In acute kidney injury (AKI), the kidneys suddenly fail and are no longer able to sustain their vital functions. This is a serious life-threatening emergency, but is generally considered treatable and reversible, often without long-term consequences in individuals with no other comorbidities.
AKI typically occurs in patients living with chronic kidney disease (CKD) due to the accumulation of kidney damage over a long period, or in previously healthy individuals after a hospitalization for general surgeries or admission to intensive care units due to a trauma or for a critical illness.
While AKI is not always predictable, the progression of CKD may be slowed using drugs, diet, and dialysis until the end stage which requires organ transplant. The gut microbiome was shown to influence CKD progression, and more recently AKI severity, which is discussed here. While the link between the microbiota and the kidney was mainly studied in the context of CKD, recent evidence also highlighted a link between AKI and the gut microbiota.
The Gut-Kidney Axis
The gut-kidney relationship is bi-directional: AKI can cause dysbiosis (changes in structure and composition of the microbiome), while microbiota composition can drive the severity of kidney injury. Data on the existence of a gut-kidney axis and the importance of the microbiome in kidney injury revealed direct crosstalk as well as indirect communication through metabolites such as uremic toxins and short-chain fatty acids. This figure illustrates the gut-kidney axis in AKI.
With a lot left to understand, new research is exploring the mechanisms and potential benefits for probiotics, prebiotics and synbiotics in the management of AKI.
Kidneys, Small but Vital
The kidneys are two bean-shaped organs, each the size of a fist, with an outsized workload. Kidneys remove wastes and extra fluids and maintain a healthy balance of water, salts, and minerals—such as sodium, calcium, phosphorus, and potassium—in blood. They also influence other vital organs such as the heart and liver by making hormones that help control blood pressure and by preventing toxins accumulation in the body. Kidneys also make red blood cells and keep bones strong and healthy. Someone can live with only one kidney, from birth or after a nephrectomy, with only minor to no consequences as long as the remaining kidney is healthy.
Acute Kidney Injury
Acute kidney injury—also called acute kidney failure—occurs when kidneys rapidly lose filtering ability, leading to dangerous levels of wastes. A multitude of diseases, medications, toxins, infections and accidental injuries can lead to AKI, which can be fatal.
The gut microbiota is involved. This diagram shows how gut dysbiosis can influence AKI.
Microbiome and Kidney Interaction
Short Chain Fatty Acids and Inflammation
AKI is associated with inflammation, both locally in the kidney and systemically. Edema and ischemia of the intestinal wall complicating kidney diseases lead to increased intestinal permeability (leaky gut), which further activates the immune system and can lead to systemic inflammation.
One mechanism by which gut microbiota may modulate inflammation in AKI is through the secretion of short chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. SCFAs—anaerobic fermentation end products of complex carbohydrates—are energy sources and are involved in inflammation.
The kidney has four receptors (GPR41, GPR43, Oflr78, and GPR109a) for SCFAs. These receptors in response to SCFAs—insufficiently generated due to dysbiosis—are integral to kidney function.
A number of findings suggest a beneficial effect of SCFAs in AKI. In one study, SCFAs reduced kidney injury by modulating the inflammatory response, apoptosis and autophagy in AKI induced mice.
Recent studies have focused on the connection between the microbiome and hypertension, a frequent finding in AKI. In a study with mice, eight weeks of high-salt-feeding resulted in hypertension and renal damage. Fecal transplantation from these mice into normal mice resulted in leaky gut and hypertensive renal damage.
Sepsis—life-threatening organ dysfunction caused by a dysregulated host response to infection—is the leading cause of AKI in the intensive care unit.
Dysbiotic changes in the gut during sepsis can initiate and propagate septic AKI, which in turn can cause further gut injury, setting up a dangerous cycle.
Abundant in kidneys of animal models, D-amino acids are metabolites of gut microbiota with distinct functions. One such amino acid, D-serine from intestinal bacteria, showed protective effects in a murine AKI model.
The gut microbiota generates toxins that are absorbed into the blood and cleared by the kidneys. Dysbiosis can lead to excessive secretion, which can lead to uremia—a buildup of toxins in the blood—which may damage the kidneys.
Uremic substances accumulate in AKI. Indoxyl sulfate (IS), p-cresyl sulfate (p-CS), and trimethylamine-N-oxide (TMAO) are uremic substances derived from gut microbiota.
- In an animal study, elevated levels of IS and p-CS in the blood were correlated with the severity of AKI.
- In a study with humans, serum IS levels were significantly elevated in patients with AKI compared to those in healthy subjects and critically ill patients and were associated with a worse prognosis of AKI.
- Limited CKD data suggest that increased TMAO may worsen kidney function during AKI, according to one review.
A novel way to limit harmful uremic toxins may be to manipulate the composition of the gut microbiota. One study demonstrated that it is possible to control host IS levels by targeting the microbiota.
The gut microbiota affects not only the levels of certain uremic toxins but both adaptive and innate immune responses. Damage from AKI leading to leaky gut allows other inflammatory toxins to circulate.
A recent systematic review of both animal and human studies shows that modifying the gut microbiota improves the prognosis of AKI.
Probiotics may be useful in AKI in several ways: by altering the gut microbiota composition, restoring mucosal barrier function, and affecting the inflammatory response. A few small studies explored their effect in AKI.
- In a study with rats, a strain of Lactobacillus salivarius protected against cisplatin-induced kidney injury by inhibition of uremic toxins such as indoxyl sulfate and pcresol sulfate.
- And in another study in rats, two probiotic formulations protected the kidneys from acetaminophen-induced acute injury and reduced the levels of uric acid in the blood.
- Also, a microbial cocktail of Escherichia, Bacillus, and Enterobacter protected against nephrotoxin-induced AKI in an animal study.
The role of various prebiotics in CKD has been studied with promising results but a role in AKI is not reported. However, anaerobic fermentation of prebiotics results in the production of short chain fatty acids. Many studies in mice have shown that administration of SCFAs (especially acetate and butyrate) improves outcomes of AKI.
Studies on synbiotics and fecal microbiota transplant in AKI are lacking.
The gut microbiota interacts with the kidneys in a bi-directional manner. Dysbiosis can drive severity of acute kidney disease, which in turn disrupts microbiota composition.
Targeting the gut microbiota may result in better AKI outcomes. Probiotics and prebiotics could potentially treat dysbiosis during AKI and increase disposal of harmful metabolites. Small interventional studies in animal models and in humans show promising results.
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Clare Fleishman RDN, MS is a Registered Dietitian with the Academy of Nutrition and Dietetics and holds a master degree in nutrition science. She bridges the gap between science and health across most platforms: major newspapers, magazines, books (Globesity), workshops, social media and websites. From corporate whiteboards to refugee schools in Egypt, Fleishman agitates for personal and public change. In 2010, she launched www.ProbioticsNow.com to share the cascade of new discovery in the microbiome. Always amazed at this “forgotten organ” Fleishman also creates white papers, blogs, videos and social media for the International Probiotics Association as well as continuing education platforms.
The International Probiotics Association (IPA) is a global non-profit organization bringing together through its membership, the probiotic sector’s stakeholders including but not limited to academia, scientists, health care professionals, consumers, industry and regulators. The IPA’s mission is to promote the safe and efficacious use of probiotics throughout the world. Holding NGO status before Codex Alimentarius, the IPA is also recognized as the unified “Global Voice of Probiotics” around the world.
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