The small intestinal epithelium has a single layer mainly composed of columnar epithelial cells (29), expressing numerous pattern recognition receptors, including toll-like receptor 5 (TLR5) (30), TLR1, TLR2, TLR3, and TLR9 (31). Further, these cells promote the expression of chemotactic factors for myeloid cells, lymphoid cells, and neutrophil chemokines, following specific stimulation to initiate and coordinate inflammatory responses (32, 33). The intestinal epithelium contains intraepithelial lymphocytes (IELs) (34), which are almost all T cells. On stimulation, these cells express interferon-γ (IFN-γ) and keratinocyte growth factor to play protective and pathogenic roles during inflammation (35–37).

The lamina propria underlies the intestinal epithelium; within this layer, αβ T-cell receptor-positive T cells are the most commonly found lymphocytes (38). Subsets within this population have drastically different functions; CD4+ and CD25+ regulatory T cells in the lamina propria can inhibit T-cell proliferation, cytokine production, and development of colitis (39). In contrast, lamina propria CD4+ T cells secrete both IL-17 and IL-22, and are associated with intestinal inflammation (40, 41). Furthermore, lamina propria dendritic cells (LPDCs) play a significant role in determining whether a particular antigen receives an inflammatory or anti-inflammatory response. CD103⁻ LPDCs promote inflammation and increase the expression of inflammatory mediators, such as tumor necrosis factor-α and IL-6, following stimulation with TLR ligands (42). Meanwhile, CD103 LPDCs prevent excessive inflammation (43).

Innate lymphoid cells (ILCs) can be classified into three broad groups (44). Group 3 ILCs are important intestinal sources of IL-17 and IL-22 and bidirectionally regulateintestinal damage (9).

B cells are the predominant lymphocytes in the lamina propria of the large intestine (38). Lamina propria B cells secrete dimeric IgA, which is transcytosed by epithelial cells into the gut lumen through the action of the polymeric immunoglobulin receptor (45, 46). Antigen-specific IgA can be generated during an intestinal infection (47). Intestinal IgA directly controls the composition of the intestinal microbiome (48). Goblet cells, another class of specialized epithelial cells, represent approximately 15% of cells found in the large intestinal epithelium (49, 50) and can produce the antimicrobial peptides Ang4, RegIIIγ, and RegIIIβ (51, 52). In addition, goblet cells may transfer antigens acquired from the intestinal lumen to dendritic cells in the lamina propria (53).

In summary, the intestinal local immune function and gut microbiota collaborate to maintain intestinal homeostasis.

Researchers have found that the disruption of intestinal barrier due to various pathological factors, leads to increased permeability of the gastrointestinal epithelium. Initially, prohibited substances (e.g. microorganisms, microbial products, and food antigens) intrude into the systemic circulation and lead to intestinal inflammation; this process is also known as “gut leaky” (54).

Gut leaky may cause a series of immune-related diseases, such as systemic lupus erythematosus (SLE) (55) and ANCA-associated vasculitis (AAV) (56).

In addition, the long-term existence of the pathological condition can also affect the remodeling of other organ tissues, which leads to fibrosis and damage to organ function (e.g. liver and kidneys) (57, 58).

It is generally believed that this hypothesis is related to mucosal infections. IgAN rarely presents with obvious lower respiratory tract infection, but an emerging series of studies on mucosal vaccines has clarified the immune connection between upper respiratory tract (URT) infections and the lungs. Twenty days after primary influenza viral infection or intranasal vaccination, IgA PCs derived from resident memory B cells were observed in the submucosal areas of murine models below the bronchial epithelium (113, 114). Four days after the secondary infection, IgA PCs were detected next to the alveoli instead of the more proximal airways (114). This suggested an immune connection between URT infection and the lungs. Furthermore, IgA-producing B cells in murine models express C-X-C motif chemokine receptor 3 (CXCR3). This receptor is important for local IgA production, as CXCR3 mice have fewer IgA cells in the lungs (113–115). This suggests the possibility of URT infection participating in the course of IgAN through the lungs.

Owing to the presence of the gut-kidney axis, increased intestinal permeability in patients with IgAN may promote absorption and circulation of LPS (116). The invasion of mucosal and systemic antigens, especially proteins, glycoproteins, and viral antigens (e.g., influenza and HIV), leads to a corresponding increase in serum IgA levels with abnormal O-glycosylation (117, 118). Moreover, some studies have proposed the possibility of bone marrow-derived abnormal IgA levels (119). After the intestinal mucosa is attacked, the lungs respond accordingly. After intranasal immunization with inactive cholera toxin (CT), lung dendritic cells stimulated retinoic acid-dependent upregulation of α4β7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these cells to the gut facilitated IgA-mediated protection against an oral challenge with active CT (120). This process significantly regulated by the microbiota, suggesting that lungs may participate in local immune communication through immune homing as early as the stage of intestinal infection.

Regarding the mechanism of abnormal IgA1 production, Coppo et al. reported that adults with IgAN have higher levels of TLR4 messenger RNA (mRNA) in peripheral hemolymph monocytes (121). Qin et al. found that LPS stimulated the activation of TLR4 in cultured peripheral B cells, inhibited cosmic mRNA expression, and resulted in galactose deficiency in IgA1 (122). When Gd-IgA1 combines with specific IgG or IgA1 antibodies to form a circulating immune complex (CIC), it remains undegraded by liver cells (123); this may be related to its excessive molecular weight and volume, which affect the normal clearance process (110). In addition, inflammation and immune activity are involved in accelerating IgA1 differentiation.

The formation of CIC also involves the intestine. A gluten diet exacerbates intestinal IgA1 secretion, inflammation, and villous atrophy, and may induce IgA1-sCD89 complex formation and mucosal immune response, ultimately potentiating IgAN development. CD89, an IgA receptor, has not been identified in human renal mesangial cells (124).

However, the mechanism underlying IgA deposition from the circulation to the kidneys remains unexplored. Some studies have suggested the presence of the CD71 receptor in human renal mesangial cells (125), which may be one of the mechanisms.

The clue to another pathway may be obtained by focusing on the B cell activating factor (BAFF). BAFF is a peripheral B-cell survival factor. Immune response against viral antigens has a positive cycle: BAFF recruits neutrophils and active B cells and generates more BAFFs through the TLR9-interferon regulatory factor 5 (IRF5) signaling pathway (126).

McCarthy et al. showed that IgA levels increased in the intestinal lamina propria, circulation, and mesangium of BAFF-overexpressing transgenic mice (127). Subsequently, a follow-up study was conducted, confirming that, in addition to BAFF levels, IgA deposition in the kidney was strongly affected by persistent symbiotic-dependent signals in the intestine (128). Some studies have shown increased serum BAFF levels in patients with IgAN, which correlated positively with disease severity, mesangial IgA deposition density, and serum BAFF and IgA1 levels (129, 130). This means that BAFF may be an important factor in gut-induced IgAN development with the involvement of the gut microbiota.

Monteiro et al. reviewed the impact of ecological changes in the gut on individuals with IgAN and found that both the abundance of gut bacteria, as well as metabolites in the blood, urine, and feces of individuals with IgAN was altered. The level of representative SCFA with anti-inflammatory effects was reduced in the feces of patients with IgAN. Disease markers of IgAN, such as proteinuria and hematuria or Gd-IgA1, were positively or negatively correlated with different bacterial abundances (131).

After circulation to the kidney, CIC can induce the proliferation of human mesangial cells, cause high expression of TLR4 in renal mesangial cells, activate the TLR4-MyD88-NF- κ B signaling pathway, release humoral factors such as TNF α, IL-6, TGF β, MCP-1, injure podocytes, change glomerular permeability, and mediate the progression of inflammation and fibrosis (132–134).

The hypothesis regarding the gut-lung-kidney axis on IgAN is shown in Figure 2 .

Most studies indicate that specific pathogens are closely related to the occurrence and development of GPA. The most widely known bacteria are gram-positive bacteria (mainly Staphylococcus aureus), which are involved in IL-17 production in humans (142). Stegeman et al. reported a correlation between WG and Staphylococcus aureus mucosal infections; 95% of patients with GPA were infected with S. aureus, compared to only 28% of healthy people (143).

Further studies found S. aureus in the lungs of patients with GPA and demonstrated the benefits of antibacterial maintenance treatment. This elucidated the vital role of S. aureus infection in the pathology of WG (144, 145). The cell wall components of S. aureus include lipid teichoic acid and peptidoglycans (both TLR2 ligands), which may stimulate the release of IL-17 via TLR2-related pathways during respiratory tract infection (146–148).

In addition, gram-negative bacteria play important roles in pathogenesis. Many animal experiments have demonstrated the process of lung infection caused by gram-negative bacteria. TLR4 mediates CD4+ T cells producing IL-17 through IL-23, which is the dominant component of IL-17-inducing activity (149). The process of IL-23 participation appears to be very complex, and it involves the Jak2, PI3K/Akt, STAT3, and NF- κ B pathways (149, 150). Most studies suggest that TLR4 is upstream of IL-17; however, some studies suggest underlying interactions between IL-17 and TLR4 (151). Neutrophil extracellular traps (NETs) are released during IL-17- neutrophil recruitment, stimulating granuloma production. Histones, the main protein components of NETs, interact with TLR2 expressed on T cells, directly induce STAT3 phosphorylation, and ultimately activate Th17 cells (152). The interactions can lead to a vicious cycle of granuloma stimulation.

Excluding cell wall components, most bacteria contain CpG DNA (the TLR9 ligand), which is involved in the release of pro-inflammatory cytokines such as TNF-a and IL-1β (153). TLR4 may further interact with inflammatory cytokines to cause pulmonary fibrosis, which is a potential pathogenesis of AAV (154).

Since clinical manifestations are significantly different in patients with GPA, particularly with regards to the respiratory system and kidneys, some patients may experience gastrointestinal symptoms such as diarrhea. Therefore, it is easy to assume the immune connection between these organs.

The aforementioned studies are limited to patients with respiratory infections. Some studies have demonstrated a relationship between GI pathogenic microorganisms, especially Helicobacter pylori (HP), and the incidence of granulomatosis, providing a theoretical basis for intestinal involvement in the pathogenesis of GPA (155). However, data on the relationship between HP and GPA is limited. Further research is needed to elucidate the potential mechanism.

In intestinal studies, NETs have been shown to promote inflammation and apoptosis by stimulating the TLR9-mediated endoplasmic reticulum stress pathway (156) or damaging the F-actin cytoskeleton of enterocyte-like cells. This leads to intestinal epithelial damage and intestinal barrier dysfunction (157), which can cause bacterial translocation and release of intestinal inflammatory factors into the circulation (158), further affecting the composition of the gut microbiota and abundance of probiotics (159). Destruction of the gut microbiota may affect IL-17 production in the intestine (101), TLR4/NF-kB signal pathways in the lungs (160), and lead to abnormal NETs production (161), ultimately damaging the immune function of the lungs.

A study on the influenza A virus suggested its possible mechanism, proposed that the lung and intestinal mucosal state of infected mice was regulated by the balance of Th17/Treg cells. After oral administration of Houttuynia cordata polysaccharides (HCP), the balance of Th17/Treg cells was first restored in the gut mucosal-associated lymphoid tissue (GALT), followed by the lungs. HCP regulates the expression of chemokine CCL20 and CCR6 (the CCL20 receptor), promoting the specific migration of Th17/Treg cells from the gut to the lungs (162).

The renal complications of GPA also involve the intestine. Krebs et al. found that mice infected with S. aureus had persistent Th17 cells in the kidney tissue and worsened crescentic glomerulonephritis (163). Th17 cells were amplified by Citrobacter rodentium infection in the intestine, migrating from the intestinal lamina propria to the kidney via the CCL20/CCR6 axis and exacerbating renal pathology in AAV mice. The cultivation of these mice under sterile conditions or antibiotic treatment significantly downregulates Th17 cells and alleviates kidney inflammation. This indicates a relationship between the gut microbiota, intestinal local immunity, and kidney involvement (164).

EBV is a common human herpes virus. After the initial infection, most patients have no symptoms; however, EBV infects the B cells through oral epithelial cells and establishes a lifelong latent infection (165).

Patients with GPA exhibited more antibodies against EBV viral capsid antigen IgG and EBV early antigen IgG compared to healthy individuals. Patients with GPA presenting with increased titers of EBV viral capsid antigen IgG antibodies suffer from increased renal damage and have a higher Birmingham vasculitis activity score (104). Due to the interconnected anatomical structure of the URT and lungs, this may indicate an underlying connection between the renal system and lungs.

Few studies exist on lupus-associated lung and GI injuries, especially on GI symptoms that are not clinically evident. However, in various human and animal experiments, serum PAMPs (e.g., LPS and BG) increased during the active period of lupus and were associated with leaky gut (169–171).

The close association of foreign pathogen infections with TLR-related pathways is detailed in the manuscript section on AAV. It has been suggested that, in TLR-2 and TLR-4 deficient mice, glomerular IgG deposition and mesangial cell proliferation are significantly reduced, and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers are decreased. This indicates the importance of pathogen infection in lupus (172).

In addition to damaging the intestinal barrier, some pathogens can expedite SLE onset through molecular simulations. Increase in anti-gut Ruminococcus gnavus (RG) was directly correlated with a high SLE disease activity index score (173). LPS cross-reacts with lupus anti-dsDNA antibodies (SLE-specific antibodies) (173). In addition, the latent viral protein Epstein–Barr virus nuclear antigen-1 (EBNA-1) cross-reacts with the Ro 60 kDa antibody, which is a common antibody in SLE (174).

Furthermore, Mu et al. confirmed that activation of LN is regulated through intestinal ecology, not only through gut leakage. Supplementing female MRL/lpr mice with lactobacillus was found to reduce IL-6, increase IL-10, and shift the Treg/Th17 balance inside the kidney toward the Treg phenotype to protect renal function (175). However, contrasting results were observed in pregnant and lactating mice, in whom indoleamine 2,3-dioxygenase enzyme is inhibited upon supplementation with lactobacilli. This reduces Treg activation and increases the levels of serum INF γ (176), an important pro-inflammatory cytokine that promotes the development of lupus (177).

As shown by some studies, particulate matter 2.5 mum or less in diameter, which is related to the incidence and severity of lupus, leads to an increase in circulating neutrophils, proteinuria, and kidney weight; in addition, improving air quality can effectively alleviate the condition (178, 179). These findings demonstrate the relationship between the respiratory system and LN.

Some researchers believe that environmental molecules (e.g., LPS and BG) can serve as TLR-4 ligands and activate the Fc gamma receptor (FcγR) together, possibly through FcγR-TLR-4 crosstalk, thereby inducing synergistic pro-inflammatory responses (180, 181). The interaction of TLR4 and inflammatory cytokines may lead to pulmonary fibrosis in AAV and lupus patients (154). In addition, blocking spleen tyrosine kinases (the shared downstream signaling molecules of Fc gamma receptor (FcγR) and TLR-4) can alleviate lupus-induced inflammation (171).

In SLE, autoantibodies bind to cell-expressed antigens to form an immune complex (IC). These ICs pass through FcγR and bind to inflammatory cells, causing chronic inflammation and target cell destruction. This induces the formation of NET, which is degraded and impaired due to IFN (182, 183). Abnormal NETs are difficult to clear; therefore, the body must be exposed to dsDNA for a long time to produce antibodies (183). Yun et al. demonstrated that anti-dsDNA antibodies bind directly to mesangial and proximal renal tubular epithelial cells, triggering subsequent inflammatory responses through protein kinase C and mitogen-activated protein kinases pathways, eventually inducing fibrosis (184).

Meanwhile, Henault et al. reported that dsDNA-specific IgE antibodies activated plasmacytoid dendritic cells (pDCs) in SLE, resulting in the production of substantial amounts of IFN-α (a cytokine closely related to the degree of SLE activity), and TLR9 mediated dsDNA sensing (185, 186). pDCs accumulate in the glomeruli of patients with active LN (187).

Overall, the intestinal leakage of lupus enhances the level of serum pathogen molecules (e.g., LPS and BG) and cytokines (IFN- γ and IL-6), leading to extracellular DNA exposure and production of autoantibodies and cross-reactive antibodies. Environmental molecules (e.g., PM2.5) may participate in this process through the lungs. However, the TLR-4-related pathway actively promotes inflammation and induces subsequent pulmonary and renal fibrosis. On the other hand, dsDNA-specific IgE antibodies activate pDCs of the peripheral circulation and glomerulus, increase secretion of IFN- α, and enhance renal inflammation.

Research has found that the potential disruption of the intestinal barrier occurs prior to the onset of sepsis. A genome study on intestinal microorganisms and metabolites in patients with severe sepsis suggests that there is a substantial negative correlation between Coprococcus2 and the incidence rate of sepsis. Coprococcus2 is known as one of the butyrate-product bacteria. There is a significant correlation between α-hydroxybutyrate, a nascent biomarker for hypoxia and/or mitochondrial dysfunction, the incidence of sepsis, and the 28-day mortality rate (197).

The imbalance of intestinal homeostasis further exacerbates sepsis through gut leaky. The subsequent development of sepsis is closely related to IRF4.

IRF4 is a transcription factor in the IRF family which is expressed in various immune cells and can regulate immune response, cell growth, and metabolism. IRF4 is a multi-effect factor. Moreover, it can promote macrophage polarization toward the M2 phenotype and macrophage apoptosis, reduce macrophage migration and inflammatory factor expression, induce fibrosis, as well as negatively regulate TLR-related pathways. Furthermore, it promotes the maturation of Th17 cells and maintains an inflammatory state of the tissue by T cell-derived IL-17 (198).

An experiment on LPS-induced sepsis mice model suggests TLR-related pathways, as principle innate immune defense lines, are extensively activated in sepsis (199). he balance of Treg/Th17 immune cells is disrupted, and a large amount of IL-17 is secreted (200).

IRF4 expression is inhibited and thereby macrophages polarize towards M1. The maintenance of an inflammatory state leads to the occurrence of ALI. After the application of Dihydroquercetin or Dexmedetomidine, IRF4 is upregulated in sepsis mice models, and macrophages polarized towards M2, producing effective anti-inflammatory effects (201, 202).

The M2 state of macrophages also promotes fibrosis of renal tissue, which is one of the core mechanisms of AKI-CKD (198).

Sasaki et al. demonstrated that IRF4-deficient mice exhibited a decrease in renal interstitial fibrosis in ischemic kidney damage compared to normal mice, confirming the core role of IRF4 in this process (203).

Interestingly, it has been observed in the mice models of inflammatory bowel disease, that the expression of IRF4 in CD3+T cells in the intestinal lamina propria is increased. Internal and exogenous IRF4 synergistically promotes the maturation of Th17 cells and maintains an inflammatory state in the intestine (204, 205).

This appears to be in contrast to the decrease in IRF4 levels measured in sepsis mice models. Hence, it is probable that depending on different organs/tissues, diseases, and compensatory states, the main regulatory direction of IRF4 may also be different.

Since the intestinal barrier disrupts before sepsis as mentioned above, we believe that changes in intestinal IRF4 expression and its impact on the internal environment may be important factors that have not yet been elucidated in our understanding of the mechanism of sepsis. Further experiments are needed in this regard.

Immune tolerance is crucial for ensuring graft function and survival of transplant recipients. Peripheral tolerance of T lymphocytes is the main mechanism of organ transplantation tolerance. In this process, Tregs inhibit alloreactive T lymphocytes (207).

Researchers have found an immunological association between the gut microbiome and prognosis of kidney transplantation.

According to Wang et al., there is a significant difference in the gut microbiota between kidney transplant recipients (KTRs) with ABMR and KTRs without graft rejection. ABMR is associated with a lower microbial abundance of Clostridia, Paraprevotellaceae, and Faecalibacterium, as well as a higher abundance of Enterococcaceae, Coprobacillus, and Enterobacter (208).

Another study analyzed the rectal microbiota of four KTRs who experienced rejection and compared their observations with KTRs who did not experience rejection before and after transplantation. The decrease in the abundance of Anaerotruncatus, Coprobacillus and other bacteria was related to the development of future exclusion events (209).

Clostridia can regulate Tregs differentiation (207) and is related to a lower IL-6 level (210). In addition, lower IL-17 production is associated with a higher abundance of Faecalibacterium, while a higher abundance of Escherichia, Anaerotruncus, Coprobacillus, and Clostridium is linked to positive regulation in IL-17 production (210).

The gut microbial community affects cytokine levels and differentiation of immune cells, thereby affecting the prognosis of transplant hosts.

Rejection reactions could be acute or chronic. However, since they are not autoimmune diseases, kidney allograft rejection seems to have little connection with the entire respiratory tract when compared to other immune-related CKD.

According to reports, the prevalence of opportunistic pathogens, such as Enterobacteriaceae, Pseudomonas fluorescens, Actinetobacter spp., and Vibrio spp., is increased in the oral microbiome of transplant patients. Oral cancer is often observed in KTRs (211). Whether the higher incidence rate of oral cancer is related to the change in microbial activity in the lungs and intestines or is a result of the use of immunosuppressants after transplantation remains unclear.