Acute Kidney Injury And Gut Dysbiosis: A Narrative Review Focus On Pathophysiology And Treatment Ⅲ

3. Treatment

As soon as the kidney-gut relationship has been made manifest, new treatments, especially those aiming to improve kidney injury by correcting dysbiosis, are widely introduced. The idea of these treatments probably stems from an exciting discovery in 2009 [68]. This murine IRI model experiment found that the germ-free mice had a higher natural killer T cell frequency, a higher IFN-γ expression, decreased IL-4 and IL-10 levels, and more importantly, a worse functional and structural impairment than control mice. However, conventionalizing germ mice with stools from the control group showed a more protective effect from AKI than the germ-free group [68]. The findings suggest that it might be beneficial in deterring AKI by reforming gut microbiota. The treatment strategies are listed below.

New Herb Discovery For Kidney Disease

3.1. Prebiotics 

Prebiotics was defined by the International Scientific Association of Probiotics and Prebiotics (ISAPP) in 2008 as "a selectively fermented ingredient that results in specific changes in the composition and/or activity of the GI microbiota; thus conferring benefit(s) upon host health [69]". The beneficial effects of many prebiotics in CKD and obese settings are encouraging, including decreased uremic toxins, reduced oxidative stress, lower inflammation state, and lower mortality rates [70–75]. Table 2 summarizes the research and the results regarding these treatments.

Nonetheless, despite the promising results in CKD, the exact link between AKI and prebiotics remains unclear. An ongoing double-blind, randomized controlled trial that focuses on the effects of prebiotics and probiotics on septic AKI patients might provide a more precise answer in the future (https://clinicaltrials.gov/ct2/show/NCT 03877081, accessed on 2 January 2022). 

3.2. Probiotics 

Probiotics were defined as "the preparation of inanimate microorganisms and/or their components that confers a health benefit on the host" by the ISAPP in 2019 [76]. Unlike prebiotic treatment, several trials were conducted targeting AKI. Several probiotics, including Lactobacillus salivarius, Bifidobacterium bifidum BGN4, and microbial cocktails, show their beneficial effects for attenuating the AKI severity [77–79]. In contrast, the gut microbiota depletion following administration of broad-spectrum antibiotics also demonstrates protective effects against kidney injury [80]. Although the discordant results still lack a valid explanation, several hypotheses have been proposed. A potential explanation focuses on the unknown influence of antibiotics on both kidney injury and the gut. For example, is it possible that antibiotics protect AKI independent of gut microbiota depletion? Or is it possible that the broad-spectrum antibiotics preferentially deplete pro-injurious bacteria but not the protective ones [21]? In summary, probiotic treatment exhibits beneficial effects in AKI, but information regarding broad-spectrum antibiotics is partially inconclusive and necessitates further investigation.

3.3. Synbiotics 

A synbiotic is a supplemental treatment combining probiotics and prebiotics. The idea of getting the synergistic effect from the two therapies is rational, but the results are not satisfying. A randomized controlled trial showed that synbiotics decreased total plasma PCS concentrations but did not improve GI symptoms in non-dialyzed CKD patients [81]. Another study, the SYNERGY trial, showed a lower serum PCS level but not IS level after synbiotics treatment [82]. Although these two trials support the effect of lowering uremic toxins [81,82], the overall clinical impact of synbiotics in CKD patients is inconclusive [44]. As for AKI, the evidence is still lacking to generate a conclusion. 

3.4. Postbiotics

The term postbiotic describes nonviable bacteria or metabolic byproducts from probiotic microorganisms, such as vitamins, SCFAs, and enzymes that can cause a positive effect on the gut microbiota and the host [83]. As listed in Table 3, many experimental studies showed promising results in improving outcomes of AKI subjects [44]. Two studies disclosed that the protective effect of postbiotics is closely associated with reduced local and systemic inflammation levels, oxidative stress, cell infiltration or activation, apoptosis, and increased autophagy. Furthermore, boosting mitochondrial biogenesis via epigenetic modi- fication and NF-κB inhibition were proposed as the possible underlying mechanism [84,85]. 

3.5. Adsorbent 

As mentioned earlier in the paper, several gut-derived uremic toxins, such as IS and PCS, cannot be effectively removed by conventional hemodialysis due to their protein-bound quality. Therefore, oral uremic toxin adsorbents are introduced as a new strategy and solution. AST-120 is one of the marketed adsorbents with great affinity to PCS and IS [44]. It shows the trend of slowing CKD progression in some phase II and phase III trials, but more concrete data remains absent [88]. Regarding AKI, administering AST-120 reduces toxin levels, weakens renal expression of mRNAs of injury-related markers, and decreases IS level in a murine AKI following myocardial infarction [87]. However, more studies are warranted before extensive application of this treatment to AKI patients. 

3.6. Fecal Microbiota Transplantation 

Fecal microbiota transplantation (FMT) is a method to restore the microbial community by introducing a healthy donor's local gut microbes to a dysbiotic gut via either capsules or colonoscopy [83]. It has been closely linked to treating infectious diseases with dysbiotic conditions such as Clostridioides difficult. Despite the protective effect of FMT shown in mice, information about FMT's benefit on kidney disease in humans is still insufficient [80]. Two sporadic cases have been reported to discuss the tricky infectious disease in a uremic patient and a kidney transplant patient [89,90]. In CKD patients, we might know more in the future since a trial that aims to solve the mystery of FMT has been completed recently (https://clinicaltrials.gov/ct2/show/ NCT04361097, accessed on 2 January 2022), while another trial is currently recruiting (https: //clinicaltrials.gov/ct2/show/NCT04222153, accessed on 2 January 2022). Nevertheless, there are still no trials evaluating FMT's effect on AKI.