Commensal communication to the brain: pathways and behavioral consequences

I n recent years there has been an explosion of investigation of the microbiota which constitutes the gut microbiome (1 5). The trillions of bacteria which together make this up are engaged in multiple interactions with each other and the host in which they live. Indeed, they have been regarded as an additional organ within the external compartment of the body which influences the endocrine, metabolic and immune functions of the host. It has only recently received attention from the point of view of influence on the nervous system and this aspect has received the title ‘microbiome-gut-brain axis’ (6). This brief paper highlights some of the recent findings which promote the functional importance of this communication between gut commensals and the enteric and central nervous systems and was part of a lecture given recently at a meeting at the Karolinska Institutet, focused on ‘The Gut and The Brain’, with focus on Autism Spectrum Disorder (ASD). It is well appreciated in clinical medicine that patients with hepatic encephalopathy are best treated with nonabsorbable wide spectrum antibiotics and laxatives thus confirming the relationship between overgrowth of certain normal conventional bacterial gut contents and brain dysfunction (7). The gut brain-axis refers to a bidirectional communication pathway which is contributed to by the gut microbiome. It is also recognized that the irritable bowel syndrome (IBS) is associated with psychiatric dysfunction and it is argued by some that this is a common co-morbidity and that the key factors linking these together are what is called dysbiosis, which refers to an imbalance of the normal gut commensal population (8). IBS has also been connected with increased psychosocial stress especially since this has particular effects on the composition of normal gut microbiota. In this regard it is important to note the landmark observations by Sudo et al. (9) who showed that germ-free (GF) mice had exaggerated hypothalamic pituitary adrenal (HPA) axis responses to acute stress and that these were normalized by conventionalization with normal feces. Additionally, they could be restored to normal adult levels by monoassociation with a probiotic bacteria, Bifidobacterium infantis, but only if these treatments occurred in early life. Thus the HPA axis in these animals was programmable and programmed since attempts to treat mice in adulthood failed to reset the HPA response in terms of the corticosterone pathway. On the other hand, Gareau et al. (10) showed that ingestion of two Lactobacilli was able to attenuate HPA responses if given in adulthood and this apparent discrepant observation is not yet resolved. Heijtz et al. (11) showed that the brains of GF mice differed neurochemically and functionally from conventionally housed animals and that again early conventionalization of the gut microbiome restored these differences to those seen in adult life, suggesting the importance of the composition of the gut microbiome to normal brain development. We have also studied GF animals and have shown that they intrinsically express anxiolytic behavior and have alterations in the neurotransmitter receptors for NMDA and 5-HT in specific brain areas and also have reduced brain-derived neurotophic factor (BDNF) expression in the dentate gyrus of the hippocampus which is compatible with their behavioral phenotype (12). Indeed, different strains of mice have different behavioral phenotypes and Bercik et al. (13) have shown remarkably that this seems to depend on the normal microbiome of each mouse strain since fecal transplantation of one strain’s microbiome to another either in antibiotic treated or GF states, conferred the donor’s behavior to the recipient. From the observations listed above, questions clearly arise as to how non-pathogenic bacteria in the intestine