Metabolomics-Guided Hypothesis Generation for Mechanisms of Intestinal Protection by Live Biotherapeutic Products

Abstract

The use of live biotherapeutic products (LBPs), including single strains of beneficial probiotic bacteria or consortiums, is gaining traction as a viable option to treat inflammatory-mediated diseases like inflammatory bowel disease (IBD). However, LBPs’ persistence in the intestine is heterogeneous since many beneficial bacteria lack mechanisms to tolerate the inflammation and the oxidative stress associated with IBD. We rationalized that optimizing LBPs with enhanced colonization and persistence in the inflamed intestine would help beneficial bacteria increase their bioavailability and sustain their beneficial responses. Our lab developed two bioengineered LBPs (SBT001/BioPersist and SBT002/BioColoniz) modified to enhance colonization or persistence in the inflamed intestine. In this study, we examined colon-derived metabolites via ultra-high performance liquid chromatography-mass spectrometry in colitic mice treated with either BioPersist or BioColoniz as compared to their unmodified parent strains (Escherichia coli Nissle 1917 [EcN] and Lactobacillus reuteri, respectively) or to each other. BioPersist administration resulted in lowered concentrations of inflammatory prostaglandins, decreased stress hormones such as adrenaline and corticosterone, increased serotonin, and decreased bile acid in comparison to EcN. In comparison to BioColoniz, BioPersist increased serotonin and antioxidant production, limited bile acid accumulation, and enhanced tissue restoration via activated purine and pyrimidine metabolism. These data generated several novel hypotheses for the beneficial roles that LBPs may play during colitis.

ProbioticEscherichia coliNISSLE 1917 for inflammatory bowel disease applications

“…67 Murch developed a bio-engineered EcN (BioPersist), which was modified to enhance its colonization ability in the inflammatory intestine for more benefits in the treatment of IBD. 68 Administration of BioPersist in mice attenuated the inflammatory response by suppressing the production of pro-inflammatory prostaglandins which exacerbate intestinal inflammation. Moreover, BioPersist showed an efficient bile acid recycling in enterohepatic circulation, indicating the alleviation of IBD.…”

Moving beyond descriptive studies: harnessing metabolomics to elucidate the molecular mechanisms underpinning host-microbiome phenotypes

“…These model systems present a powerful framework for integrating hypothesis testing into metabolomics studies of the microbiome and have been used to investigate diverse biological processes including aging 104 , reproduction 105,106 , and metabolism 13,14,16,107,108 . This strategy has been very successful in providing molecular insights into diverse diseases including colitis (both IBS and Crohn's disease) 15,17 , neurodegenerative disease 20,21 , breast cancer 32 , diabetes 109 , the biological response to toxin exposure 9,10,34,[110][111][112][113] , and the role that the microbiome plays in immunity 30,114 .…”

“…Consequently, data processing steps, including removal of noise, peak detection, identification, quantification, and missing value imputation can play pivotal role in the quality of the resulting dataset [178][179][180] . Many of these challenges are inherent to all systems-level analysis and there are well-established statistical tools such as dimensionality reduction approaches (e.g., principal component analysis) 12,16,32,105,124,181,182 , correction for multipletesting (e.g., Bonferroni correction) 183 , the use of linear models (e.g., ridge regression) 184 , and data visualization strategies (e.g., volcano or Manhattan plots) 185 that can identify statistically significant correlations and avoid common pitfalls related to false discovery and statistical overfitting. Recently, new computational approaches have been developed, including machine learning and mediation analysis, that provide a powerful new approach for unlocking the molecular underpinnings of host-microbiome dynamics [186][187][188][189][190][191] .…”

“…Disruptions in the microbiome caused by antibiotics, diet, and disease can alter these intricate host-microbiome metabolic exchanges and affect biological functions throughout the body [1][2][3]5,6,[8][9][10][11][12] . A few examples of diseases that are modulated by microbial metabolism include colitis (e.g., irritable bowel syndrome (IBS) and Crohn's disease) 10,[13][14][15][16][17] , immune diseases (e.g., multiple sclerosis) 1,18,19 , neurodegenerative diseases (e.g., amyotrophic lateral sclerosis and Alzheimer's disease) [20][21][22] , psychological conditions (e.g., depression) 8,23 , cystic fibrosis [24][25][26][27][28][29] , cancer [30][31][32] , and cardiovascular disease 33 . Microbial metabolism can also play a role in the pharmacokinetics of drugs 9,34,35 .…”

Evolutionary Insights Into Microbiota Transplantation in Inflammatory Bowel Disease

“…Therefore, in this review, we only focused on the treatment of IBD through bacterial microbiome. Gut microbe-based therapies such as fecal microbiota transplantation (FMT) ( Paramsothy et al., 2017 ), washed microbiota transplantation (WMT) ( Zhang et al., 2020 ), and live biotherapeutic products (LBP) ( Ye et al., 2021 )have been used to treat IBD related to microbial alteration.…”