Metabolic crosstalk between intestinal microbiota and dendritic cells: from homeostasis to inflammation

Abstract

The intestinal microbiota plays critical roles in regulating immunity and inflammation through intricate interactions between microbial metabolites and diverse immune cells. Dendritic cells (DCs), the most potent professional antigen-presenting cells, are essential for sensing the complicated microbiota environment and subsequently initiating and regulating adaptive immune responses. While the commensal microbiota typically mediates DC-triggered immune tolerance and thus the maintenance of intestinal homeostasis, epithelial injury or pathogenic infection generally drives the proinflammatory function of DCs, contributing to harmful inflammation and intestinal disorders. Various microbiota metabolites (such as short-chain fatty acids, bile acids, and tryptophan derivatives) play critical roles in modulating the developmental and functional diversity of DCs through metabolic, epigenetic, or signaling reprogramming. In this review, we discuss the metabolic crosstalk between the intestinal microbiota and DCs and its pivotal function in orchestrating the balance between intestinal homeostasis and pathogenic inflammation. We also discuss future directions to better elucidate the microbiota-DC dialog in intestinal immunity and develop therapeutic approaches for manipulating the microbiota-DC axis against inflammatory disorders.

1. Introduction

The gut microbiota ecosystem, which consists of bacteria, viruses, and fungi, plays a pivotal role in human health and disease by dynamically interacting with the host immune system [1]. While proper regulation of microbiota-immune crosstalk is crucial for maintaining intestinal homeostasis, its dysregulation is closely implicated in various immune-mediated intestinal disorders, such as inflammatory bowel disease (IBD), infections, and tumors [2]. DCs are the master antigen-presenting cells that bridge innate and adaptive immunity. DCs are particularly capable of sensing and presenting microbial antigenic signals to the adaptive immune system, contributing to either tolerance to commensals and dietary antigens or immune defense against pathogens. Importantly, intestinal DCs display significant developmental and functional plasticity to cope with complicated intestinal environments [3–5]. Elucidating the molecular crosstalk between the microbiota and DCs is therefore critical for an in-depth understanding of how the host-immunity-microbiota network controls both intestinal homeostasis and immunological pathogenesis.

Immune-metabolism crosstalk has emerged as an essential mechanism linking the microbiota system to health and disease. Microbial metabolites are derived from multiple sources, such as dietary components, de novo synthesis, and metabolic switching, and are critical in modulating the function and metabolism of DCs in multiple physiological and pathological processes [6]. Various metabolites, such as short-chain fatty acids (SCFAs), bile acids, and tryptophan derivatives, are derived from the intestinal microbial system. These metabolites modulate the development, phenotype, and function of DCs through various mechanisms, such as intracellular signaling modulation, epigenetic reprogramming, and metabolic remodeling, thereby establishing a balanced response of the intestinal immune system. Importantly, intestinal dysbiosis, which is triggered by factors such as gastrointestinal infections, inappropriate diets and stressful psychological events, can lead to metabolic perturbations and aberrant activation of DCs, even causing inflammatory and neoplastic disorders [7,8]. Targeting microbiota-DC crosstalk through metabolic intervention strategies offers a promising direction for shifting harmful intestinal inflammation to homeostatic tolerance. In this review, we discuss the current understanding of how microbiota-derived signals metabolically modulate the fate and function of DCs in intestinal health and disease pathogenesis.