{"id":801,"date":"2015-08-11T14:54:25","date_gmt":"2015-08-11T14:54:25","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=801"},"modified":"2017-08-21T11:41:56","modified_gmt":"2017-08-21T11:41:56","slug":"primary-care-corner-with-geoffrey-modest-md-early-life-stress-in-mice-changes-in-microbiome-and-later-anxiety","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/08\/11\/primary-care-corner-with-geoffrey-modest-md-early-life-stress-in-mice-changes-in-microbiome-and-later-anxiety\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Early Life Stress (in Mice), Changes in Microbiome, and Later Anxiety"},"content":{"rendered":"<p><strong>By: Dr. Geoffrey Modest<\/strong><\/p>\n<p><span style=\"font-family: 'Calibri',sans-serif;color: black\">I heard about this on NPR and realized that I had not blogged for awhile on the microbiome&#8230; \u00a0This study basically showed that early life stress\u00a0in mice leads to changes in their intestinal microbiome, which seems to be largely\u00a0responsible for altered behavior later in life\u00a0(see\u00a0<\/span><span style=\"font-family: 'Calibri',sans-serif;color: black\">doi:10.1038\/ncomms8735<\/span><span style=\"font-family: 'Calibri',sans-serif;color: black\">). \u00a0<\/span><\/p>\n<p><span style=\"font-family: 'Calibri',sans-serif;color: black\">Background:<\/p>\n<ul>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">There are a few human studies finding an association between traumatic childhood events\u00a0and the later development of psychiatric diseases and functional bowel disorders<\/span><\/p>\n<\/li>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">Animal studies find that maternal separation leads to long-lasting behavioral changes, gut dysfunction, hyper-responsiveness of the hypothalamic-pituitary-adrenal\u00a0(HPA)\u00a0axis,\u00a0depression\/anxiety, visceral hypersensitivity, and increased intestinal permeability in adulthood<\/span><\/p>\n<\/li>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">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)<\/span><\/p>\n<\/li>\n<\/ul>\n<p><span style=\"font-family: 'Calibri',sans-serif;color: black\">Details of this study:<\/span><\/p>\n<ul>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">Both germ-free (GF) mice (ie, no intestinal\u00a0microbiome) and specific pathogen-free (SPF) mice (ie,\u00a0all having\u00a0the same intestinal microbiome)\u00a0developed equally large increases in their serum corticosterone levels when submitted to the\u00a0stress of maternal separation shortly after weaning.<\/span><\/p>\n<\/li>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">The microbiota of those SPF mice changed a lot when subjected\u00a0to the stress of maternal separation, having\u00a0only 55-70% similarity to those not exposed to stress. And this &#8220;early-life dysbiosis&#8221; in their microbiome did not change as the mice reached adulthood.<\/span><\/p>\n<\/li>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">Later anxiety levels were higher in the mice exposed to the maternal separation, but <strong><span style=\"font-family: 'Calibri',sans-serif\">only in the SPF\u00a0group<\/span><\/strong>. there were 3 assessments of anxiety: a step-down test (going down from an elevated platform), light preference test (amount of time\u00a0in illuminated compartment) and tail suspension test (how long they were immobile).<\/span><\/p>\n<\/li>\n<li><span style=\"font-family: 'Calibri',sans-serif;color: black\">The altered microbiota was transferred\u00a0from the SPF mice with maternal separation into healthy\u00a0GF mice, finding that these\u00a0GF mice did not maintain this abnormal microbiome and did not have abnormal responses to the 3 anxiety tests. Since\u00a0those 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\u00a0suggests that there are a combination of stress-induced microbiome changes in addition to\u00a0host factors that affect later anxiety.<\/span><\/p>\n<\/li>\n<\/ul>\n<p><span style=\"font-family: 'Calibri',sans-serif;color: black\">So, my interest in the microbiome is that it provides an insight mechanistically into\u00a0at least one physiologic\u00a0way that\u00a0animals (including humans, though it is much easier to study mice)\u00a0are 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\u00a0attendant effects on\u00a0heart disease, glucose intolerance etc. But I really liked the one on diabetic\u00a0mice showing that those on metformin improved their glycemic profile (as expected), but there was a significant increase in the\u00a0bacterium Akkermansia. In a parallel\u00a0experiment, just increasing this bacterium (in the absence of\u00a0<span class=\"il\">metformin<\/span>) also enhanced glucose tolerance and decreased\u00a0adipose tissue inflammation, suggesting that an additional mechanism of action for\u00a0<span class=\"il\">metformin<\/span>\u00a0may be through its effect on the microbiome (see h<\/span><span style=\"font-family: 'Calibri',sans-serif;color: black\"><a href=\"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/01\/28\/primary-care-corner-with-geoffrey-modest-md-heart-failure-microbiome\/\">ttp:\/\/blogs.bmj.com\/ebm\/2015\/01\/28\/primary-care-corner-with-geoffrey-modest-md-heart-failure-microbiome\/<\/a>\u00a0) \u00a0&#8212; 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). \u00a0In the current mouse study, it is impressive that subsequent\u00a0anxiety is not simply a genetic\/epigenetic\u00a0response to a traumatic early childhood event, but that the putative mechanism for\u00a0this\u00a0later 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\u00a0potential microbiome improvements after the initial stress insult, such as through diet, exercise, or even meds. Interesting stuff&#8230;<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Primary Care Corner with Geoffrey Modest MD: Early Life Stress (in Mice), Changes in Microbiome, and Later Anxiety [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/08\/11\/primary-care-corner-with-geoffrey-modest-md-early-life-stress-in-mice-changes-in-microbiome-and-later-anxiety\/\">Read More&#8230;<\/a><\/p>\n","protected":false},"author":148,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[14283],"tags":[],"class_list":["post-801","post","type-post","status-publish","format-standard","hentry","category-archive"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/801","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/users\/148"}],"replies":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/comments?post=801"}],"version-history":[{"count":0,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/801\/revisions"}],"wp:attachment":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/media?parent=801"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/categories?post=801"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/tags?post=801"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}