Interactions between gut microbes and NLRP3 inflammasome in the gut-brain axis

Abstract

The role of the gut-brain axis in maintaining the brain's and gut's homeostasis has been gradually recognized in recent years. The connection between the gut and the brain takes center stage. In this scenario, the nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome promotes inflammatory cell recruitment. It plays a crucial role in coordinating host physiology and immunity. Recent evidence shows how vital the gut-brain axis is for maintaining brain and gut homeostasis. However, more research is needed to determine the precise causal link between changed gut microbiota structure and NLRP3 activation in pathogenic circumstances. This review examines the connection between gut microbiota and the NLRP3 inflammasome. We describe how both dynamically vary in clinical cases and the external factors affecting both. Finally, we suggest that the crosstalk between the gut microbiota and NLRP3 is involved in signaling in the gut-brain axis, which may be a potential pathological mechanism for CNS diseases and intestinal disorders.

Keywords: Gut microbiota; Gut-brain axis; Inflammation; LPS; NLRP3 inflammasome; Neurological disorders.

Graphical abstract

Fig. 1

The intestinal microbiota is involved in regulating intestinal homeostasis and the immune system. Gut microbiota components or metabolites regulate microbial-host interactions and immune tolerance. TLR4 in epithelial and immune cells recognizes LPS and activates NF-κB and NLRP3 inflammasome via MyD88 to produce pro-inflammatory cytokines, ultimately leading to pyroptosis. TLR5 expressed by the basolateral epithelium of the intestine detects bacterial translocation and causes chronic inflammation by recognizing the FLG of Gram-negative bacteria. TRL2 recognizes LTA in the cell wall of Gram-positive bacteria and activates mast cells via PGE2, causing edema and increased vascular permeability. PGN activates defensin synthesis in Paneth cells and increases transcription of pro-inflammatory genes by promoting NF-κB and MAPK activation via NOD family proteins. Microbial metabolites modulate immune responses through different pathways and coordinate host gut health and immune function.

Fig. 2

The activation mechanism of NLRP3 inflammasome. NLRP3 responds to a variety of PAMPs and DAMPs. Under different stimuli, signals such as TLR and TNFs promote NLRP3 expression. Oligomerized NLRP3 binds to ASC and recruits pro-caspase-1 to complete the assembly and activation of the inflammasome complex, which in turn cleaves pro-caspase-1, pro-IL-1β, and pro-IL-18. Mature IL-1β and IL-18 induce immune cell recruitment and activate pro-inflammatory signaling pathways, leading to cellular injury and inflammatory cell death. In addition, NLRP3 can activate caspase-1 through classical or non-classical pathways causing GSDMD cleavage, generating membrane pores in the plasma membrane, and causing pyroptosis.

Fig. 3

Interaction between gut microbiota and NLRP3 inflammasome in the gut-brain axis. In patients with AD, PD, and MDD, gut microbes promote activation of NLRP3 in the periphery and the center, activating an inflammatory response that damages both the gut and the blood-brain barrier. This inflammation contributes to central neuroinflammation and neurodegeneration. Additionally, the accumulation of certain proteins such as Aβ, α-syn, and Tau in the brain can stimulate the formation of NLRP3 inflammasome in microglia, further accelerating neurodegeneration. This process may also affect the structure of the gut microbiota.