early life stress (in mice), changes in microbiome, and later anxiety

I heard about this on NPR and realized that I had not blogged for awhile on the microbiome...  This study basically showed that early life stress in mice leads to changes in their intestinal microbiome, which seems to be largely responsible for altered behavior later in life (see microbiome stress and behavior mice naturecommunic 2015 in dropbox, or doi:10.1038/ncomms8735).  

background:

--there are a few human studies finding an association between traumatic childhood events and the later development of psychiatric diseases and functional bowel disorders. 

--animal studies find that maternal separation leads to long-lasting behavioral changes, gut dysfunction, hyper-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis, depression/anxiety, visceral hypersensitivity, and increased intestinal permeability in adulthood

--intestinal microbiota can affect host behavior: germ-free animals have altered HPA responses to stress which is reversed by colonization by commensal bacteria, germ-free mice have lower anxiety-like behaviors, and there are an array of altered changes in neural and hormonal function (eg, microbial colonization in early life can affect hippocampal function)

details of this study:

--both germ-free (GF) mice (ie, no intestinal microbiome) and specific pathogen-free (SPF) mice (ie, all having the same intestinal microbiome) developed equally large increases in their serum corticosterone levels when submitted to the stress of maternal separation shortly after weaning

--the microbiota of those SPF mice changed a lot when subjected to the stress of maternal separation, having only 55-70% similarity to those not exposed to stress. And this "early-life dysbiosis" in their microbiome did not change as the mice reached adulthood.

--later anxiety levels were higher in the mice exposed to the maternal separation, but only in the SPF group. there were 3 assessments of anxiety: a step-down test (going down from an elevated platform), light preference test (amount of time in illuminated compartment) and tail suspension test (how long they were immobile).

--the altered microbiota was transferred from the SPF mice with maternal separation into healthy GF mice, finding that these GF mice did not maintain this abnormal microbiome and did not have abnormal responses to the 3 anxiety tests. Since those mice with early trauma developed a long-lasting dysbiotic microbiome but just implanting this dysbiotic microbiome was not long-lasting and did not alter them clinically, this suggests that there are a combination of stress-induced microbiome changes in addition to host factors that affect later anxiety.

so, my interest in the microbiome is that it provides an insight mechanistically into at least one physiologic way that animals (including humans, though it is much easier to study mice) are changed by their environment. there are several of my blogs dealing with different diets, food additives (eg artificial sweeteners) and their effect on the microbiome, along with the attendant effects on heart disease, glucose intolerance etc. But I really liked the one on diabetic mice showing that those on metformin improved their glycemic profile (as expected), but there was a significant increase in the bacterium Akkermansia. In a parallel experiment, just increasing this bacterium (in the absence of metformin) also enhanced glucose tolerance and decreased adipose tissue inflammation, suggesting that an additional mechanism of action for metformin may be through its effect on the microbiome (see http://gmodestmedblogs.blogspot.com/2014/10/heart-failure-microbiome.html  )  -- and this blog even looks at a study in humans, finding that meat-eaters have changes in their intestinal microbiome which lead to the production of an atherogenic chemical (TMAO), which was not found in vegetarians given meat (before their gut flora could be changed).  In the current mouse study, it is impressive that both that subsequent anxiety is not simply a genetic/epigenetic response to a traumatic early childhood event, but that the putative mechanism for this later anxiety seems to be mediated through a combination of microbiome and host changes. this study, of course, begs for followup ones looking at the outcome of potential microbiome improvements after the initial stress insult, such as through diet, exercise, or even meds. interesting stuff...