Potential of Akkermansia muciniphila and its outer membrane proteins as therapeutic targets for neuropsychological diseases

Abstract

The gut microbiota varies dramatically among individuals, and changes over time within the same individual, due to diversities in genetic backgrounds, diet, nutrient supplementations and use of antibiotics. Up until now, studies on dysbiosis of microbiota have expanded to a wider range of diseases, with Akkermansia muciniphila at the cross spot of many of these diseases. A. muciniphila is a Gram-negative bacterium that produces short-chain fatty acids (SCFAs), and Amuc_1100 is one of its most highly expressed outer membrane proteins. This review aims to summarize current knowledge on correlations between A. muciniphila and involved neuropsychological diseases published in the last decade, with a focus on the potential of this bacterium and its outer membrane proteins as therapeutic targets for these diseases, on the basis of evidence accumulated from animal and clinical studies, as well as mechanisms of action from peripheral to central nervous system (CNS).

Keywords: Akkermansia muciniphila; Amuc_1100; neuropsychological disease; probiotics; treatment.

Figure 1

The protective effects of Akkermansia muciniphila against diseases. Biochemically, A. muciniphila exerts its protective function in a SCFA-dependent manner. Both butyrate and propionate bind G protein coupled receptor (GPR)-43 and GPR-41 that are expressed on the enteroendocrine L-cells, subsequently trigger secretion of gut peptides such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), leading to a reduction of food intake and an improvement of glucose metabolism. Propionate also acts as an immune regulator by binding to GPR-43, which is expressed on lymphocytes to reduce inflammation and maintain an appropriate immune defense, as well as to reduce proliferation of cancer cells. Butyrate activates peroxisome proliferator-activated receptor-γ (PPAR-γ), leading to beta-oxidation and oxygen consumption, and maintains anaerobic condition in the gut lumen. In addition, SCFAs also trigger secretory activity and motility in intestine via stimulating enteric neuron signaling. Effects on remote organs are modulated by acetate and propionate in the circulation, leading to an improved metabolism of liver, adipose tissue and brain. Physically, A. muciniphila enhances the gut barrier to defend intrusion of harmful particles and pathogens in several ways. Firstly, A. muciniphil upregulates expression of tight-junction proteins including claudin-1, zonula occluden (ZO)-1, ZO-2, ZO-3, and occludin, improving gut barrier and reducing gut permeability for LPS. Secondly, the pili-like membrane protein (Amuc_1100) from A. muciniphila is also involved in maintaining host immunological homeostasis by activating toll-like receptor 2 (TLR-2) and improving gut barrier function. Thirdly, A. muciniphila acts on Goblet cells to stimulate the secretion of mucus and thereby maintain the thickness of mucus layer.

Figure 2

Change of Akkermansia muciniphila abundance in neuropsychological diseases and attempts of modulation of A. muciniphila. Overall, the abundance of A. muciniphila was shown to decrease (red boxes) significantly in amyotrophic lateral sclerosis (ALS) and neuropsychiatric disorders (NPDs), increase (green boxes) significantly in multiple system atrophy (MSA), multiple sclerosis (MS) and Parkinson’s disease (PD), but remains ambiguous (blue boxes) in Alzheimer’s disease (AD) and cognitive deficits, autism spectrum disorder (ASD) and epilepsy.