The diverse collection of microorganisms that inhabit the gastrointestinal tract, collectively called the gut microbiota, profoundly influences many aspects of host physiology, including nutrient metabolism, resistance to infection and immune system development. Studies investigating the gut-brain axis demonstrate a critical role for the gut microbiota in orchestrating brain development and behavior, and the immune system is emerging as an important regulator of these interactions. Intestinal microbes modulate the maturation and function of tissue-resident immune cells in the CNS. Microbes also influence the activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity and neurogenesis. Accordingly, both the gut microbiota and immune system are implicated in the etiopathogenesis or manifestation of neurodevelopmental, psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer's disease. In this review, we discuss the role of CNS-resident and peripheral immune pathways in microbiota-gut-brain communication during health and neurological disease.

A sequence of seven alanine residues-too short to form an ␣-helix and whose side chains do not interact with each other-is a particularly simple model for testing the common description of denatured proteins as structureless random coils. The 3 JHN␣ coupling constants of individual alanine residues have been measured from 2 to 56°C by using isotopically labeled samples. The results display a thermal transition between different backbone conformations, which is confirmed by CD spectra. The NMR results suggest that polyproline II is the dominant conformation at 2°C and the content of ␤ strand is increased by approximately 10% at 55°C relative to that at 2°C. The polyproline II conformation is consistent with recent studies of short alanine peptides, including structure prediction by ab initio quantum mechanics and solution structures for both a blocked alanine dipeptide and an alanine tripeptide. CD and other optical spectroscopies have found structure in longer ''random coil'' peptides and have implicated polyproline II, which is a major backbone conformation in residues within loop regions of protein structures. Our result suggests that the backbone conformational entropy in alanine peptides is considerably smaller than estimated by the random coil model. New thermodynamic data confirm this suggestion: the entropy loss on alanine helix formation is only 2.2 entropy units per residue. T anford's pioneering experiments on denatured proteins in 6 M guanidinium chloride (GdmCl) (1-5) were interpreted by using the random coil model, and they anchored a widespread belief that denatured proteins are structureless chains. Tanford emphasized that 6 M GdmCl is required to eliminate all residual structure, which was detected by optical rotatory dispersion in heat-denatured proteins (6). The random coil model has been applied to modern NMR studies of backbone conformation in denatured proteins (7,8) by assuming that the backbone conformations found in protein structures, including or excluding regions of regular secondary structure, are represented with the same frequencies in denatured proteins. One might suppose, however, that the energy differences between major backbone conformations are sufficiently large to favor one conformation over others, at least in a homopeptide.We address this question by using NMR to investigate the backbone conformation as a function of temperature for a sequence of seven alanine residues in a peptide solubilized in water by two basic residues at either end of the alanine sequence. This peptide presents an appealing model system for a structureless denatured protein. It is too short to form any detectable ␣-helix in water via peptide hydrogen bonds; moreover, the OCH 3 side chain is too short to form nonpolar clusters and too inert to form other side chain interactions. To characterize the backbone conformations of this peptide, we measure system properties that are related directly to either the or the backbone angles. It is possible today to resolve and assign most backbone resonances of de...