Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases

Abstract

The gut microbiome comprises the collective genome of the trillions of microorganisms residing in our gastrointestinal ecosystem. The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer's and Parkinson's diseases. The purpose of this review is to summarize what is known about the gut microbiome, how it is connected to the development of disease and to identify the bacterial and biochemical targets that should be the focus of future research. Understanding the mechanisms behind the activity and proliferation of the gut microbiome will provide us new insights that may pave the way for novel therapeutic strategies.

Keywords: Autism; Environmental factors; Gut microbiota; Manganese; Metals; Microbiome–gut–brain axis; Neurological diseases; Neurotoxicity; Parkinson's disease.

Figure 1

Schematic representation of potentially harmful and potentially beneficial bacteria present in the gut microbiome. Pro-biotic bacteria such as Lactobacillus and Bifidobacteria modulate the gut environment by releasing bioactive compounds that enhance enteric epithelial barrier function as well as by competitively binding to the epithelium thus outcompeting pathogenic bacteria. Eubacterium rectale and Fusobacterium produce fatty acids such as acetic acid, propionate and butyrate that are important as an energy source for intestinal epithelial cells as well as for modulating mucosal immune responses. In contrast, higher counts of bacteria such as Staphylococcus and Pseudomonas are seen in various metabolic disorders such as diabetes and obesity. Clostridum tetani spores are resistant to the acidic environment of the stomach and to regular antibiotic treatments. Production of the tetanus toxin by these bacteria is thought to contribute to the “leaky gut syndrome” prevalent in autistic children. E.coli is a common commensal of the gut microbiome. However, certain serotypes are pathogenic and are known to cause gastroenteritis and urinary tract infections.

Figure 2

Bacterial species relevant to research on Autism, Parkinson’s disease, Alzheimer’s disorder, and Type-2 Diabetes. Clostridia are prevalent in many diseases and notably, presence of C. tetani in the gut microbiome of autistic children may contribute the “leaky gut” syndrome seen in these children. Lower counts of probiotic bacteria like Lactobacillus are also seen in many disorders. Understanding the differences in bacterial species seen in healthy and diseased states is crucial to understanding their importance to host health.

Figure 3

The Gut-Brain axis: Bidirectional signaling between the gastrointestinal tract (GIT) and central nervous system (CNS) occurs through spinal afferents and the vagus nerve. This mode of communication is thought to occur through peptides such as Neuropeptide Y (NpY), Cholecystokinin (CcK), ghrelin, leptin as well as by neurotransmitters like dopamine (DA), serotonin (5-HT), GABA, acetylcholine (Ach) and glutamate. Human and animal studies of various diseases demonstrate that these two systems are not exclusive of one another but do in fact show some parallels in terms of expression of pro-inflammatory cytokines and altered physiological functions.

Figure 4

Factors affecting gut microbiota composition: The host-microbiota interaction is a complex and dynamic symbiosis. While diet and environment are well known factors affecting the populations of different phyla in the gut, some reports suggest that the host’s genetic composition might pre-dispose the continued growth of certain microbiota. The microbiome population can also be modulated by the presence of neurotransmitters and metabolites secreted by the host.