An overview of host-derived molecules that interact with gut microbiota

Abstract

The gut microbiota comprises bacteria, archaea, fungi, protists, and viruses that live together and interact with each other and with host cells. A stable gut microbiota is vital for regulating host metabolism and maintaining body health, while a disturbed microbiota may induce different kinds of disease. In addition, diet is also considered to be the main factor that influences the gut microbiota. The host could shape the gut microbiota through other factors. Here, we reviewed the mechanisms that mediate host regulation on gut microbiota, involved in gut-derived molecules, including gut-derived immune system molecules (secretory immunoglobulin A, antimicrobial peptides, cytokines, cluster of differentiation 4⁺ effector T cell, and innate lymphoid cells), sources related to gut-derived mucosal molecules (carbon sources, nitrogen sources, oxygen sources, and electron respiratory acceptors), gut-derived exosomal noncoding RNA (ncRNAs) (microRNAs, circular RNA, and long ncRNA), and molecules derived from organs other than the gut (estrogen, androgen, neurohormones, bile acid, and lactic acid). This study provides a systemic overview for understanding the interplay between gut microbiota and host, a comprehensive source for potential ways to manipulate gut microbiota, and a solid foundation for future personalized treatment that utilizes gut microbiota.

Keywords: exosomal ncRNA; gut mucosal molecules; gut‐derived immune molecules; hormones; host; microbiota shaping; molecules from other organs than gut.

Figure 1

Gut‐derived immune system molecules (secretory immunoglobulin A [sIgA] and antimicrobial peptides [AMPs]) of host‐shaping gut microbiota. (A) The mechanisms of sIgA shaping gut microbiota: (1) sIgA‐coated, the sIgA‐coated commensals are confined in the lumen [14], but they could enhance inflammatory response in the mucosa layer. (2) Agglutination, the agglutination of pathogens in the lumen is promoted [15]. (3) Immune inclusion, the colonization of commensals is enhanced in the mucosa layer [16]. (4) Regulation of bacteria gene, sIgA shapes the growth and metabolic functions of bacteria by regulating bacterial gene transcription [13]. (B) The mechanisms of antimicrobial peptides shaping gut microbiota: (1) Defensins are produced by Paneth cells and can capture or kill Salmonella enterica Typhimurium (S. Typhimurium). (2) Regenerating (Reg) protein family is produced by Paneth cells and can kill Listeria monocytogenes [17], Enterococcus [18], and Yersinia pseudotuberculosis [19], but prolong the infections with S. Typhimurium [20]. (3) Ribonuclease (RNase) angiogenin 4 (Ang4) is produced by Paneth cells and can kill S. Typhimurium [21]. (4) Cathelicidins are produced by enterocytes and could kill Escherichia coli [22]. (5) Lysozymes are produced by Paneth cells and can kill S. Typhimurium [23]. (6) Lipocalin‐2 is produced by enterocytes and can quarantine the siderophore from E. coli [24].

Figure 2

Gut‐derived immune system molecules (cytokine) of host shaping gut microbiota. The mechanisms of cytokine shaping gut microbiota: (1) interleukin‐1β (IL‐1β) could regulate gut microbiota by promoting the production of antimicrobial peptides (AMPs), and the IL‐1R could suppress the process [41]. (2) IL‐1 and IL‐18 could also regulate the gut microbiota by promoting the production of AMPs [42]. (3) Tumor necrosis factor‐α (TNF‐α) could reduce the Firmicutes to Bacteroidetes ratio [43]. (4) Interferon‐β (IFN‐β) could increase the abundance of Prevotella copri [44]. (5, 6, 8) IL‐33 and IL‐21 and transforming growth factor‐β (TGF‐β) could promote the production by modulating B‐cell differentiation [45, 46, 47]. (7) IL‐17 and IL‐22 could maintain mucosal integrity [48]. (9) IFN‐γ and IL‐12 initiate the differentiation of T‐helper type (Th1) cells and accelerate the removal of pathogens [49]. (10) IL‐4 initiates the differentiation of Th2 cells and is key in helping B cells to produce antibodies [49]. (7, 11) Th17 cells produce different cytokines according to the kind of gut microbiota [50].

Figure 3

Sources related to gut‐derived mucosal molecules shaping the gut microbiota. The mechanisms of host‐derived nutrient source shaping gut microbiota: (1) Sialic acid is released into the lumen by Bacteroides thetaiotaomicron and could be utilized by pathogens [63]. (2) N‐acetyl‐galactosamine could be utilized by Erysipelotrichaceae [64]. (3) Fucose is released into the lumen by B. thetaiotaomicron and could be utilized by Salmonella enterica Typhimurium (S. Typhimurium) [63], which could be inhibited by glycosylation [63]. (4) Mucins could be utilized by Akkermansia muciniphila and Bacteroides acidifaciens [65]. (5) The leakage of the epithelium will lead to an increase in the luminal oxygen level, which could provide an ecological selective advantage to facultative anaerobes or potential aerobes [66]. (6) Nitrate could be produced by Nos2 gene of enterocytes and could be utilized by pathogens [67]. (7) Ethanolamine and (8) tetrathionate could be utilized by S. Typhimurium [68]. (9) Hydrogen peroxide could be produced by Nox1 gene of enterocytes and could be utilized by Citrobacter, but it inhibits the growth of anaerobic commensals in the mucosae layer during homeostasis [69].

Figure 4

Gut‐derived exosomal shaping gut microbiota. The mechanisms of host‐derived exosomes shaping gut microbiota: (1) hsa‐miR‐515‐5p could promote the growth of Fusobacterium nucleatum [81], (2) miR‐1226‐5p could promote the growth of Escherichia coil [81], and (3) miR142a‐3p could promote the growth of Lactobacillus reuteri [82].

Figure 5

Molecules derived from other organs than the gut‐shaping gut microbiota. (A) The mechanisms of the female reproductive system shaping gut microbiota: (1) Estrogen receptor‐α (ERα) could enhance inflammatory response [92]. (2) ERβ could inhibit Helicobacter hepaticus [93] and regulate differentiation, tight‐junction formation, and the permeability of enterocytes [94]. (3) GPR30 could increase colonic motility and may counteract inflammation [95]. (4) The regulation of intestinal estrogen receptors on antimicrobial peptide synthesis is not clear. (B) The mechanisms of the male reproductive system shaping gut microbiota: (1) The regulation of androgen on gut microbial metabolism is not clear. (2) The regulation of androgen on antimicrobial peptide synthesis is not clear. (C) The mechanisms of bile acid shaping gut microbiota: (1) The direct effect of bile acids on gut microbiota [96]. (2) The effect of bile acids on gut microbiota through farnesoid X receptor (FXR) [97]. (3) The effect of bile acids on the homeostasis of T‐helper type 17 (Th17) cells [98]. (D) The mechanism of lactic acid shaping gut microbiota: Lactic acid is produced by muscle and could promote the growth of Veillonella atypica [99].