metabolic basis
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2022 ◽  
Author(s):  
Dallas L Mould ◽  
Mirjana Stevanovic ◽  
Alix Ashare ◽  
Daniel Schultz ◽  
Deborah Hogan

Microbes frequently evolve in reproducible ways. Here, we show that differences in specific metabolic regulation explain the frequent presence of lasR loss-of-function mutations in the bacterial pathogen Pseudomonas aeruginosa. While LasR contributes to virulence, lasR mutants have been associated with more severe disease. A model based on the intrinsic growth kinetics for a wild type strain and its LasR– derivative, in combination with an experimental evolution based genetic screen and further genetics analyses, indicated that differences in metabolism were sufficient to explain the rise of these common mutant types. The evolution of LasR– lineages in laboratory and clinical isolates depended on activity of the two-component system CbrAB, which modulates substrate prioritization through the catabolite repression control pathway. LasR– lineages frequently arise in cystic fibrosis lung infections and their detection correlates with disease severity. Our analysis of bronchoalveolar lavage fluid metabolomes identified compounds that negatively correlate with lung function, and we show that these compounds support enhanced growth of LasR– cells in a CbrB-controlled manner. We propose that in vivo metabolomes are a major driver of pathogen evolution, which may influence the progression of disease and its treatment.


Author(s):  
Shuangyan Li ◽  
Fuxiaonan Zhao ◽  
Jing Ye ◽  
Kuan Li ◽  
Qi Wang ◽  
...  
Keyword(s):  

2022 ◽  
Author(s):  
Noa Barak-Gavish ◽  
Bareket Dassa ◽  
Constanze Kuhlisch ◽  
Inbal Nussbaum ◽  
Gili Rosenberg ◽  
...  

Unicellular algae, termed phytoplankton, greatly impact the marine environment by serving as the basis of marine food webs and by playing central roles in biogeochemical cycling of elements. The interactions between phytoplankton and heterotrophic bacteria affect the fitness of both partners. It is becoming increasingly recognized that metabolic exchange determines the nature of such interactions, but the underlying molecular mechanisms remain underexplored. Here, we investigated the molecular and metabolic basis for the bacterial lifestyle switch, from coexistence to pathogenicity, in Sulfitobacter D7 during its interaction with Emiliania huxleyi, a cosmopolitan bloom-forming phytoplankter. To unravel the bacterial lifestyle switch, we profiled bacterial transcriptomes in response to infochemicals derived from algae in exponential and stationary growth, which induced the Sulfitobacter D7 coexistence and pathogenicity lifestyles, respectively. We found that algal dimethylsulfoniopropionate (DMSP) was a pivotal signaling molecule that mediated the transition between the lifestyles. However, the coexisting and pathogenic lifestyles were evident only in the presence of additional algal metabolites. In the pathogenic mode, Sulfitobacter D7 upregulated flagellar motility and many transport systems, presumably to maximize assimilation of E. huxleyi-derived metabolites released by algal cells upon cell death. Specifically, we discovered that algae-produced benzoate promoted the growth of Sulfitobacter D7, and negated the DMSP-inducing lifestyle switch to pathogenicity, demonstrating that benzoate is important for maintaining the coexistence of algae and bacteria. We propose that bacteria can sense the physiological status of the algal host through changes in the metabolic composition, which will determine the bacterial lifestyle during the interactions.


Author(s):  
Mukund P Srinivasan ◽  
Kamlesh K Bhopale ◽  
Anna A Caracheo ◽  
Lata Kaphalia ◽  
Bin Gong ◽  
...  

Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase deficient (ADH-) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH- and ADH normal (ADH+) deer mice were fed Lieber-DeCarli liquid diet containing 3% (w/v) EtOH for three months. One week before the euthanization, chronic EtOH fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, endoplasmic reticulum (ER)/oxidative stress were examined using H & E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH fed groups of ADH- vs. ADH+ deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH fed groups of ADH- vs. ADH+ deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress and exacerbated chronic EtOH-induced pancreatic injury in ADH- deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP.


2022 ◽  
Author(s):  
Jen-Tsan Ashley Chi ◽  
Pao-Hwa Lin ◽  
Vladimir Tolstikov ◽  
Lauren Howard ◽  
Emily Y. Chen ◽  
...  

Background: Systemic treatments for prostate cancer (PC) have significant side effects. Thus, newer alternatives with fewer side effects are urgently needed. Animal and human studies suggest the therapeutic potential of low carbohydrate diet (LCD) for PC. To test this possibility, Carbohydrate and Prostate Study 2 (CAPS2) trial was conducted in PC patients with biochemical recurrence (BCR) after local treatment to determine the effect of a 6-month LCD intervention vs. usual care control on PC growth as measured by PSA doubling time (PSADT). We previously reported the LCD intervention led to significant weight loss, higher HDL, and lower triglycerides and HbA1c with a suggested longer PSADT. However, the metabolic basis of these effects are unknown. Methods: To identify the potential metabolic basis of effects of LCD on PSADT, serum metabolomic analysis was performed using baseline, month 3, and month 6 banked sera to identify the metabolites significantly altered by LCD and that correlated with varying PSADT. Results: LCD increased the serum levels of ketone bodies, glycine and hydroxyisocaproic acid. Reciprocally, LCD reduced the serum levels of alanine, cytidine, asymmetric dimethylarginine (ADMA) and 2-oxobutanoate. As high ADMA level is shown to inhibit nitric oxide (NO) signaling and contribute to various cardiovascular diseases, the ADMA repression under LCD may contribute to the LCD-associated health benefit. Regression analysis of the PSADT revealed a correlation between longer PSADT with higher level of 2-hydroxybutyric acids, ketone bodies, citrate and malate. Longer PSADT was also associated with LCD reduced nicotinamide, fructose-1, 6-biphosphate (FBP) and 2-oxobutanoate. Conclusion: These results suggest a potential association of ketogenesis and TCA metabolites with slower PC growth and conversely glycolysis with faster PC growth. The link of high ketone bodies with longer PSADT supports future studies of ketogenic diets to slow PC growth.


Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 824
Author(s):  
Matthew R. Medcalf ◽  
Pooja Bhadbhade ◽  
Ted R. Mikuls ◽  
James R. O’Dell ◽  
Rebekah L. Gundry ◽  
...  

Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10−16), fatty acids (p = 8.0 × 10−12), and ceramides (p = 9.8 × 10−13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism.


2021 ◽  
Vol 168 (12) ◽  
Author(s):  
J. Pamela Engelberts ◽  
Steven J. Robbins ◽  
Katarina Damjanovic ◽  
Nicole S. Webster

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 448
Author(s):  
Huawei Zeng ◽  
Shahid Umar ◽  
Zhenhua Liu ◽  
Michael R. Bukowski

Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN.


2021 ◽  
Vol 15 ◽  
Author(s):  
Yali Chen ◽  
Jun Zhang

Consciousness is considered a result of specific neuronal processes and mechanisms in the brain. Various suggested neuronal mechanisms, including the information integration theory (IIT), global neuronal workspace theory (GNWS), and neuronal construction of time and space as in the context of the temporospatial theory of consciousness (TTC), have been laid forth. However, despite their focus on different neuronal mechanisms, these theories neglect the energetic-metabolic basis of the neuronal mechanisms that are supposed to yield consciousness. Based on the findings of physiology-induced (sleep), pharmacology-induced (general anesthesia), and pathology-induced [vegetative state/unresponsive wakeful syndrome (VS/UWS)] loss of consciousness in both human subjects and animals, we, in this study, suggest that the energetic-metabolic processes focusing on ATP, glucose, and γ-aminobutyrate/glutamate are indispensable for functional connectivity (FC) of normal brain networks that renders consciousness possible. Therefore, we describe the energetic-metabolic predispositions of consciousness (EPC) that complement the current theories focused on the neural correlates of consciousness (NCC).


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