Moody microbes or fecal phrenology: what do we know about the microbiota-gut-brain axis?

Abstract

Introduction: The microbiota-gut-brain axis is a term that is commonly used and covers a broad set of functions and interactions between the gut microbiome, endocrine, immune and nervous systems and the brain. The field is not much more than a decade old and so large holes exist in our knowledge.

Discussion: At first sight it appears gut microbes are largely responsible for the development, maturation and adult function of the enteric nervous system as well as the blood brain barrier, microglia and many aspects of the central nervous system structure and function. Given the state of the art in this exploding field and the hopes, as well as the skepticism, which have been engendered by its popular appeal, we explore recent examples of evidence in rodents and data derived from studies in humans, which offer insights as to pathways involved. Communication between gut and brain depends on both humoral and nervous connections. Since these are bi-directional and occur through complex communication pathways, it is perhaps not surprising that while striking observations have been reported, they have often either not yet been reproduced or their replication by others has not been successful.

Conclusions: We offer critical and cautionary commentary on the available evidence, and identify gaps in our knowledge that need to be filled so as to achieve translation, where possible, into beneficial application in the clinical setting.

Keywords: Antibiotic; Enteric Nervous system; Germ free; Microbiome; Vagus.

Fig. 1

Proposed mechanisms and pathways of the microbiota-gut-brain axis: Gut microbes synthesize a vast array of neuroactive molecules including neurotransmitters such as GABA and through fermentation, short chain fatty acids, which have effects on the nervous system. The intestinal microbiota also has direct and indirect effects of on the intestinal epithelium, local mucosal immune system, enteric nervous system and spinal and vagal nerves. Mediators and signals from these systems, including cytokines and neurotransmitters, modulate central nervous system (CNS) function and neuroendocrine responses such as the hypothalamus pituitary adrenal axis (HPA). In turn signals from the CNS and neuroendocrine system, including cortisol, catecholamines and acetylcholine, can alter gut microbiota composition. While such bi-directional signaling has been identified, definitive evidence for the specific roles of these pathways in communication between gut microbes and the brain is largely lacking

Fig. 2

Hardwired connections between gut microbes and the brain: Gut microbes can modulate activity of spinal and vagal sensory neurons. Vagal sensory neuron may assume both primary afferent and interneuron functions via activation of enteric nervous system to vagal fiber nicotinic sensory synapse. Distinct bacterial species have been demonstrated to modulate neural activity through inhibition of the TRPV1 and KCa3.1 ion channels on spinal and intrinsic primary afferents respectively