Chronic Kidney Disease Part 2-The clear link between gut dysbiosis and chronic kidney disease

A deep dive into the gut-kidney axis, a newly researched cause of kidney disease. Part one of a two part series on this game-changing topic.

Introduction:

In my first post on treating chronic kidney disease nutritionally, I focused on the most common reasons underlying this malady: high blood pressure, high blood sugar, and metabolic syndrome, which features both of these, but with high cholesterol added in. We peeled back a few layers of the onion and discovered how NAC has been proven in the research to help reverse these symptoms and both stabilize and improve kidney function. In today’s post, we are going to peel back another layer of the onion-the gut-kidney axis.

I highly recommend reading my first article on kidney disease if you haven’t yet, as this article builds on the information presented in part one. Click Here is the link to brush up on it.

Without further ado, let’s dive in!

Part one: Introduction to the gut-kidney axis and the microbiome.

The gut-kidney axis, in a nutshell, is the chemical communication between the microbiome of the gut and the kidneys, as it pertains to chronic kidney disease (hereafter abbreviated as CKD). If learning about blood pressure and blood sugar was understanding CKD 101, this is 102, as it turns out that gut dysbiosis and the harmful metabolites that are the result thereof are a major driver of CKD.

Eubiosys vs dysbiosys.

Eubiosys, the term for a properly functioning gut microbiota, features high biodiversity with many different species. The colon in such a case presents a healthy mucosal lining and ‘tight junctions’ between the colonocytes that prevent harmful and unwanted substances from leaking out and entering the bloodstream. Nutrients are extracted properly, helpful metabolites are made, and there are normal transit times for excretion of feces.

In dysbiosis, the exact opposite is seen. Low biodiversity, fewer species, a damaged mucosal lining, and poor expression of tight junction proteins, which leads to a weakened intestinal barrier. This allows for ‘translocation’ of harmful colonic substances to the kidneys and bloodstream.

A human being is, amongst many other things, a symbiote for the 30 to 100 TRILLION bacteria that reside, on average, in the human alimentary tract. Here are some fun facts about the gut microbiome:

• Over 1000 species identified, some of the more prominent phyla are: Lactobacillus, Firmicutes, Bacteroides, Clostridia, E. coli, and Bifidobacteria, etc.

• We have as many gut bacteria as we do cells on average

• 95% or so of gut bacteria reside in the colon, where they interact with everything you eat and produce many helpful metabolites, and in dysbiosis, harmful ones.

• Colonic bacteria break down otherwise indigestible starches and fibers and produce crucial substances such as:

• certain vitamins, such as biotin and vitamin K, and short-chain fatty acids, namely acetate, propionate, and butyrate (this last one is the most important for health) (1)

Let’s look at his last point in more detail, as this is where the issues arise in dysbiosis. Short-chain fatty acids are produced by colonic bacteria upon digestion of various dietary polysaccharides, which is just a fancy way of saying fiber. Fiber is their favorite food by far, and they reward us by producing the short-chain fatty acids such as butyrate, which has so many beneficial effects in the body that it would justify its own paper (and indeed it will down the road!). However, for now, let’s focus on those effects that are directly relevant to CKD.

Short-chain fatty acids:

• Regulate blood sugar (hyperglycemia is the leading cause of CKD)

• controls T-reg cell differentiation, regulating the inflammatory cascade via NFkB (featured heavily in my last CKD paper as a driver of toxic inflammation)

• controls the production of inflammatory cytokines like IL-6 and TNFα (which were also featured heavily in my last kidney disease paper)

• It is the favorite food of enterocytes and colonocytes (intestinal lining cells) that make up the wall of the colon, and thus, they are a huge factor in preventing leaky gut.

• Reduce the pH of the colon, which prevents harmful species from flourishing (3)

• Maintains the proper functioning of the ‘tight junctions’ of the epithelial wall of the colon. See the graphic below for more details: (2)

  

  A simple picture showing the tight junctions of the lining of the gut

The above picture shows you a very basic snapshot of the anatomy of the colon:

The lumen is the space in which food and eventually poop travel in their journey of digestion to excretion. The mucus layer is the basic protection that lines the entire surface of the colon. The apical side shows, but doesn’t name cilia and the brush border, which does most of the digesting and interacting with nutrients. The basolateral surface is where we see the tight junction, whose main purpose is to NOT allow big proteins, waste material, or random nutrients to get through. Rather, the colon and small intestines also have very specific transport proteins and enzymes that import specific nutrients after they have been broken done in the correct manner into their individual vitamins, minerals, amino acids, fats, etc. The tight junctions are critical to this mechanism working properly, and when they malfunction, ‘leaky gut’ is the result. This is a condition in which the bloodstream is infiltrated with toxins, bacterial byproducts, and unwanted proteins. It’s a big topic that perhaps underlies many allergies and autoimmune conditions, but it also has a major negative effect on the kidneys.

Part 2. The role of dysbiosis in kidney disease and vice versa

Consider this quote from a 2024 clinical review by Tsuji et al:

“dysbiosis—an imbalance in the gut microbiota commonly seen in chronic kidney disease (CKD)—can disrupt these beneficial functions[ie, manufacture of helpful substances such as butyrate], leading to systemic toxicity and increased kidney burden” (1)

This says a lot in one sentence! Stool testing of CKD patients shows that they have reduced numbers of beneficial bacterial species, such as lactobacillus, prevotella, and bifidobacteria. They also show increased numbers of harmful bacteria such as proteobacteria, enterococcus, bacteroides, and clostridium. These bacteria, especially the latter two, make ammonia, thiols, phenols, and other harmful byproducts that we will discuss later.

How CKD causes dysbiosis:

Dietary protein is broken down into urea, and in a healthy situation, is excreted as urine (where urine gets its name). However, in kidney disease from any cause, such as diabetes or high blood pressure (see my first paper), urea cannot be excreted fast enough and leaks out of the kidneys back into the blood. This is what the significance of the BUN (blood urea nitrogen) test on your lab results is communicated. This blood urea can diffuse into the colon, where the gut bacteria convert it into ammonia by the enzyme urease. Ammonia raises the pH of the colonic environment and damages the tight junctions that I showed above. The presence of ammonia also encourages the growth of the bacteria that make urease, thus creating a toxic feedback loop.

The leaky gut that ensues from the weakening of the tight junctions, in turn, dumps toxins and unwanted proteins into the bloodstream, which they have to be filtered out by guess what? That’s right, the kidneys. This puts the kidneys into a state of chronic inflammation and oxidative stress, which, as you might remember from my first article, is a key factor in the genesis of kidney disease. This graphic sums up the terrible feedback loop well:

Above, we see dysbiosis leading to increased ammonia, decreased short-chain fatty acids, and increased pH, which causes leaky gut. This then leads to toxins and LPS (lipopolysaccharides) flooding the bloodstream and causing inflammation and oxidative stress on the kidneys.

Now, let’s look at how dysbiosis causes kidney disease

• Low motility occurs, and constipation is quite common, as the graphic above shows. Constipation allows more time for the toxins that are normally pooped out to be reabsorbed into the bloodstream, further damaging the kidneys.

• Reduced SCFA (short-chain fatty acids like butyrate) raises colonic pH and allows for the greater flourishing of harmful gut bacteria

  • This also allows for the weakening of tight junctions and leaky gut to develop

• Bacteria that produce the uremic toxins mentioned above (more on those in the next section) become the MOST prevalent bacteria. (2)

• Small intestinal bacterial overgrowth (SIBO) often occurs (2)

• A 100-fold increase in aerobic and proteolytic bacteria. This is a crucial point; let’s talk further about it. Consider this quote from Wu et al

It [dysbiosis] is characterized by a loss of biodiversity, more specifically a decrease in microbiota capable of digesting fiber, and consequently a decrease in the beneficial role of short-chain fatty acids, resulting in a shift from saccharolytic to proteolytic fermentation (3)

This quote highlights the toxic shift in the bacterial population to proteolytic fermentation, which essentially just means the breakdown of protein into toxic byproducts, which is what leads to the infiltration of uremic toxins.

These toxins enter the bloodstream, a process called translocation, instead of being properly filtered by the kidneys and excreted in urine. Once in the blood, they are a major risk for heart disease, worsening dysbiosis, and diminished kidney function:

Part 3: Uremic toxins, a deadly trio of protein breakdown products that wreak havoc

Uremic toxins are small molecules that are generated by normal metabolism, such as urea (which urine is named after) and creatinine, as well as toxic gut bacteria metabolites. In healthy kidneys, all of these are properly filtered and peed out before they can do harm. Unhealthy kidneys, on the other hand, cannot filter all of these out quickly or completely enough, and they reenter the bloodstream. The blood urea nitrogen (BUN) test you have seen on your kidney lab is a reflection of how much urea is failing to be filtered out, and is present in the blood where it doesn’t belong, for example. We are going to focus on the three most prevalent uremic toxins that are produced by a dysbiotic gut, which, as I mentioned above, has a microbial population that has shifted to MOSTLY the species that make these toxins, and the kidneys cannot keep up.

P-cresyl sulfate. This common toxin is created by the amino acids tyrosine and phenylalanine being broken down by various gut bacteria, especially clostridia, proteus vulgaris, bacteroidetes. The actual product produced by the gut bacteria is p-Cresyl, as is shown above. Then, you can follow the arrow to the right, where it goes through the weakened intestinal barrier into the portal vein, which in turn feeds it into the liver. The liver then converts it to p-Cresyl sulfate, most of which is then bound to albumin (a very common protein on your blood labs). This last detail is very important to CKD patients, as p-cresyl sulfate that is bound to albumin is very difficult for the kidneys, or even a dialysis machine, to filter out of the blood. Elevated levels of this toxin in the blood are highly atherogenic, as well as contributing to arterial calcification through increasing inflammation, oxidative stress. It has the same effects in the delicate tubes of the kidneys, were it leads to sclerosis (scarring) and worsening kidney disease. P-cresyl sulfate’s negative vascular effects are one reason why heart disease is such a prominent side effect of kidney disease. Since it can’t be filtered out of the blood easily, the key is to stop it at the source, which the next section will cover. (1)

Indoxyl sulfate: Perhaps more common than even P-cresyl sulfate is the toxin indoxyl sulfate. It is generated by E. coli primarily, also proteus vulgaris, and clostridium species, from the breakdown of dietary tryptophan. This is referenced in the above graphic, where it says ‘indole,’ and ‘indole acetic acid, ’ which are the bacterial metabolites. These pass through the intestine and the portal vein into the liver, where they are transformed into indoxyl sulfate and, like p-cresyl sulfate, bound to albumin. It features a similar problem of being very difficult for the kidneys and dialysis to filter. It does have effects on cardiovascular disease, but not as pronounced as the above toxin. Its principal toxic effect is to damage the delicate tubules of the kidney through oxidate stress and fibrosis, contributing to kidney disease decline.

Trimethylamine-N-Oxide (TMAO). This uremic toxin is produced from the breakdown of dietary choline (including lecithin or phosphatidyl choline) and carnitine by clostridium species, e. coli, desulfovibrio, enterococcus, and anearococcus. As with the other two toxins mentioned above, the gut bacteria make a simpler toxin, trimethylamine, which then travels via the portal vein to the kidneys, where it is turned into TMAO. TMAO normally would be filtered and excreted by healthy kidneys, but its excretion is highly impaired in CKD, and the higher blood levels of this toxin that result from this are both a risk for worsening kidney disease and cardiovascular disease.

LPS-lipopolysaccharide-bonus toxin. This is different than the toxins above. It is an endotoxin that many bacteria produce. Normally, it is not a problem as it is excreted, but in the leaky gut of kidney disease, LPS will infiltrate the bloodstream, where it has inflammatory and immune system effects. It activates toll-like receptors (these are step one in an immune system response) on the nephrons of the kidneys, which leads to macrophages and other mediators of inflammation, like IP-6 and interferons being summoned. These in turn drive inflammation and damage the kidneys, causing enormous oxidative stress, which promotes fibrosis and diminished function.

Part 4. Stopping these toxins at the source of their manufacture

So then, as usual, I’ve burdened my dear readers with the bad news that is the vicious cycle of gut dysbiosis and CKD. But be of good cheer! There is so much hope if action is taken. I think many doctors are completely overlooking the role of dysbiosis in the progression of their clients’ kidney disease, especially in the early stages, where the eGFR is still over 60. The good news is that there is a solid body of research supporting many interventions that will heal the gut, reduce the load of the uremic toxins, and allow the kidneys to heal, and the progression of the kidney disease to slow, or even stop. The goal is to focus on remedies that help to correct the dysbiosis, heal the gut mucosa, and reduce the production and translocation of the uremic toxins I wrote about above. This will reduce the burden on the kidneys, reduce inflammation and oxidative stress, which should, in turn, correspond with improved kidney labs and increased quality of life.

The interventions that I am referring to fall into 3 categories:

1. Diet. There is a substantial body of evidence that high-fiber diets will increase the good gut bacteria that make the short-chain fatty acids that are essential for colon health. Diets that are low in animal protein can also be used to reduce the uremic toxins I mentioned above, since 100% of these toxins are made from the amino acids tryptophan, phenylalanine, and tyrosine, which are found in much greater concentrations in meat vs high-vegetable diets. Now, I hesitate to write this, as people are very much attached to their high-meat diets, including yours truly. I have primarily used the keto diet over the years to lose weight, and am in fact in the middle of creating a special high-fiber, high micronutrient diet that will have all the benefits of keto, with none of the downsides. So I am NOT here to talk bad about such diets. What I am saying is that in kidney disease, the evidence is pretty clear for high-fiber, low animal protein, for delivering real-world success in reversing kidney disease through the healing of the gut and reduction of uremic toxins. (1) This is all I will say about this for now. Part 3 of my kidney disease series will cover this in much greater detail.

2. Prebiotics, probiotics, and synbiotics. Probiotics are supplements (and also foods!) that both restore missing beneficial bacteria and discourage the proliferation of harmful ones. The research is conclusive, IMO, that the proper probiotics are very helpful indeed in reducing uremic toxins. Prebiotics are the food of the gut bacteria. These are indigestible fibers that are fermented by the good bacteria in the colon and both encourage their proliferation and allow them to make life-saving short-chain fatty acids for you. I think prebiotics are equally as important, if not more so, than probiotics, even if they are overlooked by many health professionals. Synbiotics are supplements that contain both prebiotics and probiotics. Part 3 will do a deep dive into the how, why, and what of this topic! (5)

3. Nutritional supplements and herbs. Once again, we will see that NAC, which was featured heavily in part one of this series, will also play a major role in part 3. Not only does NAC reduce inflammation and oxidative stress in the kidneys directly, it also kills off harmful gut bacteria. I can’t wait to tell you all about it! Berberine is a bitter herb used in Chinese medicine for hundreds of years. I have recommended it for over a decade for metabolic syndrome and diabetes, but it also has a strong beneficial effect on the gut microbiome, killing bad ones and boosting good ones. (6)

Part 5: Conclusion and wrap-up.

Let’s review what we have studied today by looking at the picture above, which shows a nice summary with a focus on cardiovascular disease as the third leg of this terrible triangle. We studied how CKD leads to constipation and an increase of ammonia-producing species in the gut, as well as uremic toxin-producing species in the gut. This, in turn, leads to leaky gut and allows for toxic metabolites and uremic toxins to seep out into the bloodstream. This puts great stress on the kidneys, which in turn sustain damage and filter these toxins less efficiently, where they circulate in the blood freely, being bound to albumin. They both worsen kidney disease as they damage the blood vessels and tubules of the kidney, but are also the leading drivers of cardiovascular disease in CKD patients.

We also looked at this from the angle of the gut dysbiosis coming first, as a potential cause of the CKD. We found that this was due to the inflammatory nature and oxidative stress caused by the uremic toxins p-cresyl sulfate, TMAO, indoxyl sulfate, and lipopolysaccharide. These toxins are increased in dysbiosis, as the microbiota that produce them are greatly increased. They also produce ammonia as I mentioned above, which weakens the intestinal barrier and raises gut pH, which leads to worse dysbiosis.

We then very briefly reviewed the triumvirate of diet, pre, and probiotics, and certain targeted supplements, that are shown to heal leaky gut, reduce uremic toxins at their source, and lower inflammation and oxidative stress. My next post, which is already half done, will be packed with research on these remedies and provide detailed information on exactly what to do. I hope to have it out very shortly. As usual, thank you for the gift of your time and attention and for sharing this with people whose health you care about. Stay tuned for Part 3 of this transformative series on healing your kidneys.

• Disclaimer: Kevin Kirkpatrick is not a medical doctor or registered dietitian. The information in this article does not constitute medical advice and is not intended to diagnose or treat a disease; rather, this newsletter is for educational, informational, and entertainment purposes only. Readers, especially those who are pregnant or lactating, should speak with a medical professional before acting on any of the information discussed. Do not discontinue any current medication without consulting your doctor first.

References:

1. Tsuji K, Uchida N, Nakanoh H, Fukushima K, Haraguchi S, Kitamura S, Wada J. The Gut-Kidney Axis in Chronic Kidney Diseases. Diagnostics (Basel). 2024 Dec 25;15(1):21. doi: 10.3390/diagnostics15010021. PMID: 39795549; PMCID: PMC11719742.

2. National Kidney Foundation of Wisconsin. (2020). The kidney–gut axis: What is it, and what can renal dietitians do about it? (PM‑6). National Kidney Foundation of Wisconsin. https://www.kidneywi.org/wp-content/uploads/2020/11/PM-6-The-Kidney-Gut-axis.pdf

3. Kaile Wu et al. The role of the gut microbiota and its metabolites: a new predictor in diabetes and its complications, European Journal of Medical Research,30,1,(2025).https://doi.org/10.1186/s40001-025-02824-9

4. Ribeiro FPB, de Luna Freire MO, de Oliveira Coutinho D, de Santana Cirilo MA, de Brito Alves JL. Gut Dysbiosis and Probiotic Therapy in Chronic Kidney Disease: A Comprehensive Review. Probiotics Antimicrob Proteins. 2024 Dec 13. doi: 10.1007/s12602-024-10427-9. Epub ahead of print. PMID: 39668321.

5. Liu C, Yang L, Wei W, Fu P. Efficacy of probiotics/synbiotics supplementation in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Front Nutr. 2024 Aug 6;11:1434613. doi: 10.3389/fnut.2024.1434613. PMID: 39166132; PMCID: PMC11333927.

6. Pan L, Yu H, Fu J, Hu J, Xu H, Zhang Z, Bu M, Yang X, Zhang H, Lu J, Jiang J, Wang Y. Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota. Acta Pharm Sin B. 2023 Apr;13(4):1537-1553. doi: 10.1016/j.apsb.2022.12.010. Epub 2022 Dec 20. PMID: 37139409; PMCID: PMC10149897.