Abstract
Hyperammonemia is a deleterious and inevitable consequence of liver failure. However, no adequate therapeutic agent is available for hyperammonemia. Although recent studies showed that the pharmabiotic approach could be a therapeutic option for hyperammonemia, its development is clogged with poor identification of etiological microbes and low transplantation efficiency of candidate microbes. In this study, we developed a pharmabiotic treatment for hyperammonemia that employs a symbiotic pair of intestinal microbes that are both able to remove ammonia from the surrounding environment. By a radioactive tracing experiment in mice, we elucidated how the removal of ammonia by probiotics in the intestinal lumen leads to lower blood ammonia levels. After determination of the therapeutic mechanism, ammonia-removing probiotic strains were identified by high-throughput screening of gut microbes. The symbiotic partners of ammonia-removing probiotic strains were identified by screening intestinal microbes of a human gut, and the pairs were administrated to hyperammonemic mice to evaluate therapeutic efficacy. Blood ammonia was in a chemical equilibrium relationship with intestinal ammonia. Lactobacillus reuteri JBD400 removed intestinal ammonia to shift the chemical equilibrium to lower the blood ammonia level. L. reuteri JBD400 was successfully transplanted with a symbiotic partner, Streptococcus rubneri JBD420, improving transplantation efficiency 2.3×103 times more compared to the sole transplantation while lowering blood ammonia levels significantly. This work provides new pharmabiotics for the treatment of hyperammonemia as well as explains its therapeutic mechanism. Also, this approach provides a concept of symbiotic pairs approach in the emerging field of pharmabiotics.
Highlights
Ammonia is produced as a byproduct of amino acid catabolism in the body
After elucidating the therapeutic mechanism of probiotic approaches for lowering blood ammonia levels, we developed a pharmabiotic treatment for hyperammonemia that employs symbiotically-related intestinal microbes that remove ammonia from its surrounding environment
Despite various tissue damages associated with ammonia, neurotoxicity is the most notable complication of hyperammonemia that is clinically represented as encephalopathy (Teperman and Peyregne, 2010) as well as possibly Alzheimer’s disease (Adlimoghaddam et al, 2016; Jin et al, 2018)
Summary
Ammonia is produced as a byproduct of amino acid catabolism in the body. The kidney produces ammonia from glutamine in the proximal tubule, which is released into the blood circulation system or excreted after concentration in the medullary interstitium (Weiner et al, 2015; Liu et al, 2018). When the glucose level is decreased by starvation or intense exercise, the skeletal muscle and other peripheral tissues generate a significant amount of ammonia through amino acid catabolism (Kamei et al, 2020). Ammonia is a highly neurotoxic compound at even sub-millimolar concentrations (Jin et al, 2018). Ammonia in mammals is rapidly converted to a nontoxic nitrogenous compound, urea, in the liver through the urea cycle for its eventual excretion in the urine (Jover-Cobos et al, 2014; Meng and Wang, 2018)
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