Microbiota-derived metabolites as drivers of gut–brain communication

Abstract

Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut–brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut–brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut–brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein. Abbreviations: 4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood–brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(- N -oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins

The rearing environment persistently modulates mouse phenotypes from the molecular to the behavioural level

“…Several studies have shown that gut microbiota can affect brain development and behavioral functions [92,93]. These effects might be mediated by gut-microbiota products that can cross the blood brain barrier and modulate the chromatin landscape in neurons, which, in turn, can influence behavior [94][95][96]. Controlled experiments with different diets, fecal transplants, and treatment with antibiotics would be needed to elucidate these potential causal mechanisms further.…”

Exposure to Antibiotics and Neurodevelopmental Disorders: Could Probiotics Modulate the Gut–Brain Axis?

“…Nowadays, it is clear that neurotransmitters such as glutamate, GABA, serotonin, and dopamine, short-chain fatty acids (SCFAs), cytokines, neuropeptides, endocannabinoids, and hormones are the molecules used for the communication between the brain and the gut through the endocrine, immune, and neural systems in order to maintain homeostatic conditions [ 47 ] in our body. Gut microbiota [ 48 , 49 , 50 ] synthesizes a vast milieu of metabolites that may directly or indirectly impact neuronal activity as well as induce host cells to produce signaling molecules, shaping both local and extraintestinal host functions [ 51 ]. Among the neuroactive molecules, SCFAs, including butyrate, acetate, and propionate, are metabolites produced from the bacterial fermentation of nondigestible fibers in the gut [ 52 ].…”

Physical Activity, Gut Microbiota, and Genetic Background for Children and Adolescents with Autism Spectrum Disorder

“…Due to the significant importance of these functions to brain homeostasis as well as the wide range of diet-derived metabolites detected, particularly amino acid- and polyphenol-derived metabolites, it is strongly recommended that future interventions focus on these pathways and compounds in order to promote brain homeostasis. There have been few studies demonstrating that nutritional or gut microbiome modification strategies can significantly improve neurological and psychiatric disorders [ 144 ].…”