Control of brain development, function, and behavior by the microbiome

Abstract

Animals share an intimate and life-long partnership with a myriad of resident microbial species, collectively referred to as the microbiota. Symbiotic microbes have been shown to regulate nutrition and metabolism and are critical for the development and function of the immune system. More recently, studies have suggested that gut bacteria can impact neurological outcomes--altering behavior and potentially affecting the onset and/or severity of nervous system disorders. In this review, we highlight emerging evidence that the microbiome extends its influence to the brain via various pathways connecting the gut to the central nervous system. While understanding and appreciation of a gut microbial impact on neurological function is nascent, unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially novel etiologies for psychiatric and neurodegenerative disorders.

Figure 1. Pathways Linking the Microbiome and Central Nervous System

Signals from the intestinal microbiome may potentially traffic to the central nervous system (CNS) via several mechanisms. 1) Direct activation of the vagus nerve from the enteric nervous system to the CNS. 2) Production of, or induction of, various metabolites that pass through the intestinal barrier and into the circulatory system, where they may cross the blood-brain barrier to regulate neurological function. 3) Microbial associated molecular patterns (MAMPs, such as LPS, BLP, and PSA) and metabolites produced by the microbiome can signal to the immune system. Immune cells (and particularly their cytokines) can influence neurophysiology.

Figure 2. Microbiome Influence on Blood-Brain Barrier Integrity

Intestinal microbes are capable of fermenting complex carbohydrates into short chain fatty acids (SCFAs). A) Microbially-produced SCFAs signal to epithelial cells that create the blood-brain barrier (BBB) and increase production of the tight junction proteins claudin-5 and occludin. This leads to a tight and selective barrier, preventing undesired metabolites from entering the brain parenchyma. B) In the absence of microbial fermentation, no SCFA signaling occurs, and tight junction proteins are repressed. This leads to increased permeability of the BBB, and a loss of the selective barrier to serum metabolites.

Figure 3. Microbiome Modulation of Neuro-Immune Function

Microbial associated molecular patterns (MAMPs) derived from the intestinal microbiome can drive various aspects of immune function in the periphery. Cytokine signals, such as TNFα, IL-1β, and IL-6 can cross the blood-brain barrier and trigger their production by the microglia. Interaction of these cytokines with neurons influences physiology and leads to sickness behavior and depression.