Microbiota-gut-brain axis: interplay between microbiota, barrier function and lymphatic system

Abstract

The human gastrointestinal tract, boasting the most diverse microbial community, harbors approximately 100 trillion microorganisms comprising viruses, bacteria, fungi, and archaea. The profound genetic and metabolic capabilities of the gut microbiome underlie its involvement in nearly every facet of human biology, from health maintenance and development to aging and disease. Recent recognition of microbiota - gut - brain axis, referring to the bidirectional communication network between gut microbes and their host, has led to a surge in interdisciplinary research. This review begins with an overview of the current understandings regarding the influence of gut microbes on intestinal and blood-brain barrier integrity. Subsequently, we discuss the mechanisms of the microbiota - gut - brain axis, examining the role of gut microbiota-related neural transmission, metabolites, gut hormones and immunity. We propose the concept of microbiota-mediated multi-barrier modulation in the potential treatment in gastrointestinal and neurological disorders. Furthermore, the role of lymphatic network in the development and maintenance of barrier function is discussed, providing insights into lesser-known conduits of communication between the microbial ecosystem within the gut and the brain. In the final section, we conclude by describing the ongoing frontiers in understanding of the microbiota - gut - brain axis's impact on human health and disease.

Keywords: Microbiota-gut-brain-axis; blood brain barrier; intestinal barrier; lacteal; lymphatic system.

Figure 1.

Illustration of gastrointestinal barrier. A layer of mucus, secreted by epithelial cells, coats the luminal side of the gut epithelium. The gut endothelial barrier comprises gut epithelial cells, tightly sealed by junctional complexes consisting of tight and adherens junctions. Within the gut epithelium are specialized cells, including enteroendocrine cells, which secrete gut hormones and serve as a crucial link in the communication between the central and enteric nervous systems. The gut vascular barrier is composed of fenestrated epithelium, also sealed by junctional complexes of tight and adherens junctions. Beneath the villus, intestinal lymphatic capillaries (lacteals) are situated, which drain into the mesenteric collecting vessels and the thoracic duct. This structure form a semipermissive barrier for lipid absorption and focal immune surveillance. This figure was created with BioRender (https://biorender.com/).

Figure 2.

The microbiota-gut-brain axis. The bidirectional communication between the brain and gut microbiota is mediated by several pathways including the immune system, neuroendocrine system, ENS, circulatory system, and vagus nerve. Microbiota can promote production of essential metabolites, neurotransmitters, and other neuroactive compounds that influence the gut epithelial barrier and brain barrier. Different types of microbial metabolites have been shown to modulate barrier function by blood circulation (arrows). Alterations in gut microbiota have been linked to the development of autism spectrum disorders, anxiety, depressive-like behavior, impaired physical performance, and motivation, as well as neurodegenerative diseases. Recent research also suggesting the potential for microbiota to traverse the lymphatic system, serving as a secret pathway, linking the gut and the brain, may contribute to the development of disease. This figure was created with BioRender (https://biorender.com/).