Table 1.

Alteration of gut microbiota by PRRs.

PRRs	Possible Mechanisms	Microbiota Changes
Nod1	Nod1 is a cytoplasmic receptor that can recognize iE-DAP, activate NF-κB and MAPK signals, regulate AMPs, proinflammatory cytokines, autophagy, and acquired immunity to enhance epithelial barrier function, promote intestinal homeostasis, and resist the invasion of pathogens that may cause colitis. Nod1 knockout enhances the damage and apoptotic responses of intestinal epithelial cells, enhances intestinal epithelial permeability, reduces epithelial barrier, and increases bacterial abundance [42], thereby increasing susceptibility to colitis. However, antibiotic treatment of Nod1 knockout mice significantly inhibits the formation of intestinal tumors, suggesting that gut microbiota plays an important role in the development of colorectal associated tumors; the specific microbial species have not been elucidated [19,22].	The number of bacteria has increased, but the specific species are not characterized.
Nod2	Nod2 is a cytoplasmic receptor that can recognize MDP and recruit RIP2, thereby activating NF-κB and MAPK signaling pathways. Nod2 also plays an important role by promoting the production of antibacterial compounds (including defensin) in Paneth cells. After Nod2 knockout, the production of AMPs decreases, and the tumor necrosis factor α and interferon γ increase, resulting in the overexpression of MLCK. MLCK phosphorylates Ser19 and Thr18 of the myosin light chain, changing its spatial conformation, promoting the contraction of actin and myosin filaments, and opening epithelial cell contacts, thus increasing the permeability of the intestinal epithelial mucosa. Nod2 knockout results in reduced goblet cells in colon mucosa, decreased expression of MUC2 and phospholipase A2, impaired intestinal epithelial barrier function, bacterial translocation and imbalance, and increased susceptibility to colitis and CRC [28,32,33,34,43]. One study showed that gut microbiota richness increases after Nod2 knockout. For example, Firmicutes, Corynebacteriaceae, Bdellovibrionaceae, and Deferribacteriaceae were increased [27].	Firmicutes ↑ Proteobacteria ↑ Deferribacteres phyla ↑ Lachnospiraceae ↑ Ruminococcaceae ↑ Corynebacteriaceae (Actinobacteria) ↑ Bdellovibrionaceae (Proteobacteria) ↑ Deferribacteriaceae (Deferribacteres) ↑
Nlrp3	Nlrp3 is a cytoplasmic receptor that promotes IL-18 production by non-hematopoietic cells, thereby maintaining gut microbiota homeostasis and the integrity of the intestinal epithelial barrier. After Nlrp3 deletion, the expression of IL-1β, IL-18, IL-10, and TGF-β is decreased, the secretion of antibacterial products is decreased, and the expression of β defensin altered, resulting in the destruction of the intestinal integrity, and altered gut microbiota (Rikenellaceae, Enterobacteriaceae, Mycobacterium, Clostridium are increased, Bacteroidaceae is decreased) [37,38]. These mice are more likely to develop CRC and have more severe disease manifestations. Nlrp3R258W mice have increased Treg cell numbers by increasing IL-1β production and AMPs secretion to reshape gut microbiota composition (such as decreased Actinobacteria, Verrucomicrobia, and Akkermansia, while Lactobacillus are increased). Their resistance to colitis and CRC is increased [41].	Rikenellaceae ↑ Enterobacteriaceae ↑ Clostridium ↑ Lactobacillus ↑ Bacteroidaceae ↓ Verrucomicrobia ↓ Akkermansia ↓
Nlrp6	Nlrp6 is a cytoplasmic receptor that is highly expressed in intestinal epithelial cells and myeloid-derived immune cells, such as dendritic cells, macrophages, and monocytes [44]. It can regulate mucus secretion of goblet cells in response to bacterial invasion and also regulate microbial colonization by regulating AMPs secretion. After Nlrp6 knockout, secretion of mucus in goblet cells is decreased, secretion of IL-18 is decreased, the ability of intestinal epithelial cells to recover after DSS-induced injury is weakened, and the expression of intestinal downstream AMPs genes is altered, thus increasing the susceptibility to colitis and related tumors. Nlrp6 knockout mice have changes in gut microbiota (Prevotellaceae, TM7, Bacteroidetes, Proteobacteria are increased, while Firmicutes are decreased); this change could not be repeated in the same littermate control experiment and contradictory results were identified, indicating that unidentified genetic or environmental factors may play a critical role [45,46,47,48,49]. Therefore, the effect of Nlrp6 on the relative abundance of gut microbiota needs to be further verified.	Prevotellaceae ↑ TM7 ↑ Akkermansia muciniphila ↑ Firmicutes ↓
Nlrp12	Nlrp12 is a cytoplasmic receptor that is primarily expressed in DCs and neutrophils [50]. It can inhibit intestinal inflammation by inhibiting both typical and atypical NF-κB and excessive immune signaling. The activation of NF-κB, ERK, and STAT3 is increased after Nlrp12 deletion, and the diversity and composition of gut microbiota are altered (Bacteroidales, Clostridiales, and Lachnospiraceae are decreased, while Erysipelotrichaceae is increased) and dyshomeostasis of the intestinal environment occurs, thereby increasing host susceptibility to colitis and related tumors [51].	Bacteroides ↓ Clostridia ↓ Lachnospiraceae ↓ Erysipelotrichaceae ↑
Aim2	Aim2 is a cytosolic innate immune receptor that can inhibit colitis and related CRC by regulating intestinal stem cell proliferation and gut microbiota composition. Specifically, Aim2 mediates IL-18 secretion, which in turn regulates IL-22 secretion and increases the release of AMPs such as Reg3β and Reg3γ to maintain intestinal homeostasis. After Aim2 knockout, intestinal microbial composition is changed significantly (the abundance of Akkermansia, Muciniphila, and Anaeroplasma is increased, while the abundance of Anaerostipes, Bifidobacterium, Flexispira, Prevotella, and Paraprevotella is decreased), AKT activation and transcription of genes related to cell proliferation increased, further increasing the host susceptibility to colitis and related tumors [52,53].	Akkermansia muciniphila ↑ Odoribacter ↑ Anaeroplasma ↑ Anaerostipes ↓ Flexispira ↓ Paraprevotella ↓ Bifidobacterium ↓ Prevotella ↓ Fusobacterium ↓
RIG-I	RIG-I is a cytoplasmic RNA sensor. After Rig-I knockout, IgA secretion is decreased, STAT3 phosphorylation is decreased, and Reg3γ secretion is decreased, inducing a gut microbiota disorder, leading to colitis and related tumors. The species richness and diversity of the gut microbiota are increased in Rig-I−/− mice, but the bacterial species have not been elucidated. However, antibiotic-treated Rig-I−/− mice remain susceptible to colitis, suggesting that gut microbiota disorders are not the primary underlying cause of susceptibility [54]. Therefore, the role of gut microbiota in CRC needs to be further verified.	The species richness and diversity of intestinal microbiota are increased, but the bacterial species have not been characterized.
cGAS/Sting	cGAS/Sting is a cytoplasmic DNA sensor that can be activated by CDNs or cytoplasm dsDNA to recruit TBK1, phosphorylate IRF3 and NF-κB, and induce IFN-Ⅰ production. In Sting−/− mouse, intestinal mucosa secretion and IgA production are decreased, cup cells are decreased, the secretion of IL-1β and IL-10 is decreased, and the gut microbiota is altered (Allobacolum, Bifidobacterium, and Actinomycetes are decreased, while Disulfovibrio and Proteus are increased), increasing the susceptibility to DSS-induced colitis [55,56].	Disulfovibrio↑ Proteus↑ Allobacolum ↓ Bifidobacterium ↓ Actinomycetes ↓
CLRs	CLRs are localized at the cell surface that recognizes carbohydrates on the surface of fungal pathogens in a Ca2+-dependent manner to initiate an antifungal immune response. Loss of CLRs leads to the decreased activation of NF-κB, decreased production of cytokines such as IL-6, TNF-α, and Th17, decreased production of AMPs such as S100A8 and S100A9, decreased repair ability of intestinal epithelial tissue, decreased phagocytosis and bactericidal ability of macrophages, and altered gut microbiota (for example, Lactobacillus murinus and Lactobacillus Johnsonii Gal-2 are increased in the intestinal tract after Dectin-1 deletion, and Candida Tropicalis is increased in the intestinal tract after Dectin-3 deficiency.), further aggravating DSS-induced colitis [57,58].	Dectin-1−/−: Lactobacillus murinus ↑ Lactobacillus johnsonii GAL-2 ↑ Dectin-3−/−: Candida tropicalis ↑

Note: ↑ indicates the increased abundance of the bacteria. ↓ indicates the decreased abundance of the bacteria.