HomeENGLISH MAGAZINEAcute kidney injury: microbes get hired with a duty call

Acute kidney injury: microbes get hired with a duty call

The kidney is an organ not only for excreting body waste by urine but also for maintaining body homeostasis in close cooperation with other organs. By producing various hormones, the kidney generates new erythrocytes in the bone marrow through erythropoietin, maintain bones turnover through activation of vitamin D, and controls blood pressure through renin-angiotensin system. In addition, it has recently been shown that the kidney plays an important role in affecting longevity. However, the relationship of the kidney to the gut (the microbiota) have not been studied in detail. Aminoacids exist as enantiomers, i.e., D-aminoacids and their L-forms. The D-aminoacids and their L-forms of an aminoacid have the same chemical formula, but are mirror images in three-dimensional structure, analogous to the difference between the left and right hand. Most interestingly, the D-aminoacids and their L-forms differ significantly in their functions in living systems. L-aminoacids are constituents of proteins; on the other hand, the functions and mechanisms of production of D-amino acids are less clear.

Acute kidney injury (AKI) as a result of ischemia reperfusion (IR) or nephrotoxins is a significant clinical problem in both native and transplanted kidneys. There has been a large body of work on immune cells in the kidney and AKI, but it is unclear why immune cells inhabit the kidney, a traditional non-immune organ. Work on kidney-distant organ cross talk in AKI generated the possibility that gut bacterial load could alter kidney inflammation. The first mechanistic work on microbiome and AKI initially hypothesized that a low bacterial burden would decrease kidney lymphocytes. ON this account, scientist already proven that when germ free (GF) mice kidneys were analyzed for lymphocyte content, Contrary to expectations, they were found to have an increased kidney natural killer T (NKT) cells and ample numbers of other T cells. This increase was confirmed by a later study demonstrating increased invariant NKT (iNKT) cell numbers and activity in GF mice predisposed to inflammatory bowel disease and asthma. GF mice subjected to kidney IR injury (IRI) had indeed worse kidney function.

In another study using a kidney IRI model as well as a cisplatin-induced AKI model in normal mice, 16s RNA metagenomics sequencing of stool post AKI demonstrated unique patterns of fecal microbiota, where Erysipelotrichia and Lactobacillus were specifically found to increase. Colonization of mixed AKI-specific Bacteroides sp. to GF mice led to decrease in kidney NKT and B cell frequency, whereas the frequency of CD8 T cells increased. The existing data supports the hypothesis that gut microbiota affects kidney function and kidney resident immune cells through short chain fatty acids (SCFAs), constantly produce by fermentating strains in the gut community. The simple administration of SCFAs (acetate, propionate, and butyrate) was found to significantly improve renal dysfunction in a model of IR-induced AKI. Although all three SCFAs protected from AKI, both functionally and histologically, the protection was most pronounced in the group of animals that received acetate. Beisde the effects on resident immune cells, it is also possible that SCFAs regulate nephron vitality and metabolism through specific receptors that have these organic acids as ligands (GPR41, OLFR7 and others).

Researchers from Kanazawa University, in collaboration with those from Waseda University, RIKEN, Okayama University, Kyushu University and Kitasato University have investigated kidney functions in relation to gut microbiota, paying particular attention to the fact that the kidney maintains body homeostasis and the internal environment in cooperation with a number of other organs. To assess the effect of acute kidney injury (AKI) on gut microbiota, we performed gut microbiota analysis with mouse feces after ischemia/reperfusion (I/R) injury to an AKI model. The gut microbiota were examined to reveal that specific gut bacteria were influenced by AKI. Interestingly, fecal transplantation from normal mice attenuated the renal pathology in the Gf B6 mice.  These results suggested that the gut microbiota changed due to I/R injury and that possible substance(s) protective for the kidney was produced by the gut microbiota. Next, in order to identify the substance(s) protecting the kidney against I/R injury produced by gut microbiota, comprehensive analyses of chiral aminoacids were performed. While various D-amino acids were detected in the feces, only D-serine was detected in the kidney.

The result suggested that D-serine was produced by the gut microbiota of AKI mice and transported to the kidney via the blood circulation. Furthermore, since D-serine was not detected in the feces of Gf mice, it was suggested that gut microbiota produced D-serine in response to AKI. In addition, D-serine metabolizing enzymes in the kidney were found to increase the D-serine concentration after I/R injury. Thus, the D-serine concentration in the kidney increased due to augmentation of D-serine production in the kidney in addition to the production of D-serine by the gut microbiota after I/R injury. Scientists examined also the effects of D-serine on the kidney, buy dissolving the aminoacid in drinking water and administered to normal mice. The oral administration of D-serine mitigated the kidney injury in normal mice and D-serine-depleted mice. These results showed that D-serine played roles in protecting the kidney from AKI. Lastly, it was investigated whether similar mechanisms exist in human patients with AKI. The blood D-serine level of such patients was found to be higher than that of healthy subjects, showing a high correlation with creatinine, one of the markers of renal disorders.

This study has elucidated the mechanism by which the kidney interacts with gut microbiota through the D-aminoacids. Thus, it was revealed that some gut bacteria respond to AKI, producing D-serine, that is protective for the kidney via the blood circulation. These discoveries might allow personalized treatment options for patients. The public may also be more receptive to therapies based on “natural” approaches targeting the gut microbiota compared to pharmacologic and recombinant DNA based therapeutics felt to be less holistic. These “natural’ approaches using prebiotic, probiotics and synbiotics could potentially treat dysbiosis during AKI. Even certain dietary supplements or choices would be more accepted than “synthetic” or “lab” options. For example, very recently, it has been experimentally proven that fermented soy extracts can mitigate chronic kidney disease and its inflammatory landscape beneath, acting right on the microbiota component. Therefore, natural choices enhancing the chances for recovery and a lesser mortality in AKI do exist. They start from a correct lifestyle, where the regular introduction of fruits and vegetables would enhance the health of our gut microbiota, slimming the chances that it would not protect our kidneys in case of sudden injury.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

He LX, Abdolmaleky HM et al. Nutrients 2020; 12(8):2376.

Gharaie S, Noel S, Rabb H. Nephron 2020; 144(12):662.

Gong J et al. Semin Nephrol. 2019; 39(1):107-116.

Nakade Y et al., Wada T. JCI Insight. 2018 Oct; 3(20).

Zhang J, Ankawi G et al. Crit Care. 2018; 22(1):117.

Sasabe J, Suzuki M. Front Microbiol. 2018 May; 9:933.

Kawase T et al. Brit J Nutr. 2017 Mar; 117(6):775-783.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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