The issue on how septic exosomes and their miRNAs participate in reshaping inflammatory progression remains controversial. Platelet-derived circulating exosomes in sepsis are capable of causing myocardial dysfunction and endothelial apoptosis (Azevedo et al., 2007; Gambim et al., 2007). Moreover, those platelet exosomes enhance neutrophil extracellular trap (NET) formation to aggravate sepsis-induced organ injury through a mechanism by which exosomal miR-15b-5p and miR-378a-3p target phosphoinositide-dependent protein kinase 1 (PDK1) (Jiao et al., 2020). In contrast, mesenchymal stem cell (MSC)-derived exosomes play a role in attenuating, via their miR-223, heart damages in sepsis (Wang et al., 2015). In addition, endothelial progenitor cell-derived exosomes seem to ameliorate lung injury in sepsis through miR-126’s post-transcriptional regulation of key targets, such as Sprouty-related protein with an EVH1 domain (SPRED-1), high mobility group box 1 (HMGB1), and vascular cell adhesion molecule 1 (VCAM1) (Wu et al., 2018; Zhou et al., 2018; Zhou et al., 2019). In contrast, polymorphonuclear cell-derived exosomes devastate lung alveolar injury in chronic pulmonary inflammation (Genschmer et al., 2019). Accordingly, sepsis-induced inflammatory tissue injury and multiple organ failure may produce a variety of functionally altered exosomes released from multiple sources, although these effects of exosomes might be differed at least partly depending on source cells.

Luminal IEC exosomes increased, following Cryptosporidium parvum infection, and were shown to activate toll-like receptor 4 (TLR4) signaling, which further mediate epithelial exosomes to shuttle antimicrobial peptides and thus attenuate C. parvum infectivity (Hu et al., 2013). Activation of TLR4 signaling was revealed to downregulate the expression of the let-7 family, which coupled to an increase in synaptosome-associated protein 23 (SNAP23) and a promotion of exosomal secretion of IECs (Hu et al., 2013). Tong et al. have shown that IEC-derived miR-146a-5p aggravates intestinal damage during sepsis using a model of rats (Tong et al., 2020). In this study, miR-146a-5p–mediated reduction in expressions of Kruppel-like factor 4 (Klf4) and cyclin D2 were thought to inhibit IEC proliferation and worsen gut injury on sepsis, although the role of the septic IEC exosome-derived miR-146b-5p remains unknown. Mitsuhashi et al. have observed that luminal aspirate-derived exosomes of inflammatory bowel disease (IBD) patients exhibit an increase in proinflammatory cytokines, such as interleukin 6 (IL-6), IL-8, and tumor necrosis factor α (TNF-α), compared to those of healthy volunteers (Mitsuhashi et al., 2016). These IBD exosomes were shown to promote macrophage migration in vitro, reflecting their increased traits of the proinflammatory activity (Mitsuhashi et al., 2016). Related to these notes, it will be imperative to probe any functional and expressional changes in aspirate exosomal miRNAs during inflammation.

As distinct from the issue about contrasting effects of exosomes, probing activities of the exosomes present in biological samples remain a technical challenge, especially in isolating single origin-derived exosomes from liquid biopsies such as blood or bronchoalveolar lavage fluid. It is critical to uncover the roles played by sepsis-induced exosomes and their miRNAs, which are derived from identified origin, in aggravation or amelioration of septic pathology. A majority of the exosomes isolated from the intestinal-lavage fluid in sepsis were shown to be IEC-derived and appeared to contain miRNAs exhibiting the anti-inflammatory activity to downregulate the expression of proinflammatory mediators, including TNF-α and IL-17A (Appiah et al., 2020). These luminally released exosomes from IECs are thought to reach neighboring cells back in a paracrine manner and transfer miRNAs, including miR-19a, miR-21a, miR-27a, and miR-126a, functional in negatively regulating the expression of proinflammatory cytokines (Appiah et al., 2020). Consequently, these findings suggest that IEC exosomes can potentially alter inflammatory symptoms via their bioactive contents, including miRNAs, implying the functional variety of these exosomes and their cargoes. Figure 1 illustrates the proposed model for the potential roles of apically secreted IEC exosomes in affecting tissue damage and gut inflammation, in which their functional miRNAs contribute to regulating expressions of key molecules.

Exosomes possess dynamic properties to undergo intertissue traffic via systemic circulation and home to target organs, which is often mediated by interaction of integrins and their cognate ligands as do their source cells (Yanez-Mo et al., 2015; Park et al., 2020). The inter-organ migration played by exosomes was conducted to deliver their cargoes and remodel target tissue niches in an integrin-dependent manner (Myint et al., 2020). Breast cancer exosomes were found to reach the lung tissue via α6β4- fibronectin and liver tissue via αVβ5-laminin interactions to activate Src kinase and elicit a proinflammatory trait to form premetastatic niches (Hoshino et al., 2015). In addition, T-cell exosomes expressing α4β7 were shown to contain the gut-tropic property and downregulating the endothelial expression of the main α4β7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) (Park et al., 2019a). The functional miRNAs contained in α4β7-positive T-cell exosomes may play a role in regulating the MAdCAM-1 expression in the small intestine (Park et al., 2019b). The findings obtained in these previous reports suggest that IEC exosomes may remodel microenvironmental niches in both local and distant organs. Involvement of integrins in the migration of IEC exosomes to different organs remains a mystery, which might be a fascinating issue. Following this section, we discussed possible roles played by IEC exosomes in distant organs with the exclusion of integrin’s possible engagement but with focusing on passive migration to distant organs via systemic dissemination.

The functional polarity is a hallmark of IECs and critical in maintaining intestinal homeostasis (Lee et al., 2008; Klunder et al., 2017) and mediating inflammation (Serrano et al., 2019). IECs face the external environment at the apical side and simultaneously interact with other cells such as lymphocytes or dendritic cells (DCs) and the extracellular matrix in the lamina propria (LP) (Boyd, 2008; Iftekhar and Sigal, 2021). IECs are supposed to secrete exosomes from both sides (Park et al., 2017). Apart from the exosomes released from the apical surface, basolaterally secreted epithelial exosomes are thought to be effective in inducing immune responses. Thus, exosomes taken up by DCs transfer exogenous peptides onto major histocompatibility complex class II (MHC II) of these DCs, thereby eliciting adaptive immune responses of CD4 T cells in the LP region (Mallegol et al., 2007). The basolaterally released exosomes may have a chance to reach inflammatory lymphocytes such as T helper 17 (Th17) cells to transfer distinct miRNAs (e.g., miR-22, miR-126a, etc.), thereby downregulating the expression of IL-17A (Figure 2A). This process is thought to contribute to mitigating inflammatory response and damage in the local tissue (Figure 2A).

The basolaterally released IEC exosomes undergo intertissue traffic via a systemic circulation and affect septic pathogenesis in distant organs (Park et al., 2019b). Likewise, the exosomes basolaterally secreted by IECs can be feasible to reach distant organs via the thoracic duct and systemic circulation (Figure 2B). As a compelling speculation, these IEC exosomes possessing regulatory miRNAs alter functions of inflammatory T cells in multiple organs by miRNA transfer to those cells, which may implicate a recovery process to protect the tissues from further inflammatory injury (Figure 2B). Previous reports support the current speculation for in vivo trafficking of IEC exosomes into different organs. Kojima et al. showed that the IEC exosomes were found to enter mesenteric lymph nodes (MLNs) through lymphatic vasculature and further reach distant organs such as the lungs in the study using a trauma/hemorrhagic shock model (Kojima et al., 2018a). Intriguingly, the same researchers have also found that these exosomes are involved in induction of acute lung injury via macrophage activation (Kojima et al., 2018b). Accordingly, the MLNs might play a role as an anatomical linchpin to transport the exosomes via the intestinal lymphatic vasculature from the intestine to the distant organs affecting the pathologic progression of various diseases (Fanous et al., 2007; Bernier-Latmani and Petrova, 2017). As a plausible speculation, the functional miRNAs of perhaps septic IEC-produced exosomes may contribute to fine-tuning systemic inflammation by regulating the expression of proinflammatory mediators at the post-transcriptional stage (Figure 2B).

On the other hand, an enterocytic infection has been thought to boost IEC secretion of exosomes. Huang et al. reported that the enterovirus A71 infection promoted the IEC secretion of exosomes, and an abrogation of the exosomal pathway increased survival rates of the infected animal (Huang et al., 2020). The fact that whether other types of enteroviruses also exert the effect identical to A71 remains unexplored (Huang et al., 2020). More recently, Xi et al. reported that the fecal microbiota transplantation (FMT)-mediated intestinal microfloral change induced IECs to facilitate secretion of their exosomes in a sepsis model using rats (Xi et al., 2021). Moreover, these IEC exosomes turned out to play a role in M1 polarization of macrophages in MLNs, thereby increasing IL-1β circulation, which consequently elicited neuronal damage and apoptosis (Xi et al., 2021). This study raises a possibility that IEC exosomes function as a systemic messenger to devastate sepsis-associated brain disease, although a question about how these IEC exosomes’ miRNAs functionally associate with developing this neurological illness needs to be addressed.

Aging raises septic incidence, severity, and mortality (Girard et al., 2005; Martin et al., 2006; Martin-Loeches et al., 2019). Sepsis-induced intestinal barrier dysfunction becomes devastated with age, which might be partly attributed to multiple factors, including oxidative stress, metabolic impairment, antimicrobial peptides, and microbial dysbiosis (Rera et al., 2012; Crapser et al., 2016; Thevaranjan et al., 2017; Nie et al., 2019). In addition, defective bloodstream, ischemic alterations, and the increased use of anti-inflammatory drugs associated with malnutrition and pathogenic microflora are expected to contribute to disruption of epithelial integrity in elderly patients (Meier and Sturm, 2009). Aging itself is thought to increase intestinal permeability and resultant inflammation due to alterations in barrier molecules (Man et al., 2015; Nicoletti, 2015) and microbiota (Thevaranjan et al., 2017). Interestingly, this intestinal barrier dysfunction can be seen even in Drosophila with aging (Rera et al., 2012), indicating that this pathologic event is common to various species of aged living organisms. Among the molecules functional in maintaining epithelial integrity, tight junction (TJ) proteins connecting the plasma membrane of IECs at apical sides can be a representative target whose expression is declined by aging (Mitic and Anderson, 1998). Accordingly, aging increases IEC permeability and the subsequent microbial influx through reducing the expression of integral proteins, which also contributes to an age-linked chronic state of inflammation, termed inflammaging (Franceschi and Campisi, 2014; Branca et al., 2019).

In this section, we discussed more about the possible roles played by epigenetic regulators (e.g., miRNAs) in remodeling TJ proteins of intestinal epithelia and disrupting the epithelial integrity on intestinal inflammation or aging. Cichon et al. have overviewed the miRNAs engaged in regulating the intercellular permeability in both epithelial and endothelial barriers of different tissues, including the brain (Cichon et al., 2014). Ye et al. have reported that the miR-122a accelerates the intestinal permeability by targeting occludin to downregulate its expression (Ye et al., 2011). In this study, using in vitro (Caco-2 cells) and in vivo (mice) analyses, disruption of the TJ occludin barrier under the inflammatory condition has proven to be because of the roles played by the IEC miR-122a increased by TNF-α (Ye et al., 2011) (Figure 3). In a model of a non-human primate, baboon, aging was shown to enhance permeability in the large intestine in which the expressions of different TJ molecules, including zonula occludens 1 (ZO-1), occludin, and junctional adhesion molecule A (JAM-A), were downregulated in the biopsy (Tran and Greenwood-Van Meerveld, 2013). Of note is the fact that the increase in miR-29a occurred in the same biopsy along with elevation of proinflammatory cytokines such as IFN-γ, IL-6, and IL-1β (Tran and Greenwood-Van Meerveld, 2013) (Figure 3). It still remains obscure for molecular mechanisms by which miR-29a epigenetically regulates the expression of TJ molecules. Nonetheless, these findings acquired using the non-human primate model would be an imperative addition to the scientific note that the age-driven increase in intestinal permeability arises from remodeling the epithelial TJ expression, which is perhaps induced by miRNAs such as miR-29a.

Long non-coding RNAs (lncRNAs), which are a class of non-coding RNA molecules and >200 nucleotides in length, regulate the gene expression and a variety of cellular processes (Ulitsky and Bartel, 2013). Zou et al. reported the interesting findings of roles played by a lncRNA in regulating intestinal epithelial integrity (Zou et al., 2016). H19 lncRNA was shown to act as a precursor of miR-675 in the study, in which the H19 overexpression in epithelial cells enhanced miR-675 to post-transcriptionally downregulate ZO-1 and E-cadherin important for the intestinal barrier function (Zou et al., 2016). Wang and colleagues demonstrated another lncRNA, uc.173, played a role in alleviating the gut permeability (Wang et al., 2018). Specifically, debilitation of epithelial integrity in the septic mouse model was relieved by uc.173 treatment, via the role played by uc.173 in neutralizing the miR-29b that targets TJ claudin-1 (Wang et al., 2018) (Figure 3). Circular RNAs (circRNAs), another class of ncRNAs, are known to possess single or more binding sites for miRNAs (Memczak et al., 2013; Thomas and Saetrom, 2014). Recently, Xiao et al. demonstrated a role of circular RNAs (circRNAs) in ameliorating the intestinal epithelial barrier (Xiao et al., 2021). In this study, using in vivo models of sepsis mice and in vitro cell lines, circular homeodomain-interacting protein kinase 3 (circHIPK3), a circRNA transcribed from the HIPK3 gene (Zheng et al., 2016), was shown to recover intestinal barrier integrity by binding miR-29b to reduce its function, which was presumably due to the restored expression of its targets such as Rac1, Cdc42, and cyclin B1 (Xiao et al., 2021) (Figure 3). Zou et al. have reported a transcription factor JunD enhances miR-29b levels to interfere with IEC growth (Zou et al., 2015), providing a possibility to treating the intestinal degenerative disorder by exploiting an option of JunD inhibition and subsequent decrease in miR-29b. Eventually, the miRNA-induced increase in intestinal permeability and subsequent influx of microflora and their products cause intestinal inflammation (Figure 3). Collectively, some of the epigenetic gene regulators including miRNAs, lncRNAs, and circRNAs are thought to contribute to controlling the intestinal epithelial barrier.

With regards to regulatory roles of miRNA to target IECs in a cell type-specific manner, Kwon et al. showed that miR-195 was capable of suppressing the function of Tuft and Paneth cells by targeting double cortin-like kinase 1 (DCLK1) (Kwon et al., 2021). The epithelial miR-195-transgenic mice exhibited the enhanced permeability of intestinal epithelia upon LPS treatment, suggesting that the blockade of this miRNA can be a potential therapeutic option to improve the intestinal integrity (Kwon et al., 2021). In the investigation of miRNA-mRNA network profiles in the IECs of mice with inflammatory bowel disease, the increase in miR-3473a, miR-1224, and miR-5128 was expected to associate with downregulating aquaporin 8, which may induce mucus reduction and barrier loss of IECs (Lee et al., 2015). In another study using aged mice, the activation of key pathways implicated to TLRs and notch signaling was shown in IEC miRNAs in an age-dependent manner (Lee et al., 2021). Specifically, the miRNAs, including let-7, miR-7a, miR-92a, miR-200c, miR-760, miR-1224, miR-5099, and miR-5129, were thought to participate in driving those cascades (Lee et al., 2021). Thus, further examinations on IEC miRNAs and their regulatory pathways will be beneficial in better understanding the molecular mechanisms by which age devastates or the pathophysiological events in the gastrointestinal tissues. Table 1 summarizes IEC- or IEC exosome-derived non-coding RNAs, including miRNAs, lncRNAs, or circRNAs, and their functions discussed in this review.