The trillions of bacteria that constitutively colonize the human gut collectively generate thousands of unique small molecules. These microbial metabolites can accumulate both locally and systemically and potentially influence nearly all aspects of mammalian biology, including immunity, metabolism, and even mood and behavior. In this review, we briefly summarize recent work identifying bioactive microbiota metabolites, the means through which they are synthesized, and their effects on host physiology. Rather than offering an exhaustive list of all known bioactive microbial small molecules, we select a few examples from each key class of metabolites to illustrate the diverse impacts of microbiota-derived compounds on the host. In addition, we attempt to address the microbial logic behind specific biotransformations. Finally, we outline current and emerging strategies for identifying previously undiscovered bioactive microbiota metabolites that may shape human health and disease.

Small Molecule Metabolites at the Host-Microbiota Interface.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease, and the diagnosis is quite difficult due to the unavailability of reliable clinical markers. This study aimed to investigate the fecal metabolites in PsA by comparison with rheumatoid arthritis (RA), and to identify potential diagnostic biomarkers for PsA. The metabolic profiles of the fecal samples from 27 PsA and 29 RA patients and also 36 healthy controls (HCs) were performed on ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). And differentially altered metabolites were screened and assessed using multivariate analysis for exploring the potential biomarkers of PsA. The results showed that 154 fecal metabolites were significantly altered in PsA patients when compared with HCs, and 45 metabolites were different when compared with RA patients. A total of 14 common differential metabolites could be defined as candidate biomarkers. Furthermore, a support vector machines (SVM) model was performed to distinguish PsA from RA patients and HCs, and 5 fecal metabolites, namely, α/β-turmerone, glycerol 1-hexadecanoate, dihydrosphingosine, pantothenic acid and glutamine, were determined as biomarkers for PsA. Through the metabolic pathways analysis, we found that the abnormality of amino acid metabolism, bile acid metabolism and lipid metabolism might contribute to the occurrence and development of PsA. In summary, our research provided ideas for the early diagnosis and treatment of PsA by identifying fecal biomarkers and analyzing metabolic pathways.

/pdf/altered-fecal-metabolomics-and-potential-biomarkers-of-1hhsoxrp.pdf

Altered Fecal Metabolomics and Potential Biomarkers of Psoriatic Arthritis Differing From Rheumatoid Arthritis

Multi-strain probiotics show increased protection of intestinal epithelial cells against pathogens in rainbow trout (Oncorhynchus mykiss)

Feces are the product of our diets and have been linked to diseases of the gut, including Chron's disease and metabolic diseases such as diabetes. For screening metabolites in heterogeneous samples such as feces, it is necessary to use fast and reproducible analytical methods that maximize metabolite detection. As sample preparation is crucial to obtain high quality data in MS-based clinical metabolomics, we developed a novel, efficient and robust method for preparing fecal samples for analysis with a focus in reducing aliquoting and detecting both polar and non-polar metabolites. Fecal samples (n = 475) from patients with alcohol-related liver disease and healthy controls were prepared according to the proposed method and analyzed in an UHPLC-QQQ targeted platform in order to obtain a quantitative profile of compounds that impact liver-gut axis metabolism. MS analyses of the prepared fecal samples have shown reproducibility and coverage of n = 28 metabolites, mostly comprising bile acids and amino acids. We report metabolite-wise relative standard deviation (RSD) in quality control samples, inter-day repeatability, LOD (limit of detection), LOQ (limit of quantification), range of linearity and method recovery. The average concentrations for 135 healthy participants are reported here for clinical applications. Our high-throughput method provides a novel tool for investigating gut-liver axis metabolism in liver-related diseases using a noninvasive collected sample. 

https://www.mdpi.com/2218-1989/12/3/211/pdf?version=1647858390

High-Throughput UHPLC-MS to Screen Metabolites in Feces for Gut Metabolic Health

We aimed to evaluate the prospective association of vitamin B5 with all‐cause mortality and explore its potential modifiers in Chinese adults with hypertension. A nested, case‐control study was conducted in the China Stroke Primary Prevention Trial, including 505 deaths of all causes and 505 matched controls. The median follow‐up duration was 4.5 years. The primary outcome measure in this investigation was all‐cause mortality, which encompassed deaths for any reason. The mean plasma vitamin B5 concentration for cases (43.7 ng/mL) was higher than that in controls (40.9 ng/mL) (p = .001). When vitamin B5 was further assessed as quintiles, compared with the reference group (Q1: < 33.0 ng/mL), the risk of all‐cause mortality increased by 29% (OR = 1.29, 95% CI: 0.83‐2.01) in Q2, 22% (OR = 1.22, 95% CI: 0.77‐1.94) in Q3, 62% (OR = 1.62, 95% CI: 1.00‐2.62) in Q4, and 77% (OR = 1.77, 95% CI: 1.06‐2.95) in Q5. The trend test was significant (p = .022). When Q4‐Q5 were combined, a significant 41% increment (OR = 1.41, 95% CI: 1.03‐1.95) in all‐cause death risk was found compared with Q1‐Q3. The adverse effects were more pronounced in those with normal folate levels (p‐interaction = .019) and older people (p‐interaction = .037). This study suggests that higher baseline levels of plasma vitamin B5 are a risk factor for all‐cause mortality among Chinese patients with hypertension, especially among older adults and those with adequate folate levels. The findings, if confirmed, may inform novel clinical and nutritional guidelines and interventions to optimize vitamin B5 levels.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jch.14516

Association between plasma Vitamin B5 levels and all‐cause mortality: A nested case‐control study

Trillions of microorganisms, termed the “microbiota”, reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic host-microbiota interactions can have deep consequences for host health. However, the mechanisms by which the immune system regulates the microbiota and by which the microbiota shapes host immunity are still not fully understood. This article discusses the contribution of metabolites in the crosstalk between gut microbiota and immune cells. The identification of key metabolites having a causal effect on immune responses and of the mechanisms involved can contribute to a deeper insight into host-microorganism relationships. This will allow a better understanding of the correlation between dysbiosis, microbial-based dysmetabolism, and pathogenesis, thus creating opportunities to develop microbiota-based therapeutics to improve human health. In particular, we systematically review the role of soluble and membrane-bound microbial metabolites in modulating host immunity in the gut, and of immune cells-derived metabolites affecting the microbiota, while discussing evidence of the bidirectional impact of this crosstalk. Furthermore, we discuss the potential strategies to hear the sound of such metabolite-mediated crosstalk.

https://www.mdpi.com/2218-1989/11/6/406/pdf

What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk.

Microbiota-derived metabolites have biological importance for their host. Spermidine, a metabolite described for its protective effect in age-related diseases, is now studied for its role in the resolution of inflammation and gut homeostasis. Strategies to modulate its production in the gastrointestinal tract are of interest to increase host spermidine intakes. Here, we show that metabolic engineering can be used to increase spermidine production by the probiotic Escherichia coli Nissle 1917 (EcN), used in humans. First, we found that increasing the expression of genes involved in polyamine biosynthesis, namely the S-adenosylmethionine synthase speD and the spermidine synthase speE, resulted in an increase in spermidine produced and excreted by our engineered bacteria. The major drawback of this first attempt was the production of acetylated forms of spermidine. Next, we propose to solve this problem by increasing the expression of the spermidine exporter system MdtI/MdtJ. This second strategy had a major impact on the spermidine profile found in the culture supernatant. Our results demonstrate, for the first time, the feasibility of rationally engineering bacterial probiotic strains to increase their ability to deliver the microbiota-derived metabolite, spermidine. This work illustrates how metabolomic and synthetic biology can be used to design and improve engineered Live Biotherapeutic Products that have the potential to be used in personalized medicine.

/pdf/bioengineering-of-escherichia-coli-nissle-1917-for-2itbswnd.pdf

Clément Caffaratti

Papers

What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk.

Bioengineering of Escherichia coli Nissle 1917 for Production and Excretion of Spermidine, a Key Metabolite in Human Health