments revealed that IgAlow mice had profound deficiency in secretory component of IgA complexes in fecal samples. Secretory component is known to protect IgA from degradation.
Finally, the authors showed that microbial pellets derived from IgAlow mice could degrade secretory component in a protease-dependent manner (use of germ-free host mice would have been beneficial to know exactly what microbe was responsible for this effect).
In summary, these results showed that non-genomic microbiota could influence hereditary immune phenotype. When studying gene-manipulated mice models, it is of critical importance to evaluate the model in proper manner (fecal transplantation, co-housing or heterozygous parents).
David Usharauli
Surprisingly, co-housing experiments revealed that IgAlow phenotype was dominant. This dominance of IgAlow phenotype was reversed when fecal materials were passed through 0.45 micron filter before transplantation into IgAhigh hosts.
In addition, the authors found that pre-treatment of IgAlow mice with broad-spectrum antibiotics or ampicillin could reverse IgAlow phenotype as well, indicating that presence of ampicillin sensitive large microbes were responsible for this microbiota effect.
The authors found that IgAlow mice intestine were more sensitive to chemical injury compared to IgAhigh mice.
However, intestinal sensitivity to DSS were independent of microbiota and dependent of intestinal IgA secretion.
To understand the mechanism behind IgAlow phenotype the authors tested components of fecal IgA complexes. These experiments revealed that IgAlow mice had profound deficiency in secretory component of IgA complexes in fecal samples. Secretory component is known to protect IgA from degradation.
Finally, the authors showed that microbial pellets derived from IgAlow mice could degrade secretory component in a protease-dependent manner (use of germ-free host mice would have been beneficial to know exactly what microbe was responsible for this effect).
In summary, these results showed that non-genomic microbiota could influence hereditary immune phenotype. When studying gene-manipulated mice models, it is of critical importance to evaluate the model in proper manner (fecal transplantation, co-housing or heterozygous parents).
David Usharauli
In other words, nothing new under the sun :)
ReplyDeleteThe great humanist and Renaissance scientist, Rene Dubos, derived by C-section a mouse colony, NCS, from another strain, Standard Swiss (SS). He found, 'The most striking peculiarities of NCS mice: namely their very rapid weight gain on complete diets, their ability to gain weight on deficient diets, their great susceptibility to experimental bacterial infections, and their resistance to the lethal effect of endotoxins--can be rapidly obliterated by the mere artifice of contaminating these animals with a culture of E. coli derived from SS mice'. All this, in 1960! All forgotten by 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137267/