**5. Interaction and regulation between microbiota and the CNS and immune system**

The human immune system has evolved to maintain a symbiotic relationship between the host and the microbiota, and disruption of the dynamic immunemicrobial interaction leads to profound effects on human health (e.g., interaction between resident microbiota and immune signals, CNS development) as described in below [94].

### **5.1 Inflammasome signaling pathway**

Inflammasome is an innate immune signaling complex, which is activated in response to diverse microbial and endogenous danger signals. Also, the various pattern-recognition receptors (PRRs) in different families, including NLRP1, NLRC3, NLRP6, NLRP7, NLRC4, and AIM2, have been identified to effect in inflammasome activity. Inflammasomes activation recruits ACS (apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine protease caspase 1 through caspase activation and recruitment domain (CARD) to induce the proteolytic cleavage of pro-caspase1 to generate mature and active caspase 1, which further

process pro-IL-1β and pro-IL-18 to the final production of bioactive IL-1β and IL-18 proteins [93].

### **5.2 IFN-I signaling pathway**

IFN-I is a pleiotropic and ubiquitous cytokine that plays an essential role in both innate and adaptive immunity and maintenance of host homeostasis. IFN-I is induced by pathogen-associated molecular patterns (PAMPs). Secretion of endogenous IFN-I depends on activation of several classes of PRRs. They play a significant role in priming the host to various viral, bacterial, or tumor components. Effects of IFN-I on inflammation and host hemostasis have been linked to the recruitment of Tregs. Also, the commensal lactic acid bacteria have been shown to trigger TLR3-mediated IFN-β secretion by DCs in the intestine [93].

## **5.3 NF-κB signaling pathway**

The interaction between microbiota and NF-κB signaling is also responsible for CNS inflammation. NF-κB family of transcription factors contribute to both innate and adaptive immune responses and maintenance of the immune system. So, the NFκB family of transcription factors contribute to both innate and adaptive immune responses and maintenance of the immune system [93].
