The gut microbiome, kidney disease, and targeted interventions

Abstract

The human gut harbors >100 trillion microbial cells, which influence the nutrition, metabolism, physiology, and immune function of the host. Here, we review the quantitative and qualitative changes in gut microbiota of patients with CKD that lead to disturbance of this symbiotic relationship, how this may contribute to the progression of CKD, and targeted interventions to re-establish symbiosis. Endotoxin derived from gut bacteria incites a powerful inflammatory response in the host organism. Furthermore, protein fermentation by gut microbiota generates myriad toxic metabolites, including p-cresol and indoxyl sulfate. Disruption of gut barrier function in CKD allows translocation of endotoxin and bacterial metabolites to the systemic circulation, which contributes to uremic toxicity, inflammation, progression of CKD, and associated cardiovascular disease. Several targeted interventions that aim to re-establish intestinal symbiosis, neutralize bacterial endotoxins, or adsorb gut-derived uremic toxins have been developed. Indeed, animal and human studies suggest that prebiotics and probiotics may have therapeutic roles in maintaining a metabolically-balanced gut microbiota and reducing progression of CKD and uremia-associated complications. We propose that further research should focus on using this highly efficient metabolic machinery to alleviate uremic symptoms.

Figures

Figure 1.

The human gut is host to >100 trillion bacteria with an enteric reservoir of >1 g of endotoxin. Alterations in gut microbiota and impaired intestinal barrier function in patients with CKD/ESRD have been linked to endotoxemia and accumulation of gut-derived uremic toxins leading to insulin resistance, protein energy wasting, immune dysregaulation, and atheroscleroisis. CVD, cardiovascular disease; IR, insulin resistance; PEW, protein energy wasting.

Figure 2.

(A) Intestinal epithelial barrier and inflammatory responses in symbiotic and dysbiotic gut microbiota. A symbiotic gut microbiota leads to development of a functional barrier, with normal amounts of mucus, pattern recognition receptors (PRRs), antimicrobial peptides (AMPs), and secreted IgA, which in turn contain the microbiota in the intestinal lumen and away from the intestinal epithelial cells. As a result, the intestinal immune system becomes largely tolerant to the resident commensals. Similar to immune cells, the signaling cascades that occur downstream of TLRs (enlarged on the left) are used by epithelial cells to detect microbes through PRRs, such as the TLR4. Briefly, upon LPS ligation, the MYD88 is recruited, which activates the NF-κB pathway and leads to production of antimicrobial proteins and proinflammatory cytokines. In a symbiotic gut, epithelial cells are desensitized by continuous exposure to LPS or are attenuated by (1) LPS-mediated downregulation of the IL-1 receptor–associated kinase 1 (IRAK1), which is the proximal activator of the NF-κB cascade; (2) LPS-mediated induction of peroxisome proliferator-activated receptor-γ (PPArγ), which can divert NF-κB from the nucleus; or (3) commensal bacteria-derived reactive oxygen species (ROS)–mediated inhibition of polyubiquitylation and degradation of the aortic inhibitor of κB. (T bars indicate the checkpoints that are controlled by the microbiota.) Exposure to LPS induces epithelial cells to secrete TGF-β, B-cell–activating factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), all promoting the development of tolerogenic immune cell responses to the microbiota. CD103+ dendritic cells (DCs) support the development of regulatory T (Treg) cells secreting IL-10 and TGF-β, and together they stimulate the production of commensal-specific IgA. (B) Increased intestinal concentration of uremic toxins associated with the progression of CKD leads to microbial dysbiosis and overgrowth of pathobionts. Pathobiont overgrowth leads to the loss of barrier integrity and the breach in the epithelia barrier. Translocation of bacteria and bacterial components triggers the intestinal immune system to direct a potentially harmful proinflammatory response to clear invading bacteria by secreting IL-1 and -6 from intestinal epithelial cells, promoting a TH1 and TH17 response by DCs and macrophages and producing higher levels of commensal-specific IgG by B cells. In this context, LPS binding to its receptor complex on macrophages (enlarged on the left) results in enhanced production of inflammatory cytokines including IFN-β, IFN-γ, IL-1β, IL-6, TNFα, and IL-12, the production of which has been shown to require activation of p38MAPK. Subclinical endotoxemia is a potential cause of inflammation in CKD.– Dysregulated immune response and chronic production of proinflammatory cytokines lead to systemic inflammation, which could further accelerate the progression of CKD and development of cardiovascular disease. IκB, inhibitor of NF-κB.

Figure 2.

(A) Intestinal epithelial barrier and inflammatory responses in symbiotic and dysbiotic gut microbiota. A symbiotic gut microbiota leads to development of a functional barrier, with normal amounts of mucus, pattern recognition receptors (PRRs), antimicrobial peptides (AMPs), and secreted IgA, which in turn contain the microbiota in the intestinal lumen and away from the intestinal epithelial cells. As a result, the intestinal immune system becomes largely tolerant to the resident commensals. Similar to immune cells, the signaling cascades that occur downstream of TLRs (enlarged on the left) are used by epithelial cells to detect microbes through PRRs, such as the TLR4. Briefly, upon LPS ligation, the MYD88 is recruited, which activates the NF-κB pathway and leads to production of antimicrobial proteins and proinflammatory cytokines. In a symbiotic gut, epithelial cells are desensitized by continuous exposure to LPS or are attenuated by (1) LPS-mediated downregulation of the IL-1 receptor–associated kinase 1 (IRAK1), which is the proximal activator of the NF-κB cascade; (2) LPS-mediated induction of peroxisome proliferator-activated receptor-γ (PPArγ), which can divert NF-κB from the nucleus; or (3) commensal bacteria-derived reactive oxygen species (ROS)–mediated inhibition of polyubiquitylation and degradation of the aortic inhibitor of κB. (T bars indicate the checkpoints that are controlled by the microbiota.) Exposure to LPS induces epithelial cells to secrete TGF-β, B-cell–activating factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), all promoting the development of tolerogenic immune cell responses to the microbiota. CD103+ dendritic cells (DCs) support the development of regulatory T (Treg) cells secreting IL-10 and TGF-β, and together they stimulate the production of commensal-specific IgA. (B) Increased intestinal concentration of uremic toxins associated with the progression of CKD leads to microbial dysbiosis and overgrowth of pathobionts. Pathobiont overgrowth leads to the loss of barrier integrity and the breach in the epithelia barrier. Translocation of bacteria and bacterial components triggers the intestinal immune system to direct a potentially harmful proinflammatory response to clear invading bacteria by secreting IL-1 and -6 from intestinal epithelial cells, promoting a TH1 and TH17 response by DCs and macrophages and producing higher levels of commensal-specific IgG by B cells. In this context, LPS binding to its receptor complex on macrophages (enlarged on the left) results in enhanced production of inflammatory cytokines including IFN-β, IFN-γ, IL-1β, IL-6, TNFα, and IL-12, the production of which has been shown to require activation of p38MAPK. Subclinical endotoxemia is a potential cause of inflammation in CKD.– Dysregulated immune response and chronic production of proinflammatory cytokines lead to systemic inflammation, which could further accelerate the progression of CKD and development of cardiovascular disease. IκB, inhibitor of NF-κB.