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See detailAstin C production by the endophytic fungus Cyanodermella asteris in planktonic and immobilized culture conditions
Vassaux, Antoine ULiege; Tarayre, Cédric; Arguelles Arias, Anthony ULiege et al

in Biotechnology Journal (2019)

The fungal endophyte Cyanodermella asteris was recently isolated from the medicinal plant Aster tataricus. This fungus produces astin C, a cyclic pentapeptide with anticancer and anti-inflammatory ... [more ▼]

The fungal endophyte Cyanodermella asteris was recently isolated from the medicinal plant Aster tataricus. This fungus produces astin C, a cyclic pentapeptide with anticancer and anti-inflammatory properties. The production of this secondary metabolite was compared in immobilized and planktonic conditions. For immobilized cultures, a stainless steel packing immersed in the culture broth was used as a support. In these conditions, the fungus exclusively grew on the packing, which provides a considerable advantage for astin C recovery and purification. C. asteris metabolism was different according to the culture conditions in terms of substrate consumption rate, cell-growth, and astin C production. Immobilized-cell cultures yielded a 30% increase of astin C production associate to a 39% increase in biomass. The inoculum type as spores rather than hyphae, and a pre-inoculation washing procedure with sodium hydroxide, turned out to be beneficial both for astin C production and fungus development onto the support. Finally, influence of culture parameters such as pH and medium composition, on astin C production was evaluated. With optimized culture conditions, astin C yield was further improved reaching a five times higher final specific yield compared to the value reported with astin C extraction from Aster tataricus (0.89 and 0.16 mg/g respectively). [less ▲]

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See detailEffect of Sequential Acclimation to Various Carbon Sources on the Proteome of Acetobacter senegalensis LMG 23690T and Its Tolerance to Downstream Process Stresses
shafiei, Rasoul; Leprince, Pierre ULiege; Sombolestani, Atena Sadat et al

in Frontiers in Microbiology (2019), 10

Acetic acid bacteria are very vulnerable to environmental changes; hence, they should get acclimated to different kinds of stresses when they undergo downstream processing. In the present study ... [more ▼]

Acetic acid bacteria are very vulnerable to environmental changes; hence, they should get acclimated to different kinds of stresses when they undergo downstream processing. In the present study, Acetobacter senegalensis LMG 23690T, a thermotolerant strain, was acclimated sequentially to different carbon sources including glucose (condition Glc), a mixture of glucose and ethanol (condition EtOH) and a mixture of glucose and acetic acid (condition GlcAA). Then, the effects of acclimation on the cell proteome profiles and some phenotypic characteristics such as growth in culture medium containing ethanol, and tolerance to freeze-drying process were evaluated. Based on the obtained results, despite the cells acclimated to Glc or EtOH conditions, 86% of acclimated cells to GlcAA condition were culturable and resumed growth with a short lag phase in a culture medium containing ethanol and acetic acid. Interestingly, if A. senegalensis LMG 23690T had been acclimated to condition GlcAA, 92% of cells exhibited active cellular dehydrogenases, and 59% of cells were culturable after freeze-drying process. Proteome profiles comparison by 2D-DiGE and MS analysis, revealed distinct physiological status between cells exposed to different acclimation treatments, possibly explaining the resulting diversity in phenotypic characteristics. Results of proteome analysis by 2D-DiGE also showed similarities between the differentially expressed proteins of acclimated cells to EtOH condition and the proteome of acclimated cells to GlcAA condition. Most of the differentially regulated proteins are involved in metabolism, folding, sorting, and degradation processes. In conclusion, acclimation under appropriate sub-lethal conditions can be used as a method to improve cell phenotypic characteristics such as viability, growth under certain conditions, and tolerance to downstream processes. [less ▲]

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See detailPhysico-chemical approach for characterizing probiotics at the solid and dispersed states
Razafindralambo, Hary ULiege; Delvigne, Frank ULiege; Blecker, Christophe ULiege

in Food Research International (2019), 116

A physico-chemical approach was used for characterizing and generating fingerprints of single (L. Bulgaricus and S. thermophilus) and multiple (Vivomixx) probiotic species. Such a methodology included ... [more ▼]

A physico-chemical approach was used for characterizing and generating fingerprints of single (L. Bulgaricus and S. thermophilus) and multiple (Vivomixx) probiotic species. Such a methodology included thermal, colloidal, and surface analyses of powder (solid-in-gaseous phase) and dispersed (solid-in-aqueous phase) samples. Decomposition and transition phases analyzed by thermogravimetry and differential scanning calorimetry provide specific qualitative and quantitative data that serve as a probiotic fingerprint, and therefore a product quality control for each sample. Investigation of colloidal and surface properties of dispersed samples by light scattering and contact angle measurements informs on the probiotic size average, electrokinetic charge, and surface hydrophobicity. Besides their relevance in identity control, the physico-chemical data are also useful in probiotic performance prediction, since they govern the most crucial microbial functionalities such as thermostability, aggregation, and adhesion. [less ▲]

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See detailpH level has a strong impact on population dynamics of the yeast Yarrowia lipolytica and oil micro-droplets in multiphasic bioreactor
Bouchedja D. N.; Danthine, Sabine ULiege; Kar T. et al

in FEMS Microbiology Letters (2018), 365(6),

The oleaginous yeast Yarrowia lipolytica has the ability to use oils and fats as carbon source, making it a promising cell factory for the design of alternative bioprocesses based on renewable substrates ... [more ▼]

The oleaginous yeast Yarrowia lipolytica has the ability to use oils and fats as carbon source, making it a promising cell factory for the design of alternative bioprocesses based on renewable substrates. However, such a multiphasic bioreactor design is rather complex and leads to several constraints when considering emulsification of the oil-in-water mixture, foaming and cell growth/physiology on hydrophobic substrate. This study aims to shed light on the effect of pH changes on the physico-chemical properties of the cultivation medium and on cell physiology. It was indeed observed that at a pH value of 6, cell growth rate and intracellular lipid accumulation were optimized. Additionally, foaming was significantly reduced. In order to avoid over foaming in bioreactor, without impairing cell physiology, the use of alternative processes that can only act on the physical structure of culture medium, seems to be an effective alternative to usual chemical anti-foam agents. [less ▲]

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See detailYarrowia lipolytica morphological mutant enables lasting in situ immobilization in bioreactor
Vandermies, Marie ULiege; Kar, Tambi ULiege; Carly, Frédéric et al

in Applied Microbiology and Biotechnology (2018)

In the present study, we have isolated and characterized a Yarrowia lipolytica morphological mutant growing exclusively in the pseudohyphal morphology. The gene responsible for this phenotype ... [more ▼]

In the present study, we have isolated and characterized a Yarrowia lipolytica morphological mutant growing exclusively in the pseudohyphal morphology. The gene responsible for this phenotype, YALI0E06519g, was identified as homologous to the mitosis regulation gene HSL1 from Saccharomyces cerevisiae. Taking advantage of its morphology, we achieved the immobilization of the Δhsl1 mutant on the metallic structured packing of immobilized-cell bioreactors. We obtained significant cell retention and growth on the support during shake flask and bioreactor experiments without an attachment step prior to the culture. The system of medium aspersion on the packing ensured oxygen availability in the absence of agitation and minimized the potential release of cells in the culture medium. Additionally, the metallic packing proved its facility of cleaning and sterilization after fermentation. This combined use of morphological mutation and bioreactor design is a promising strategy to develop continuous processes for the production of recombinant protein and metabolites using Y. lipolytica. [less ▲]

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See detailNew filamentous mutant of Yarrowia lipolytica and its use in biofilm bioreactors
Vandermies, Marie ULiege; Kar, Tambi; Carly et al

Poster (2018, May 17)

The non-conventional yeast Yarrowia lipolytica is regarded as a promising cell factory for the production of recombinant proteins as well as added value chemicals. This organism possesses interesting ... [more ▼]

The non-conventional yeast Yarrowia lipolytica is regarded as a promising cell factory for the production of recombinant proteins as well as added value chemicals. This organism possesses interesting metabolic properties, such as high capacity of biomolecule synthesis and secretion, substrate flexibility and adequacy with culture at high-cell density. Another characteristic trait of Y. lipolytica lies in its ability to adopt an ovoid or filamentous morphology (hyphae and pseudohyphae) according to environmental conditions. To date, several effectors of the dimorphic transition have been identified and characterized at the molecular level. However, the dimorphic transition remains difficult to master during cultures in bioreactor, thus negatively affecting the process reproducibility. Yet, filamentous organisms are particularly well suited for the development of immobilized-cell processes. In the present study, we have isolated and characterized a Y. lipolytica morphological mutant growing exclusively in the pseudohyphal morphology by means of insertion mutagenesis and high throughput screening methods. The gene responsible for this phenotype, YALI0E06519g, was identified as homologous to the mitosis regulation gene HSL1 from Saccharomyces cerevisiae. Taking advantage of its morphology, we achieved the immobilization of the Δhsl1 mutant on the stainless steel structured packing of immobilized-cell bioreactors. We obtained significant cell retention and growth on the support during shake flask and bioreactor experiments without an attachment step prior to the culture. The system of medium aspersion on the packing ensured oxygen availability in the absence of agitation and minimized the potential release of cells in the culture medium. Additionally, the metallic packing proved its facility of cleaning and sterilization after fermentation. This combined use of morphological mutation and bioreactor design is a promising strategy to develop continuous processes for the production of recombinant protein and metabolites using Y. lipolytica. [less ▲]

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See detailImpact of microbial composition of Cambodian traditional dried starters (Dombea) on flavor compounds of rice wine: combining amplicon sequencing with HP-SPME-GCMS
Ly, Sokny ULiege; Mith, Hasika; Tarayre, Cédric ULiege et al

in Frontier in microbiology (2018)

Dombae is a traditional ferment starter which has been used for starchy based wine production in Cambodia. However, the production technology of rice wine in Cambodia is not optimized. The current study ... [more ▼]

Dombae is a traditional ferment starter which has been used for starchy based wine production in Cambodia. However, the production technology of rice wine in Cambodia is not optimized. The current study aimed to investigate the microbiota associated in five ferment starters and the effect of a traditional fermentation process using a metagenomics sequencing analysis and HS-SPME-GCMS for the characterization of the aromatic profiles at the end of fermentation. Most of bacteria identified in this study were lactic acid bacteria including Weissella cibaria, Pediococcus sp. MMZ60A, Lactobacillus fermentum and Lactobacillus plantarum. Saccharomyces cerevisiae and Saccharomycopsis fibuligera were found to be abundant yeasts while the only amylolytic filamentous fungus was Rhizopus oryzae. A total of 25 aromatic compounds were detected and identified as esters, alcohols, acids, ketones and aldehydes. The alcohol group was dominant in each rice wine. Significant changes were observed at the level of microbial communities during fermentation, suggesting microbial succession for the assimilation of starch and subsequently assimilation of fermentation by-products leading to the production of flavor compounds. At this level, the presence of Weissella, Pediococcus and Lactobacillus genus was strongly correlated with most of the flavor compounds detected. [less ▲]

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See detailAroma profile of pilot plant-scale produced fruit vinegar using a thermotolerant Acetobacter pasteurianus strain isolated from Moroccan cactus
Mounir, Majid; Fauconnier, Marie-Laure ULiege; Afechtal, Mohamed et al

in Acetic Acid Bacteria (2018), 7(1), 11

In this study, new thermotolerant Acetobacter pasteurianus CV01 strain recently isolated from local product of Morocco has been investigated for its ability to perform efficient acetous fermentation at a ... [more ▼]

In this study, new thermotolerant Acetobacter pasteurianus CV01 strain recently isolated from local product of Morocco has been investigated for its ability to perform efficient acetous fermentation at a large-scale. Firstly, the thermotolerance basis bioconversion of CV01 strain was compared to other mesophilic and thermotolerant acetic acid bacteria. Subsequently, CV01 strain was assessed for its ability to produce and tolerate high amount of acetic acid at optimal and thermal stress conditions in lab-scale bioreactor. It was found that the studied strain exhibited thermotolerant properties compared to reference strains and could withstand the increase in temperature during acetous fermentation in fermenter. Furthermore, gas chromatography-mass spectrometry (GC-MS) was used on the samples prepared with solid phase microextraction (SPME) to determine the volatile compounds of the pilot plant produced apple vinegar based on developed start-up and semi-continuous fermentation protocol. The operation strategy in the 500-L pilot plant scale acetator allowed achieving 7.3% (w/v) of final acetic acid concentration recording high yield and acetification rate. The aroma profile of experimentally produced vinegar was found different from that of the commercial reference one. According to the literature, the results obtained show that major volatile compounds found in pilot-plant produced apple vinegar are related to good aromatic note descriptors which could have a positive impact on the organoleptic quality of industrial vinegar. Consequently, it can be concluded that CV01 Acetobacter strain is well suited for large-scale production of high quality fruit vinegar. [less ▲]

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See detailIntegrating metabolic modeling and population heterogeneity analysis into optimizing recombinant protein production by Komagataella (Pichia) pastoris
Theron, Chrispian ULiege; Berrios, J.; Delvigne, Frank ULiege et al

in Applied Microbiology and Biotechnology (2018), 102(1), 63-80

The methylotrophic yeast Komagataella (Pichia) pastoris has become one of the most utilized cell factories for the production of recombinant proteins over the last three decades. This success story is ... [more ▼]

The methylotrophic yeast Komagataella (Pichia) pastoris has become one of the most utilized cell factories for the production of recombinant proteins over the last three decades. This success story is linked to its specific physiological traits, i.e., the ability to grow at high cell density in inexpensive culture medium and to secrete proteins at high yield. Exploiting methanol metabolism is at the core of most P. pastoris-based processes but comes with its own challenges. Co-feeding cultures with glycerol/sorbitol and methanol is a promising approach, which can benefit from improved understanding and prediction of metabolic response. The development of profitable processes relies on the construction and selection of efficient producing strains from less efficient ones but also depends on the ability to master the bioreactor process itself. More specifically, how a bioreactor processes could be monitored and controlled to obtain high yield of production. In this review, new perspectives are detailed regarding a multi-faceted approach to recombinant protein production processes by P. pastoris; including gaining improved understanding of the metabolic pathways involved, accounting for variations in transcriptional and translational efficiency at the single cell level and efficient monitoring and control of methanol levels at the bioreactor level. © 2017, Springer-Verlag GmbH Germany, part of Springer Nature. [less ▲]

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See detailInvestigating the effects of hydrodynamics and mixing on mass transfer through the free-surface in stirred tank bioreactors
de Lamotte, Anne ULiege; Delafosse, Angélique ULiege; Calvo, Sébastien ULiege et al

in Chemical Engineering Science (2017), 172

In stirred-tank bioreactors, flow structures of various length and time scales are implied in scalar transport phenomena, such as gas species transfer through the liquid free-surface and their ... [more ▼]

In stirred-tank bioreactors, flow structures of various length and time scales are implied in scalar transport phenomena, such as gas species transfer through the liquid free-surface and their homogenization in the bulk. A proper understanding of the underlying mechanisms, i.e. hydrodynamics, mixing and mass transfer, and of their interactions is required to design and develop reliable and efficient production-scale bioprocesses. The objective of the present work is to experimentally investigate the coupling between gas-liquid mass transfer of oxygen with mixing efficiency and circulation patterns inside an arbitrarily chosen stirred-tank configuration aerated through the liquid free-surface, a baffled 20 L-vessel agitated by two Rushton turbines. Based on global parameter values, the most appropriate rotating speed, N = 300 rpm, is selected in order to further study local hydrodynamic quantities using Particle Image Velocimetry (PIV), as well as mixing and mass transfer dynamics using Planar Laser-Induced Fluorescence (PLIF). The results obtained with these local experimental methods are analyzed in detail. Their averages are first successfully compared to global data. Statistical analysis of their spatial distributions show that large-scale flow patterns significantly influence mass transfer through the free-surface of the stirred tank. Even if global measurements show that global characteristic times for mixing and mass transfer differ by two orders of magnitude, local experimental characterization shows persistent vertical gradients of dissolved gas concentrations. So the dissolved gas concentration is not as perfectly uniform as one might expect. [less ▲]

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See detailPhysico-chemical Approach for Characterising Probiotics: example of High Concentrated Multistrain-Based Formulation
Razafindralambo, Hary ULiege; Delvigne, Frank ULiege; Blecker, Christophe ULiege

Poster (2017, October 09)

Probiotics are receiving today unprecedented growing interests in Europe, Asia, and in the rest of the world. Their applications are not only limited to food and health sectors, but cover also agriculture ... [more ▼]

Probiotics are receiving today unprecedented growing interests in Europe, Asia, and in the rest of the world. Their applications are not only limited to food and health sectors, but cover also agriculture and aquaculture areas. The quality of probiotic products depends on many factors such as, the properties of each individual strain and its proportion in mixed products, the viable probiotic dose, and other selective ingredients like prebiotics and protectant agents incorporated into the formulation. Several strategies are employed for ensuring high product qualities, which can be controlled by different methods and techniques. To date, the physico-chemical approach for characterizing and controlling probiotic qualities and performances appears very attractive, but less exploited. It particularly consists in characterizing probiotic products in terms of thermal, surface and colloidal properties, which could be correlated to probiotic viability and functionalities. In this communication, we report the efficiency of such an approach when applied to a high concentrated multistrain-based formulation which has been shown a metabolic variability impacting on the inflammatory response, depending on the production site. [less ▲]

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See detailMicrobial lipopeptide production and purification bioprocesses, current progress and future challenges
Coutte, F.; Lecouturier, D.; Dimitrov, K. et al

in Biotechnology Journal (2017), 12(7),

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See detailAn anticancer molecule stemming from a plant root produced in a bioreactor
Vassaux, Antoine; Tarayre, Cédric ULiege; Delvigne, Frank ULiege et al

Poster (2017, May 24)

Secondary metabolites produced by plants or their symbionts have already shown specific properties: anticancer, anti-inflammatory, antibacterial, antifungal effects, etc. Astin C is a non-ribosomal ... [more ▼]

Secondary metabolites produced by plants or their symbionts have already shown specific properties: anticancer, anti-inflammatory, antibacterial, antifungal effects, etc. Astin C is a non-ribosomal peptide (secondary metabolite) produced by the fungus Villosirosea asteris, endosymbiont of the medicinal plant Aster tataricus, which has shown an interesting anticancer activity. The current challenge is the production of the molecule on a large scale and in higher quantities, either from the original fungus through fermentation technologies, or by a heterologous yeast strain having integrated the genes involved in the astin C biosynthesis pathway. The purpose of this workshop is to highlight the implementation possibilities of a strain producing a metabolite of interest. [less ▲]

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See detailLooking for phosphate-accumulating bacteria in activated sludge processes : a multidisciplinary approach
Tarayre, Cédric ULiege; Charlier, Raphaëlle; Delepierre, Anissa ULiege et al

in Environmental Science and Pollution Research (2017)

Over the past decades, an increasing need in renewable resources has progressively appeared. This trend concerns not only fossil fuels but also mineral resources. Wastewater and sewage sludge contain ... [more ▼]

Over the past decades, an increasing need in renewable resources has progressively appeared. This trend concerns not only fossil fuels but also mineral resources. Wastewater and sewage sludge contain significant concentrations in phosphate and can be considered as a fertilizer source of the utmost importance. In wastewater treatment plants, the biological uptake of phosphate is performed by a specific microbiota: the phosphate-accumulating organisms. These microorganisms are recovered in sewage sludge. Here, we aimed to investigate the occurrence of phosphate accumulators in four wastewater treatment plants. A 16S metagenetic analysis identified the main bacterial phyla extracted from the aerobic treatment: α-Proteobacteria, β-Proteobacteria, and Sphingobacteria. An enrichment stage was performed to stimulate the specific growth of phosphate-accumulating bacteria in an acetate medium. An analysis of metabolic activities of sulfur and phosphorus highlighted strong modifications related to phosphorus and much less distinguishable effects with sulfur. A solid acetate medium containing 5-Br-4-Cl-3-indolyl phosphate was used to select potential phosphate-accumulating bacteria from the enriched consortia. The positive strains have been found to belong in the genera Acinetobacter, Corynebacterium, and Pseudomonas. Finally, electron microscopy was applied to the strains and allowed to confirm the presence of polyphosphate granules. Some of these bacteria contained granules the size of which exceeded 100 nm. [less ▲]

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See detailBioprocess scale-up/down as integrative enabling technology: from fluid mechanics to systems biology and beyond
Delvigne, Frank ULiege; Takors, R.; Mudde, R. et al

in Microbial Biotechnology (2017), 10(5), 1267-1274

Efficient optimization of microbial processes is a critical issue for achieving a number of sustainable development goals, considering the impact of microbial biotechnology in agrofood, environment ... [more ▼]

Efficient optimization of microbial processes is a critical issue for achieving a number of sustainable development goals, considering the impact of microbial biotechnology in agrofood, environment, biopharmaceutical and chemical industries. Many of these applications require scale-up after proof of concept. However, the behaviour of microbial systems remains unpredictable (at least partially) when shifting from laboratory-scale to industrial conditions. The need for robust microbial systems is thus highly needed in this context, as well as a better understanding of the interactions between fluid mechanics and cell physiology. For that purpose, a full scale-up/down computational framework is already available. This framework links computational fluid dynamics (CFD), metabolic flux analysis and agent-based modelling (ABM) for a better understanding of the cell lifelines in a heterogeneous environment. Ultimately, this framework can be used for the design of scale-down simulators and/or metabolically engineered cells able to cope with environmental fluctuations typically found in large-scale bioreactors. However, this framework still needs some refinements, such as a better integration of gas–liquid flows in CFD, and taking into account intrinsic biological noise in ABM. © 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology. [less ▲]

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See detailScale-up/Scale-down of microbial bioprocesses: a modern light on an old issue
Delvigne, Frank ULiege; Noorman, H.

in Microbial Biotechnology (2017), 10(4), 685-687

The bio-economy is in transit from innovation to commercialization. The bioprocess industry is expected to increasingly deliver bio-products to the market, in large amounts, at high quality and at ... [more ▼]

The bio-economy is in transit from innovation to commercialization. The bioprocess industry is expected to increasingly deliver bio-products to the market, in large amounts, at high quality and at competitive cost levels. This requires flawless start-up of new large-scale bioprocesses and continuous improvement of running processes. Fermentation scale-up and operation can benefit from recent advances in three areas: 1. computation-driven design of scale-down simulators, 2. omics-driven metabolic engineering and 3. sensing and understanding of population heterogeneity. Integration of these fields requires a unified computational approach, linked to big data and simulated reality frameworks, of which the contours are becoming visible today. © 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology. [less ▲]

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See detailTaking control over microbial populations: Current approaches for exploiting biological noise in bioprocesses
Delvigne, Frank ULiege; Baert, J.; Sassi, Hosni ULiege et al

in Biotechnology Journal (2017), 12(7),

Phenotypic plasticity of microbial cells has attracted much attention and several research efforts have been dedicated to the description of methods aiming at characterizing phenotypic heterogeneity and ... [more ▼]

Phenotypic plasticity of microbial cells has attracted much attention and several research efforts have been dedicated to the description of methods aiming at characterizing phenotypic heterogeneity and its impact on microbial populations. However, different approaches have also been suggested in order to take benefit from noise in a bioprocess perspective, e.g. by increasing the robustness or productivity of a microbial population. This review is dedicated to outline these controlling methods. A common issue, that has still to be addressed, is the experimental identification and the mathematical expression of noise. Indeed, the effective interfacing of microbial physiology with external parameters that can be used for controlling physiology depends on the acquisition of reliable signals. Latest technologies, like single cell microfluidics and advanced flow cytometric approaches, enable linking physiology, noise, heterogeneity in productive microbes with environmental cues and hence allow correctly mapping and predicting biological behavior via mathematical representations. However, like in the field of electronics, signals are perpetually subjected to noise. If appropriately interpreted, this noise can give an additional insight into the behavior of the individual cells within a microbial population of interest. This review focuses on recent progress made at describing, treating and exploiting biological noise in the context of microbial populations used in various bioprocess applications. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim [less ▲]

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See detailHomogenizing bacterial cell factories: Analysis and engineering of phenotypic heterogeneity
Binder, D.; Drepper, T.; Jaeger, K.-E. et al

in Metabolic Engineering (2017), 42

In natural habitats, microbes form multispecies communities that commonly face rapidly changing and highly competitive environments. Thus, phenotypic heterogeneity has evolved as an innate and important ... [more ▼]

In natural habitats, microbes form multispecies communities that commonly face rapidly changing and highly competitive environments. Thus, phenotypic heterogeneity has evolved as an innate and important survival strategy to gain an overall fitness advantage over cohabiting competitors. However, in defined artificial environments such as monocultures in small- to large-scale bioreactors, cell-to-cell variations are presumed to cause reduced production yields as well as process instability. Hence, engineering microbial production toward phenotypic homogeneity is a highly promising approach for synthetic biology and bioprocess optimization. In this review, we discuss recent studies that have unraveled the cell-to-cell heterogeneity observed during bacterial gene expression and metabolite production as well as the molecular mechanisms involved. In addition, current single-cell technologies are briefly reviewed with respect to their applicability in exploring cell-to-cell variations. We highlight emerging strategies and tools to reduce phenotypic heterogeneity in biotechnological expression setups. Here, strain or inducer modifications are combined with cell physiology manipulations to achieve the ultimate goal of equalizing bacterial populations. In this way, the majority of cells can be forced into high productivity, thus reducing less productive subpopulations that tend to consume valuable resources during production. Modifications in uptake systems, inducer molecules or nutrients represent valuable tools for diminishing heterogeneity. Finally, we address the challenge of transferring homogeneously responding cells into large-scale bioprocesses. Environmental heterogeneity originating from extrinsic factors such as stirring speed and pH, oxygen, temperature or nutrient distribution can significantly influence cellular physiology. We conclude that engineering microbial populations toward phenotypic homogeneity is an increasingly important task to take biotechnological productions to the next level of control. © 2017 International Metabolic Engineering Society [less ▲]

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See detailTools for the determination of population heterogeneity caused by inhomogeneous cultivation conditions
Lemoine, A.; Delvigne, Frank ULiege; Bockisch, A. et al

in Journal of Biotechnology (2017), 251

Population heterogeneity among a microbial culture can occur in various stages of a bioprocess. When a nutrient-limited fed-batch process is applied in the large scale, gradient formation (e.g. at the ... [more ▼]

Population heterogeneity among a microbial culture can occur in various stages of a bioprocess. When a nutrient-limited fed-batch process is applied in the large scale, gradient formation (e.g. at the substrate concentration or the pH-value) can have a tremendous impact on the process performance. It might also have an impact on population heterogeneity, as the cells are opposed to stressful conditions that is an oscillating environment, when they pass the different zones evolved in the liquid phase. Nevertheless, the question whether these conditions support heterogeneity of a culture has not been clearly answered so far. Furthermore, if such a heterogeneity affects product formation, the usual analysis tools, which do not rely on a single-cell basis, certainly do not gain sufficiently suitable information for process optimization. This overview on the one hand provides information about the contribution of an oscillating environment to the formation of heterogeneities within a population and on the other hand a summary of tools, which can be used to investigate physiologic and morphologic heterogeneity during process development, scale up and production. If these techniques are considered, the identification of targets for accelerated process optimization on a single-cell basis becomes easier and faster. © 2017 Elsevier B.V. [less ▲]

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