Is There a Gut–Kidney Axis?

Gut got your kidney? Emerging research suggests another gut–organ connection: the gut–kidney axis. Read on to learn how the gut influences kidney function, its role in chronic kidney disease, and how we can manipulate our gut microbes to promote healthy renal function.

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The gut microbiota is intricately connected with virtually every organ in its human host. You may have seen a few of my previous blog posts on the gut microbiota, including its connections to the skin, allergies, food cravings, bone health, ocular health, thyroid, heart health, autoimmune disease, brain health, and detoxification, and even its involvement in human evolution. But of course, these aren’t the only connections.

The gut microbiota has also been connected to kidney health. The kidneys are important for waste excretion, acid–base balance, and regulation of red blood cell production. They also regulate blood pressure through the renin–angiotensin–aldosterone system, and renal dysfunction may be one of the primary causes of uncontrolled hypertension (1).

In recent years, the prevalence of kidney dysfunction, kidney stones, and chronic kidney disease has continued to rise (2, 3). Several studies suggest that diet and lifestyle changes are to blame and that gut health may be a key factor in preventing and treating kidney conditions. In this article, I’ll discuss the role of the gut and gut microbiota in kidney function, both in healthy and diseased states. First up, the role of salt in renal dysfunction.

Gut health may be a key factor in preventing and treating kidney conditions.

Salt-Induced Gut Dysbiosis and Renal Dysfunction

For years, it was thought that salt must directly impair kidney function—perhaps while it was being filtered through the kidneys—but the relationship between high salt intake and kidney injury was unclear. Now, a new study suggests that no direct link is required. Published in Experimental & Molecular Medicine in 2017, the study shows that a high salt intake alters the gut microbiota in mice, leading to bacterial translocation and kidney injury (4). Let’s break down their findings.

Researchers split mice into two groups and fed one a normal-salt (NS) diet and one a high-salt (HS) diet for eight weeks. Fecal microbiota analysis found that at the phylum level, chronic HS intake significantly lowered levels of Firmicutes and increased levels of Bacteroidetes. HS-fed mice also had enriched abundance of the order Burkholderiales and the family Alcaligenaceae and different microbes that colonized the gut mucus layer.

HS feeding also impacted the gut mucosal immune system. HS-fed mice had higher expression of genes encoding pro-inflammatory cytokines and inflammatory response pathways in the ileum (distal third of the small intestine). HS-fed mice also exhibited markedly increased intestinal permeability and reduced expression of tight junction proteins in both the ileum and the colon.

Not surprisingly, disruption of the barrier led to bacterial translocation into the bloodstream and colonization of other organs. Using PCR techniques, they identified elevated levels of Bacillales, specifically Bacillus and Planomicrobium, associated with the kidneys. HS-fed mice showed increased levels of plasma creatinine, a marker of kidney dysfunction, and significantly elevated systolic blood pressure.

The researchers performed several follow-up studies to tease out the relationships. Fecal transplant of the microbiota from HS-fed mice into naïve mice was sufficient to cause gut permeability and alter kidney markers, whereas antibiotic treatment restored gut barrier function, reduced renal bacterial load, and almost completely restored renal function and blood pressure levels.

Altogether, this research suggests that gut dysbiosis itself is sufficient to induce renal dysfunction. But what about more severe kidney conditions? Does the gut play a role there?

The Gut and Kidney Stones

About 80 percent of kidney stones are of the calcium oxalate type. Oxalate is the salt-forming ion of oxalic acid. It is widely found in both plants and animals and is normally excreted by the kidneys. While sodium, potassium, and magnesium oxalate are water-soluble, calcium oxalate is insoluble. Increased oxalate excretion in the urine can result in supersaturation and the deposition of calcium oxalate crystals in the renal tissue.

While many factors influence oxalate load in the body, the gut plays a major role (5). Oxalate-degrading bacteria are normal inhabitants of the healthy human gut microbiota. One of the best known is Oxalobacter formigenes, which relies exclusively on oxalate as its energy source. Colonization with O. formigenes has been shown to reduce intestinal oxalate absorption and urinary oxalate excretion in both mice and humans (6, 7, 8). It is even able to induce oxalate secretion by the gut epithelium, clearing oxalate from systemic circulation (9).

In fact, this oxalate secretion into the gut lumen is a little-known way that the gut protects the kidneys. A defect in the gene responsible for this secretion has been shown to promote high oxalate levels in the urine and calcium oxalate stone formation in mice (10). Genetic polymorphisms in this gut oxalate transporter in humans may also explain the predisposition to kidney stones in certain populations (11).

The Kidney and Gut Protein Metabolites

While we typically think about carbohydrates when we talk about gut microbial fermentation, protein is also fermented by the gut microbiota. Unfortunately, some protein metabolites are less than friendly to the host.

p-cresyl Sulfate and Indoxyl Sulfate

The fermentation of the amino acid tyrosine results in the formation of p-cresol, while the fermentation of tryptophan results in the formation of indole. These compounds are absorbed and further conjugated to form p-cresyl sulfate and indoxyl sulfate, respectively. p-cresyl sulfate and indoxyl sulfate are toxic and can induce insulin resistance, activate the renin–angiotensin–aldosterone system, and cause endothelial dysfunction and atherogenesis (12, 13, 14, 15). They are normally cleared by the kidneys.

Trimethylamine N-oxide (TMAO)

TMAO is a product of microbial metabolism of choline and carnitine (16, 17). The gut metabolite trimethylamine (TMA) is transported via the portal vein to the liver, where hepatic enzymes oxidize it to trimethylamine N-oxide. TMAO enters circulation and is a strong predictor of cardiovascular disease. It enhances the development of atherosclerosis and promotes progressive renal tubule fibrosis (18). It is predominantly excreted in the urine by the kidneys.

The Gut in Chronic Kidney Disease

Chronic kidney disease (CKD) is a condition defined as the gradual loss of kidney function over time. In CKD stage 5, or end-stage renal disease (ESRD), patients must be on permanent renal replacement therapy such as dialysis. CKD is characterized by increased protein fermentation, uremia, altered microbiota composition, and intestinal permeability.

Increased Protein Fermentation and Uremia

Impaired assimilation of protein in the small intestine, slow transit time, and reduced fiber intake all contribute to increased protein fermentation in CKD patients. CKD patients are often restricted in the amount of phosphate they consume, which puts many fiber-containing foods off limits. When carbohydrate sources are not readily available, proteolytic fermentation becomes dominant.

Indeed, progression of CKD has been shown to dramatically increase the concentrations of protein metabolites p-cresyl sulfate, indoxyl sulfate, and TMAO in circulation, likely due to both increased production and decreased clearance (19, 20). Hemodialysis has a limited ability to remove these compounds, and those in end-stage renal disease have levels 10- to 50-fold higher than healthy controls (21). This buildup of toxins in the blood, called uremia, also has implications for the gut.

Microbiota Alterations and Leaky Gut

In 2016, a group of researchers gave rats nephrectomies (surgically removed their kidneys) to induce uremia and then collected fecal samples to sequence their microbiota. Within 12 weeks, uremia profoundly changed the composition of the microbiota (22).

Several studies have corroborated this finding, showing that the microbiota is significantly altered in human CKD patients. One study found 100-fold higher abundance of enterobacteria and enterococci, significantly lower abundance of Bifidobacteria, and higher abundance of Clostridium perfringens in patients on hemodialysis compared to healthy controls (23). Another study of patients on peritoneal dialysis found lower levels of Bifidobacteria, Lactobacillus plantarum, Lactobacillus casei, and Klebsiella pneumonia than in healthy matched controls (24).

The metabolic potential of the gut microbiota also changes. Patients with ESRD have been found to have increased numbers of bacteria that possess uricase, urease, and p-cresol- and indole-forming enzymes, and fewer microbes with short-chain fatty acid-producing enzymes (25). This may in part explain why CKD is associated with increased intestinal permeability, or “leaky gut” (26). Exposure to uremic toxins is thought to reduce the expression of tight junction proteins in the gut mucosa (27).

Modulating Microbes for Renal Health

The gut–kidney axis is just beginning to be explored, and there are still many pieces left unanswered. Still, there are quite a few takeaways from this information that we can use to support renal health in the clinic.

Salt Restriction Is Unnecessary If We Avoid Processed Foods

Were you worried I was going to say that we need everyone to reduce their salt intake? A low-salt diet can be just as harmful as a high-salt diet, so patients don’t need to take the salt shaker off the table. The real problem is the massive amounts of salt in processed foods that, along with refined carbohydrates, are causing an epidemic of gut dysbiosis:

Increasing consumption of processed foods means that salt intake is now dependent almost entirely on the amount of salt added by the food manufacturers, now accounting for 70% to 80% of our current intake. Indeed, not realized by the public is that the concentration in many processed foods is similar to that of sea water (0.9 g Na/100 g). (28)

In other words, if we eat a diet of fresh, unprocessed foods, adding a bit of salt during cooking or to our plates is unlikely to negatively impact the gut microbiota or kidney function. For more on salt, read my series Shaking Up the Salt Myth.

Protein Restriction Is Unnecessary If Fiber Consumption Is Adequate

I have written before on why there is no need for people without kidney disease to restrict protein. In healthy individuals, protein metabolites are filtered by the kidneys, and they aren’t all toxic. Even in patients with CKD, though, protein is important:

Limiting dietary protein, although efficacious in limiting protein fermentation … may be ill-advised because of associated risks of protein malnutrition, especially in susceptible populations. A valuable and safe alternative to dietary protein restriction to suppress protein fermentation is dietary fiber supplementation … (21)

Remember that protein fermentation only becomes the modus operandi when fermentable carbohydrates are not available. This is where prebiotics come in..

Emphasize Prebiotics to Reduce Inflammation and Uremia

Prebiotics are the nondigestible components of plants that selectively feed microbes in the gut and have beneficial effects on human physiology. Most prebiotics are dietary fibers. Dietary fiber is associated with better kidney function and lower inflammation in the general population (29, 30). In people with advanced CKD, many food items rich in dietary fiber, such as fruits and vegetables, are restricted to prevent or correct hyperkalemia and hyperphosphatemia. However, several placebo-controlled studies have shown that supplementation with inulin or resistant starch can reduce serum levels of toxic protein metabolites (31, 32).

Promote Probiotics and Fermented Foods

Probiotics and fermented foods contain live bacteria that can help promote a healthy gut ecosystem. At least two studies have found that supplementation with lactic acid bacteria like Lactobacillus reduces the amount of uremic protein metabolites in circulation in CKD patients (33, 34). At present, probiotics containing oxalate-degrading bacteria like O. formigenes are in late-stage clinical development but may in the future offer a simple but effective therapy for patients with recurring kidney stones.