The gut-kidney axis refers to the relationship between gut integrity and microbiome diversity with kidney disease. The connection between the gut and kidneys is very complex but we can break it down into two major categories: the gut-derived uremic toxins, and the inflammatory immune response that can trigger kidney disease. In this blog, we will focus on the gut-kidney connection as it relates to autoimmune kidney diseases.
The Immune Response: The Firefighters and Sharpshooters
Before we dive into autoimmune kidney diseases, let’s review the basics of the immune system. The immune response can be generally be divided into two arms: innate and adaptive immunity.
Innate Immune response, sometimes referred to as the “primitive” arm, refers to a nonspecific defense mechanism. When a foreign invader, called an antigen, the innate system responds immediately.
The “first responders” of cells that make up the innate system tend to be concentrated around the physical barriers of the body including the skin, gastrointestinal tract, the airways of the lungs. The response is fast and fairly effective, but it’s not very specific so there tends to be some collateral damage. Think of this as the firefighters that work to extinguish a house fire without any regards to the water damage that might impact the house.
Adaptive immune response, on the other hand, is a more targeted immune response. In exchange, this response is more complex than the innate response and takes more time to mount. The antigen’s unique identifying markers is first processed, and the details are committed to memory. When the antigen matches a memory in the database, it’s recognized, and the adaptive immune response triggers a focused immune cells meant to attack and destroy it. This type of adaptive “memory” makes future responses that specific antigen more efficient. You can think of this as a sharpshooter, it takes time, training, and experience, but it’s effective and there’s typically little collateral damage as a result. That said, any problem with the cascade can result in misfiring that turns against the wrong target, as is the case of autoimmune disease.
The GALT
The mucosa of the GI tract has a built-in immune system. In fact, the gut is the largest immune organ in the whole body. This system is called gut-associated lymphoid tissue (GALT) and it is in constant interaction with the intestinal microbiome. The balance of the microbiome is an essential part of managing the GALT, and dysbiosis can trigger a complex immune response involving multiple pathways.
One particular pathway engages what is called the toll-like receptor (TLR) family. These receptors are basically proteins that span the cellular membrane of the many immune cells in the gut and act like scanners. In humans, there are 11 members of this receptor family. Of particular interest, TLR-4 and TLR-2 play important roles and are present on the mucosal epithelial cells of the gut.
These receptors are capable of detecting the unique molecular patterns present on the surface of microbes that are presented when there’s intestinal hyperpermeability (leaky gut). TLR-4, for example, can be activated by lipopolysaccharides (LPS) which are released by certain gram-negative bacteria such as Escherichia Coli (E. Coli). TLR-2 receptors are activated by lipoteichoic acid of gram-positive bacteria and yeast.
So, in essence, the gut has an intricate mechanism to detect pathogens and stimulate the necessary response. At the same time, friendly flora also communicates via the GALT and helps to regulate and improve immune response.
The Inflammatory Response
In the presence of LPS, TLR-4 is activated by binding with their receptors on the surface of the cell (CD14). This triggers a cascade of signals inside the cells (including NF-κB, MAPK, and others). This response leads to the formation of inflammatory molecules broadly called cytokines such as tumor necrosis factor-α (TNF-α) and interleukin among others.
In other words, the domino sequence is triggered when the immune system recognizes a pattern it associates with a pathogen and signals to the immune system to take action. Leaky gut increases the odds of immune response because it increases the exposure of the antigen to the immune receptors. This demonstrates an important concept, the overlap between the innate and adaptive immune system. Hyperpermeability of the gut barrier is often a result of “collateral damage” from non-specific innate response to antigens in the GI (food allergies/sensitivities, toxins, and pathogenic bacteria, yeast, or viruses) which then goes on to train and trigger the more sophisticated adaptive response.
Furthermore, genetics play a role in the likelihood of this complex system over or under performing. Minor genetic code alterations such as single nucleotide polymorphisms (SNPs) in protein presentation of various components (including CD14 and TLR-4) can be associated with an increased risk of immune misfiring and increasing incidence of systemic inflammation, insulin resistance, and autoimmune disorders. Basically, genetics load the gun, the environmental influences pull the trigger.
The Autoimmune Response & the Kidney
Keep in mind, TLR-4 are present not only in the gut but also in the systemic immune system, including the brain and the kidneys. In fact, the signaling pathways between the gut microbiome and the kidneys have been well-documented. The activation of this gut-kidney cascade has been critical in the development of many autoimmune disorders such as antineutrophil cytoplasmic antibody associated vasculitis such as Wegner’s granulomatosis. Furthermore, the activation of toll-like receptors has also been associated in systemic lupus erythematosus (SLE) and IgA nephropathy.
The Bottom Line on the Gut-Kidney Connection and Autoimmune Kidney Disease
The gut houses the GALT, an intricate mechanism necessary to identify and eradicate pathogens. In the presence of pathogenic invaders, an inflammatory response is triggered like a cascade of dominos. When triggered, this response in the presence of certain genetic predisposition can be the perfect storm that leads to various kidney-related immune diseases including vasculitis, lupus, and IgA nephropathy.
This is why when we consider the comprehensive approach to kidney health, it is important to address leaky gut and dysbiosis by employing a comprehensive gut restoration protocol in order to manage the progression of autoimmune kidney disorders and ultimately preserve kidney function.
