The brain-gut-microbiota axis

Introduction

The realization that gastrointestinal physiology is closely linked to the brain and vice versa is not new. Almost 2500 ago, Hippocrates, the “father of medicine,” allegedly stated that “All disease begins in the gut.” From direct observation, the brain has a direct effect on the stomach and intestine, where the very thought of eating can cause the release of intestinal digestive products before the food even arrives. On the other hand, distress in the gastrointestinal tract can send signals to the brain.

It is clear from human experience that various foods can affect mood. Some foods have a calming effect whereas others may cause excitement. Anxiety and excitement are often accompanied with changes in bowel habits. These are a few examples of bidirectional signaling between the gut and the brain, termed the gut-brain axis . Relationships suggesting bidirectional signaling between gut and brain have been described for several centuries. Additional support for the gut-brain axis concept is emerging. This includes the finding that there is a cooperation between intestinal bacteria and their animal hosts that regulates development and function of the immune system as well as the metabolic and nervous systems. Nevertheless, many aspects of this cooperative triad remain unclear largely because their mechanisms remain to be elucidated.

In this chapter we will provide an overview of several aspects of the gut-brain-microbiota axis. These include bidirectional signaling processes, how the components of this axis interact in disease, the evidence linking brain injury with the intestinal microbiota, immunology, inflammation as it pertains to the fetus and preterm infants, and the effects of antibiotics and other environmental perturbations on neurodevelopment via inflammatory processes and microbial metabolites.

It is important to note that much of the information currently available on the gut-brain-microbiota axis and its relation to health and disease in humans is based on single-omic technologies and is associative rather than causal. Although we have extrapolated considerable information from in vitro studies and studies in animals, how well they directly relate to the human remains unclear. We will briefly describe how integrated multiomics may help us better understand mechanisms and causality of central nervous system (CNS) diseases in humans and how they relate to the gut-brain axis.

Here we also present some of the information relating intestinal microbes to neurologic disorders, identify gaps in our current knowledge, and discuss future directions for research to clarify these relationships with the hope that this will lead to preventive and therapeutic strategies.

Overview of brain-gut-microbial signaling

Bidirectional signaling

The CNS plays a major role in various gut functions. Included among these are motility, secretion, blood flow, and gut-associated immune function in response to psychological and physical stressors. This has been known for a long time but was amplified in the 1840s when William Beaumont, the father of gastrointestinal medicine, experimentally showed that emotional status affected the rate of digestion and thus that the brain affects the gut. Beaumont’s observations of Alexis St. Martin, a fur trader who incurred a gunshot wound that exposed his stomach, showed how various behaviors of the stomach related to mood, hunger, and other factors and thus was one of the first direct observations of a brain-gut axis. This concept was subsequently recognized by numerous famous scientists including Darwin and Pavlov, but it took until the early to mid-20th century for accurate observations to be made that correlated gut physiology changes with changes in emotion.

The gastrointestinal tract also sends signals to the brain via the gut-brain axis. The intestinal microbiota play an integral role in this signaling. Components of the gut-brain axis include the CNS, neuroendocrine system, neuroimmune system, hypothalamic-pituitary-adrenal axis, autonomic nervous systems (both sympathetic and parasympathetic), enteric nervous system, vagus nerve, and intestinal microbiota. ^,

As seen in Fig. 4.1 , the bidirectional communication is accomplished by neural, humoral, endocrine, and immune connections between the gastrointestinal tract and the CNS. The microbes in the intestinal tract influence the brain via the release of cytokines, neurotransmitters, neuropeptides, endocrine messengers, and microbial metabolites.