An oral bacterial cocktail for kidney protection

Abstract

The oral delivery of a microencapsulated bacterial cocktail into animal models of kidney disease promotes the degradation of nitrogenous waste in the gut, thereby supporting renal function.

The gut microbiome, which is integral to human health¹, influences the production and consumption of small molecules that affect human physiology. Recent attempts to leverage the gut microbiome therapeutically include engineered probiotics for Phenylketonuria² and hyperammonemia³, and immunotherapy⁴. Although the kidney is the primary processor of nitrogenous waste in the body, the waste can also be processed in the gut by resident bacteria⁵. However, whether these properties of gut-resident bacteria could be harnessed for therapeutic intervention in the context of the inadequate excretion of nitrogenous waste, as occurring in chronic kidney disease, is unclear⁶. Writing in Nature Biomedical Engineering, Xian-Zheng Zhang and colleagues now show, in murine models of acute kidney injury and chronic kidney failure and in porcine models of kidney failure, that encapsulated bacteria delivered orally can degrade accumulated nitrogenous waste⁷.

Zhang and co-authors assembled a small bacterial consortium, consisting of three bacteria isolated from the gut microbiome, that cooperatively eliminated waste products. Each bacterium acted on a different step in nitrogenous-waste metabolism: an Escherichia strain converted urea to ammonia, a Bacillus strain converted creatinine to ammonia, and an Enterobacter strain converted ammonia to amino acids. In combination, the bacterial consortium eliminated nitrogenous waste products in vitro effectively. However, translating a particular in vitro function of bacteria to the complexity of the gut microbiome is challenging, even more so when that function is split among three distinct bacteria strains that may not localize to the same portion of the intestinal tract. The authors encapsulated the bacteria in calcium alginate microspheres, which have been previously used to encapsulate other orally delivered cargo⁸. The microspheres ensured that the three bacteria remained spatially organized and that the metabolic reactions remained linked in such a ‘bacterial microecosystem’. A polydopamine coat filtered nutrients to the bacteria consortium, ensuring that small nitrogenous waste products were preferentially consumed over other sources of nitrogen (such as protein).

In multiple mouse models of acute kidney injury, the oral administration of the microencapsulated bacteria reduced blood levels of nitrogenous wastes, and increased overall survival. The microspheres outperformed the administration of non-encapsulated bacteria, although the administration of free bacteria also led to some improvement in survival and in the levels of urea in the serum. They also reduced nitrogenous wastes in the blood of a porcine model of acute kidney injury, suggesting broad applicability in mammals. In mouse models of chronic kidney disease (induced by a high adenine diet), the oral delivery of the microspheres was as effective as daily dialysis in the reduction of mortality and of the levels of nitrogenous waste in the blood. Similar to dialysis, the microspheres were renal-protective (that is, they preserved the ability of the kidney to accumulate and process small molecules), and did not lead to any adverse effects in the mice. The microspheres can therefore leverage the coordinated metabolism of native microbiota for therapeutic benefit, potentially also in other metabolic diseases.

Recent attempts to modulate nitrogenous waste via the microbiome have been motivated by the early success of using the microbiome to treat recurrent C. difficile infections⁹: transplantation of an urease-negative microbiome for reducing ammonia production showed benefit in a mouse model of chemically induced liver failure¹⁰; and an engineered probiotic cocktail that converted ammonia to non-degradable amino acids through synthetic metabolic pathways increased ammonia consumption³. In contrast to synthetic-biology approaches that genetically assemble metabolic functional parts from different microbes within a single cell, Zhang and co-authors’ microencapsulated bacteria assemble these functions via confinement (Fig. 1), circumventing an important limitation in synthetic biology: that pathways from exogenous organisms do not always function optimally when introduced into a synthetic microbial chassis.

Fig. 1 |. Genetic metabolic coordination vs. spatial metabolic coordination.

Synthetic biotics introduce genes from multiple bacteria into a single host organism. Bacterial microecosystems spatially confine multiple bacteria in a single environment. Both of these strategies link complex metabolic functions from multiple organisms.

Further characterization of Zhang and co-authors’ encapsulated bacterial-cocktail formulation would be necessary to determine how effective it may be for use with other strains. Notably, the authors did not use strictly anaerobic bacteria — which are predominant in the distal gastrointestinal tract. Also, because free bacteria have some benefit, sometimes even comparable to that of the encapsulated bacterial cocktail in the animal models, the practical benefits of bacterial encapsulation over free bacteria should be determined more broadly. Overall, the authors’ microbiome-based metabolic therapy lays the foundation for a form of treatment that harnesses the natural and cooperative capabilities of gut bacteria. As functional understanding of the gut microbiome increases, so will the capabilities of microencapsulated bacteria.