Part Two Postbiotics And Kidney Disease

Postbiotics in Non-Kidney Disease

Data from postbiotics in human studies are limited. Salminen et al. recently discussed the clinical postbiotic studies in adults and pediatric cohorts identified in the Cochrane Central registration of controlled trials and in a MEDLINE database search for randomized controlled trials (RCTs), cohort studies, and meta-analysis in adults and children [5] (Tables 1 and 2) [24–54]. They identified fifteen clinical trials with postbiotics. Three studies tested postbiotics in gut diseases, these being two in irritable bowel syndrome (IBS) and one in chronic diarrhea. In five studies, postbiotics were used to treat pulmonary and respiratory diseases. The remaining others involved patients with cancer, obstructive jaundice, tuberculosis, and Helicobacter pylori. Three of them aimed to treat chronic stress or improve inflammatory response and performance during training [31]. Of these studies, eleven made use of inactivated bacteria and four bacterial lysates.

Several studies reported efficacy for oral administration. Inactivated Lactobacillus acidophilus in Helicobacter pylori-positive patients treated with rabeprazole, clarithromycin, and amoxicillin resulted in a higher eradication rate than antibiotics alone (p = 0.02) [24]. In patients with IBS, a heat-inactivated Bifidobacterium bifidum MIMBb75 decreased pain over the placebo group [26]. Patients with chronic diarrhea treated with heat-killed L. acidophilus LB (Lacteol Fort) also showed improved symptoms [27]. Medical students treated with heat-inactivated L. gasseri strain CP2305 showed a significant reduction in anxiety and sleep disturbance (p < 0.05) [30]. In pre-term infants, one RCT observed a reduced incidence of abdominal distention and lower fecal calprotectin (p = 0.001) when treated with formula fermented by Bifidobacterium breve and S. thermophilus [44]. A systematic review that considered four studies in healthy infants showed that fermented formula could provide benefits for gastrointestinal symptoms [55]. A meta-analysis of four RCTs that involved children with acute gastroenteritis reported that heat-inactivated Lactobacillus acidophilus LB reduced the duration of diarrhea in hospitalized patients but not outpatients, compared to placebo [45–47]. In a postbiotic trial, the heat-inactivated Lacticaseibacillus paracasei CBA L74 prevented common infectious diseases in children who were attending daycare probably by stimulating innate or acquired immunity [49]. Another clinical trial confirmed that supplementation with cow’s skim milk fermented with L. paracasei CBA L74 could be a valid approach to preventing common infectious diseases in children [50]. Finally, one study investigated the supplementation of infant formula with viable or heat-inactivated L. famous GG and found that only viable L. famous GG might be an efficient strategy to treat cow’s milk allergy and atopic eczema [52].

Overall, there is limited evidence suggesting that postbiotics may have beneficial effects in the treatment of diseases and this must be investigated in detail in well-designed controlled clinical trials.

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Postbiotics in Kidney Disease

To our knowledge, there are no human studies conducted so far that investigated the use of postbiotics in kidney disease. However, a PubMed search performed in May 2022 identified several preclinical studies that examined the role and function of postbiotics in kidney-related diseases in animal models (Supplementary materials). In this search, we also found manuscripts published between 2020–2022 that used the term “postbiotic” to refer to compounds that would not be considered postbiotics according to the 2019 consensus definition [5]. In this regard, the short-chain fatty acid (SCFA) butyric acid and its derivative N-[2-(2-Butyrylamino-ethoxy)-ethyl]-butyramide (BA-NH-NH-BA) are produced by Cutibacterium acnes and reported to solubilize calcium phosphate [56]. A study that applied BA-NH-NH-BA topically in a murine model of uremic itching, considered this compound as a postbiotic [56]. However, this does not comply with the novel definition proposed by the ISAAP panel since a purified microbial metabolite itself cannot be considered a postbiotic [56].

Several studies on postbiotics and kidney disease were not very informative as they studied healthy animals or were too preliminary and did not address in vivo and functional consequences following administration. In aged or adult mice, treatment with probiotics or probiotics and postbiotics mix (Lactobacillus and Bifidobacterium strains and their postbiotics compounds selected for potential antioxidative activity) decreased oxidative stress as assessed by MDA (malondialdehyde) in the kidneys [57]. However, an impact on kidney function was not assessed, and whether or not the combination of postbiotics with probiotics added up to the impact of probiotics alone was not formally assessed, although a trend towards a greater impact was observed in the higher dose groups.

Fifteen weeks of a diet supplemented by a postbiotic based on lactic acid bacteria in healthy male rabbits was not associated with differences in kidney function parameters, including serum urea and creatinine [58]. Based on the design, this study should be considered a safety study, as the impact on a disease condition was not assessed.

The postbiotic OM-85 is a standardized lysate of 21 bacterial strains, often found in human airways, that is undergoing clinical trials for diverse respiratory conditions and it has already been authorized in several European countries [59]. The EMA limits its use to the prevention of recurrent respiratory infections [60]. A clinical trial investigating children following the first episode of idiopathic nephrotic syndrome is not yet recruiting (NCT05044169) but plans to enroll 83 patients to whom OM-85 will be administered for 6 months after remission with a primary endpoint of a one-year relapse-free survival rate. Since nephrotic syndrome relapse is frequently preceded by infections, OM-85 is hypothesized to reduce the incidence of bacterial respiratory infections and, thus, reduce infection-related relapses. Unfortunately, a comparison to placebo was not considered, making the results of the trial difficult to interpret. In cultured epithelial cells, including kidney-derived Vero E6 monkey cells, OM-85 downregulated ACE2 and TMPRSS2 and, as a result, inhibited SARS-CoV-2 cell infection [61]. Whilst these results are promising, the absence of in vivo and clinical studies hampers the translatability and applicability of these observations. Despite the generally weak and preliminary data on postbiotics and kidney disease, promising, mainly preclinical, results were reported for postbiotics in hyperoxaluria, AKI, high-fat diet-induced kidney disease, and hypertension, as discussed below.

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Postbiotics in Hyperoxaluria: Oxalobacter formigenes Lysates

In hyperoxaluria, increased oxalate absorption from diet or endogenous oxalate production results in increased urinary oxalate excretion potentially leading to calcium oxalate (CaOx) urolithiasis and CaOx crystal formation in kidney tissue, which can lead to renal calculi- fication and, eventually, to kidney failure and systemic CaOx deposition or oxalosis [62]. CaOx crystals may cause kidney injury, inflammation, and tubular obstruction that drive the progressive loss of kidney function, eventually leading to a need for kidney replacement therapy in the most severe cases [63–65]. Hyperoxaluria results from either a hepatic oxalate overproduction caused by genetic disorders of glyoxylate metabolism (primary hyperoxaluria) or ingestion of oxalate precursors, or an elevated intestinal oxalate absorption (secondary hyperoxaluria). Secondary hyperoxaluria is more common and usually milder than primary hyperoxaluria and is treatable with a diet (low oxalate, calcium-containing diet). However, hyperoxaluria may cause AKI if oxalate ingestion is suddenly excessive (e.g., juicing) especially if this is linked to decreased gut calcium availability (e.g., during fat malabsorption as fat chelates calcium) as gut calcium oxalate crystals are not absorbed but excreted in feces.

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by a deficient liver alanine-glyoxylate transaminase enzyme activity. Being the most severe form of hyperoxaluria, considerable efforts have been made to develop novel therapies. Current treatment options for PH1 are suboptimal. To date, supportive treatments focus on high fluid intake and crystallization inhibitors as well as pyridoxine treatments [66]. The eventual development of kidney failure is, however, associated with oxalosis and premature death. Liver transplantation restores hepatic alanine-glyoxylate transaminase enzyme activity. Novel therapies based on RNA interference (RNAi) can target enzymes upstream and reduce or prevent oxalate production. For this, lumasiran, targeting liver glycolate oxidase (GO) is already approved by EMA and FDA, while nedosiran, targeting liver lactate dehydrogenase A (LDH-A) is currently undergoing RCTs [67].

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Probiotics and, more recently, postbiotics have been studied for the therapy of preclinical hyperoxaluria and human PH. O. formigenes is an anaerobic bacterium found in the gut that might help reduce the risks of developing urinary oxalate stones [68,69]. O. formigenes relies solely on oxalate for its growth and is a key oxalate-degrading bacterium that prevents kidney toxicity in animals fed on an oxalate-rich plant diet [69]. Clinical studies suggest an association between the absence of O. formigenes in the gut and the development of oxalate stone disease and hyperoxaluria [70–72]. Interestingly, treatment with either whole O. formigenes to colonize the gut (i.e., probiotics) or encapsulated O. formigenes lysates (i.e., postbiotics) reduced urinary oxalate excretion in rats [73]. Artificial or natural colonization of control Sprague-Dawley rats with O. formigenes promoted oxalate degradation and there is also evidence for physical interaction with the mucosa initiating colonic oxalate secretion. Urinary oxalate excretion was also decreased. In longer-term studies, nephrocalcinosis was reduced [74]. Interestingly, dietary calcium influenced the ability to maintain O. formigenes colonization, which was persistent only when dietary calcium was low, i.e., when the amount of available calcium to bind to oxalate was low [73]. This would create a problem for the efficacy of live O. formigenes therapy since the potential benefits of O. formigenes on oxalate absorption in the gut could be offset by the need to maintain a low calcium diet. The benefits of probiotics could be reproduced by using postbiotic enteric-coated encapsulated O. formigenes freeze-dried lysates twice daily for five days that also reduced urinary oxalate excretion by 50% and supported colonic oxalate secretion in hyperoxaluric rats with renal insufficiency [73]. The O. formigenes lysate was hypothesized to have both a secretagogue function and an enzymatic degradation effect on luminal oxalate. The gelatin capsules used in the study contained freeze-dried lysate of the O. formigenes strain, oxalyl CoA, and thiamine pyrophosphate (8:1:1) and thus fit the current ISAAP definition of a postbiotic. Unfortunately, comparing the results obtained with the probiotic (live O. formigenes) and postbiotic (freeze-dead O. formigenes) is not possible, since dead bacteria were only tested in rats with renal insufficiency induced by unilateral nephrectomy and not in healthy rats [73]. These results support the idea that the O. formigenes postbiotic could contribute to the maintenance of the balance between renal and enteric oxalate [73], however, the efficacy of the postbiotic should be confirmed in clinical studies. If efficacious to reduced oxalate load in vivo in humans, postbiotic O. formigenes may address several of the issues associated with postbiotic O. formigenes: the difficulty to grow and maintain alive a strict anaerobe, the potentially negative impact of calcium-containing diets (a current recommendation to prevent oxalate absorption) on maintaining O. formigenes colonization in vivo and the negative impact of antibiotic courses on O. formigenes colonization [75,76]. As an additional potential barrier to the success of prebiotic O. formigenes therapy, colonization is associated with a more complex microbiota (higher alpha-diversity), and the association of O. formigenes with other multiple taxa known also to be stimulated by oxalate in rodent models better-differentiated gut microbiota from patients with and live-in individuals without the urinary stone disease [75,77,78]. These findings suggest that O. formigenes may better protect from oxalate-associated diseases in conjunction with other components of the microbiota. Eventually, postbiotics may be designed that promote this associated microbiota.

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More recently, O. formigenes culture conditioned medium was found to increase oxalate uptake (>2.4 fold) in human intestinal Caco-2-BEE cells when compared to the control medium [68]. In contrast, conditioned medium from Lactobacillus did not stimulate oxalate uptake. The observed increase in oxalate transport might involve signaling via protein kinase A (PKA), as this was inhibited by H89 and required transport by a 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)-sensitive anionic exchanger. There are two well-known DIDS-sensitive anionic exchangers: SLC26A2 (also known as SulfateAnion Transporter 1 and diastrophic dysplasia sulfate transporter, DIDST) and SLC26A6(also known as CFEX and PAT1). SLC26A6 knockout using siRNA led to a 50% decrease in oxalate transport in Caco-2-BEE treated with a conditioned medium (68]. These results were not reproduced by others (79], however, it should be pointed out that both groups tested different strains of O. formigenes that had been previously shown to promote oxalate transportin colonized mouse gut: sheep rumen strain of Oxalobacter (OxB, ATTC #35274) (68] and a human strain of Oxalobacter (HC-1) (79]. In vivo, in PH1 mice treated with O. formigenesconditioned medium, a postbiotic, (rectal administration), the urinary oxalate excretion was significantly reduced (32.5%) and the distal colonic oxalate secretion increased (42%) (68Figure 3). Thus, the postbiotic O. formigenes OxB, ATTC #35274 conditioned medium modulates oxalate transport in both in vitro cultured human intestinal epithelial cells and in vivo in murine colon. Nonetheless, these observations may not apply to otherOxalobacter strains. A more recent study observed that the increase in oxalate flux across the colon of mice colonized with live Oxalobacter was still observed in mice deficient for the apical oxalate transporters Slc26a6 and Slc26a3/Dra (80], suggesting that other oxalate transporters might be involved as well (79].

Postbiotic preparations of O. formigenes should not be confused with Oxabacttm, a lyophilized O. formigenes formulation that aims at colonizing the gut with live 0. formigenesOxabactrm is a capsule containing lyophilized O. formigenes, strain HC-1 (> 10% to <510colony forming units per dose). Since lyophilization does not kill bacteria, Oxabactrm is considered a probiotic. However, Oxabact will be discussed in certain detail as, similar to other prebiotics, the ratio of live/dead bacteria could change during the shelf life resulting in variable postbiotic contents whose contribution to any efficacy result remains understudied.

Oxabact™ has been tested in various RCTs: in phase II, an open-label trial aimed at PH1 patients on dialysis, Oxabact™ administration for 24 months decreased plasma oxalate levels and improved or stabilized cardiac function as well as clinical status when compared with placebo [81]. Oxabact™ also improved clinical disease progression in a female infant with severe PH1 [82]. However, placebo-controlled trials were not that successful. The most recent phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of Oxabact™, orally administered for 1 year, in reducing oxalate levels in PH patients, but failed to find a significant difference in plasma oxalate as compared to placebo (p = 0.06) [83]. Other studies with Oxabact™ also did not observe differences versus placebo, including two randomized, placebo-controlled, double-blind studies assessing urinary oxalate in PH patients treated with Oxabact™ for 24 weeks [84,85]. In this regard, no active Oxabact™ trials are listed on clinicaltrials.gov as of 16 June 2022 and a phase 3 extension study to evaluate the long-term efficacy and safety of Oxabact™ in patients with PH (NCT03938272) was terminated in July 2021 when the parent trial failed to meet the primary endpoint. At the time of termination, no advantage of Oxabact™ was observed for the primary endpoint investigating eGFR. Thus, attempts at human colonization by O. formigenes cannot be considered successful. Whether this may be the result of the probiotic's bioavailability issues or the viability of O. formigenes in the formulations, is currently unclear. Maintaining O. formigenes alive proved to be challenging due to its anaerobic need. Its stability could also be a limitation, as this can be affected during both industrial processing and storage. Moreover, the ratio of live/dead bacteria could substantially change during the shelf life, affecting its overall efficacy. Accordingly, to overcome such challenges, a postbiotic approach should be considered by taking into consideration different dosing and administration strategies.

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Chiara Favero 1 , Laura Giordano 2 , Silvia Maria Mihaila 2 , Rosalinde Masereeuw 2 , Alberto Ortiz 1,3,4, and Maria Dolores Sanchez-Niño 1,3,5,

1 Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28049 Madrid, Spain

2 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands

3 Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) 2040, 28049 Madrid, Spain

4 Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain

5 Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain