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Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid.

ABSTRACT: Lactic acid or lactate, a key byproduct of anaerobic glycolysis, plays pivotal roles in routine metabolism. An increase in lactic acid is observed in various pathological conditions such as cancer, diabetes, genetic mitochondrial disease, and aging. While several groups have proposed small molecule inhibitors to reduce circulating lactic acid, there are few clinically relevant ways to manage acute or chronic elevations in lactic acid in patients. In addition, recent evidence suggests that lactic acid exchanges between the gut, blood, and peripheral tissues, and professional marathon runners harbor specific gut microbial species that more efficiently metabolize lactic acid. Inspired by these findings, this work sought to engineer probiotic B. subtilis strains to express lactate oxidase that could increase circulating lactic acid catabolism after delivery to the gut. After optimization, oral administration of engineered B. subtilis to the gut of mice reduced the elevation in blood lactic acid levels after exogenous lactic acid challenge without affecting normal gut microbiota composition, inflammation or liver enzymes. Taken together, through the oral delivery of engineered probiotics to the gastrointestinal tract, our proof-of-concept study offers a new opportunity to therapeutically target diseases where blood lactic acid is elevated, and provides a new approach to "knocking down" metabolites to help understand the roles of metabolites in host physiological and pathological processes.

SUBMITTER: Yang M

PROVIDER: S-EPMC10705430 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Engineered <i>Bacillus subtilis</i> as oral probiotics to enhance clearance of blood lactate.

Yang Mengdi M Hutchinson Noah N Ye Ningyuan N Yin Jianing J Guan Ming M Wang Zongqi Z Chen Peiru P Yang Shaobo S Crane Justin D JD Zhang Ke K He Xuesong X Li Jiahe J

bioRxiv : the preprint server for biology 20240512

Elevated lactate concentrations are implicated in various acute and chronic diseases such as sepsis and mitochondrial dysfunction, respectively. Conversely, ineffective lactate clearance is associated with poor clinical prognoses and high mortality in these diseases. While several groups have proposed using small molecule inhibitors and enzyme replacement to reduce circulating lactate, there are few practical and effective ways to manage this condition. Recent evidence suggests that lactate is e ...[more]

PMID: 38076834

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Project description:BackgroundLignocellulosic biomass is an attractive and sustainable alternative to petroleum-based feedstock for the production of a range of biochemicals, and pretreatment is generally regarded as indispensable for its biorefinery. However, various inhibitors that severely hinder the growth and fermentation of microorganisms are inevitably produced during the pretreatment of lignocellulose. Presently, there are few reports on a single microorganism that can detoxify or tolerate toxic mixtures of pretreated lignocellulose hydrolysate while effectively transforming sugar components into valuable compounds. Alternatively, microbial coculture provides a simpler and more efficacious way to realize this goal by distributing metabolic functions among different specialized strains.ResultsIn this study, a novel synthetic microbial consortium, which is composed of a responsible for detoxification bacterium engineered Pseudomonas putida KT2440 and a lactic acid production specialist Bacillus coagulans NL01, was developed to directly produce lactic acid from highly toxic lignocellulosic hydrolysate. The engineered P. putida with deletion of the sugar metabolism pathway was unable to consume the major fermentable sugars of lignocellulosic hydrolysate but exhibited great tolerance to 10 g/L sodium acetate, 5 g/L levulinic acid, 10 mM furfural and HMF as well as 2 g/L monophenol compound. In addition, the engineered strain rapidly removed diverse inhibitors of real hydrolysate. The degradation rate of organic acids (acetate, levulinic acid) and the conversion rate of furan aldehyde were both 100%, and the removal rate of most monoaromatic compounds remained at approximately 90%. With detoxification using engineered P. putida for 24 h, the 30% (v/v) hydrolysate was fermented to 35.8 g/L lactic acid by B. coagulans with a lactic acid yield of 0.8 g/g total sugars. Compared with that of the single culture of B. coagulans without lactic acid production, the fermentation performance of microbial coculture was significantly improved.ConclusionsThe microbial coculture system constructed in this study demonstrated the strong potential of the process for the biosynthesis of valuable products from lignocellulosic hydrolysates containing high concentrations of complex inhibitors by specifically recruiting consortia of robust microorganisms with desirable characteristics and also provided a feasible and attractive method for the bioconversion of lignocellulosic biomass to other value-added biochemicals.

Project description:BackgroundIndividuals with hyperlipidemia are two times more likely to develop atherosclerotic cardiovascular disease (ASCVD) as opposed to those with controlled serum total cholesterol (TC) levels. Considering the documented adverse events of the current lipid-lowering medications which ultimately affect patient's compliance, substantial efforts have been made to develop new therapeutic strategies. Probiotics, on the other hand, are reported to have lipid-lowering activity with the added benefit of being generally well-tolerated making it an appealing adjuvant therapy.MethodsA total of fifty Lactic acid bacteria (LAB) were isolated from raw milk (human and animal) and dairy products. Isolates demonstrating promising in vitro cholesterol removal capabilities were morphologically and biochemically characterized. Lastly, two bacterial candidates were selected for evaluation of their potential hypolipidemic activity using a laboratory animal model. Statistical differences between the means were analyzed by one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test. A p-value < 0.05 was considered statistically significant.ResultsMost of the isolates demonstrated an in vitro cholesterol removal activity. The six LAB isolates showing the highest cholesterol removal activity (36.5-55.6%) were morphologically and biochemically identified as Lactobacillus, Pediococcus, and Lactococcus species. The results demonstrated two promising antihyperlipidemic candidates, a Lactococcus lactis ssp. lactis with an in vivo significant reduction of serum triglycerides (TG) levels by 34.3%, and a Pediococcus sp. that was able to significantly reduce both the serum TC and TG levels by 17.3% and 47.0%, respectively, as compared to the diet-induced hyperlipidemic animal group.ConclusionThis study further supports the growing evidence regarding the antihyperlipidemic activity among probiotics, presenting them as a promising therapeutic approach for the management of hyperlipidemia.

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Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid.

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Engineered <i>Bacillus subtilis</i> as oral probiotics to enhance clearance of blood lactate.

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Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid.

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Engineered &lt;i&gt;Bacillus subtilis&lt;/i&gt; as oral probiotics to enhance clearance of blood lactate.

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OmicsDI is part of the ELIXIR infrastructure

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Engineered <i>Bacillus subtilis</i> as oral probiotics to enhance clearance of blood lactate.