Bacterial Metabolism Pdf
Jules Altier
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Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)2,3,4. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced Treg (pTreg) cells5,6,7, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids8 with a range of physiological functions9. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pTreg cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of Treg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing Treg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.
C.C., P.T.M and A.Y.R. conceived the study, designed experiments and wrote the manuscript; C.C. and P.T.M performed experiments and analysed data; D.K. designed and cloned the original B. theta constructs; K.K. and C.M. provided technical assistance with experiments; M.S. and O.I.I. analysed gene-expression data sets; J.V. maintained germ-free mouse strains; C.-J.G. and W.-B.J. analysed bacterial bile acid transformation by mass spectrometry; S.V., R.J.R. and J.R.C. quantified SCFAs by mass spectrometry; J.H. and A.Y.R. supervised the study.
An invention disclosure has been filed based on the data generated in this study. P.T.M. and A.Y.R. received funding from Boehringer Ingelheim. A.Y.R. is a co-founder and member of the scientific advisory board of, and holds stock options in, Vedanta Biosciences. P.T.M. receives licensing royalties from Seres Therapeutics and is a co-inventor on patent applications US20170087196A1, US20180256653A1 and WO2018195467A1.
Heterotrophic metabolism is the biologic oxidation of organic compounds, such as glucose, to yield ATP and simpler organic (or inorganic) compounds, which are needed by the bacterial cell for biosynthetic or assimilatory reactions.
Respiration is a type of heterotrophic metabolism that uses oxygen and in which 38 moles of ATP are derived from the oxidation of 1 mole of glucose, yielding 380,000 cal. (An additional 308,000 cal is lost as heat.)
In fermentation, another type of heterotrophic metabolism, an organic compound rather than oxygen is the terminal electron (or hydrogen) acceptor. Less energy is generated from this incomplete form of glucose oxidation, but the process supports anaerobic growth.
In the final stage of respiration, ATP is formed through a series of electron transfer reactions within the cytoplasmic membrane that drive the oxidative phosphorylation of ADP to ATP. Bacteria use various flavins, cytochrome, and non-heme iron components as well as multiple cytochrome oxidases for this process.
The Mitchell hypothesis explains the energy conservation in all cells on the basis of the selective extrusion of H+ ions across a proton-impermeable membrane, which generates a proton motive force. This energy allows for ATP synthesis both in respiration and photosynthesis.
Bacterial photosynthesis is a light-dependent, anaerobic mode of metabolism. Carbon dioxide is reduced to glucose, which is used for both biosynthesis and energy production. Depending on the hydrogen source used to reduce CO2, both photolithotrophic and photoorganotrophic reactions exist in bacteria.
The nitrogen cycle consists of a recycling process by which organic and inorganic nitrogen compounds are used metabolically and recycled among bacteria, plants, and animals. Important processes, including ammonification, mineralization, nitrification, denitrification, and nitrogen fixation, are carried out primarily by bacteria.
Metabolism refers to all the biochemical reactions that occur in a cell or organism. The study of bacterial metabolism focuses on the chemical diversity of substrate oxidations and dissimilation reactions (reactions by which substrate molecules are broken down), which normally function in bacteria to generate energy. Also within the scope of bacterial metabolism is the study of the uptake and utilization of the inorganic or organic compounds required for growth and maintenance of a cellular steady state (assimilation reactions). These respective exergonic (energy-yielding) and endergonic (energy-requiring) reactions are catalyzed within the living bacterial cell by integrated enzyme systems, the end result being self-replication of the cell. The capability of microbial cells to live, function, and replicate in an appropriate chemical milieu (such as a bacterial culture medium) and the chemical changes that result during this transformation constitute the scope of bacterial metabolism.
The bacterial cell is a highly specialized energy transformer. Chemical energy generated by substrate oxidations is conserved by formation of high-energy compounds such as adenosine diphosphate (ADP) and adenosine triphosphate (ATP) or compounds containing the thioester bond
Heterotrophic bacteria, which include all pathogens, obtain energy from oxidation of organic compounds. Carbohydrates (particularly glucose), lipids, and protein are the most commonly oxidized compounds. Biologic oxidation of these organic compounds by bacteria results in synthesis of ATP as the chemical energy source. This process also permits generation of simpler organic compounds (precursor molecules) needed by the bacteria cell for biosynthetic or assimilatory reactions.
The Krebs cycle intermediate compounds serve as precursor molecules (building blocks) for the energy-requiring biosynthesis of complex organic compounds in bacteria. Degradation reactions that simultaneously produce energy and generate precursor molecules for the biosynthesis of new cellular constituents are called amphibolic.
All heterotrophic bacteria require preformed organic compounds. These carbon- and nitrogen-containing compounds are growth substrates, which are used aerobically or anaerobically to generate reducing equivalents (e.g., reduced nicotinamide adenine dinucleotide; NADH + H+); these reducing equivalents in turn are chemical energy sources for all biologic oxidative and fermentative systems. Heterotrophs are the most commonly studied bacteria; they grow readily in media containing carbohydrates, proteins, or other complex nutrients such as blood. Also, growth media may be enriched by the addition of other naturally occurring compounds such as milk (to study lactic acid bacteria) or hydrocarbons (to study hydrocarbon-oxidizing organisms).
Glucose oxidation is the most commonly studied dissimilatory reaction leading to energy production or ATP synthesis. The complete oxidation of glucose may involve three fundamental biochemical pathways. The first is the glycolytic or Embden- Meyerhof-Parnas pathway (Fig. 4-1), the second is the Krebs cycle (also called the citric acid cycle or tricarboxylic acid cycle), and the third is the series of membrane-bound electron transport oxidations coupled to oxidative phosphorylation.
Metabolically, bacteria are unlike cyanobacteria (blue-green algae) and eukaryotes in that glucose oxidation may occur by more than one pathway. In bacteria, glycolysis represents one of several pathways by which bacteria can catabolically attack glucose. The glycolytic pathway is most commonly associated with anaerobic or fermentative metabolism in bacteria and yeasts. In bacteria, other minor heterofermentative pathways, such as the phosphoketolase pathway, also exist.
In addition, two other glucose-catabolizing pathways are found in bacteria: the oxidative pentose phosphate pathway (hexose monophosphate shunt), (Fig. 4-3) and the Entner-Doudoroff pathway, which is almost exclusively found in obligate aerobic bacteria (Fig. 4-4). The highly oxidative Azotobacter and most Pseudomonas species, for example, utilize the Entner-Doudoroff pathway for glucose catabolism, because these organisms lack the enzyme phosphofructokinase and hence cannot synthesize fructose 1,6-diphosphate, a key intermediate compound in the glycolytic pathway. (Phospho-fructokinase is also sensitive to molecular O2 and does not function in obligate aerobes). Other bacteria, which lack aldolase (which splits fructose-1,6-diphosphate into two triose phosphate compounds), also cannot have a functional glycolytic pathway. Although the Entner-Doudoroff pathway is usually associated with obligate aerobic bacteria, it is present in the facultative anaerobe Zymomonas mobilis (formerly Pseudomonas lindneri). This organism dissimilates glucose to ethanol and represents a major alcoholic fermentation reaction in a bacterium.
Glucose dissimilation also occurs by the hexose monophosphate shunt (Fig. 4-3). This oxidative pathway was discovered in tissues that actively metabolize glucose in the presence of two glycolytic pathway inhibitors (iodoacetate and fluoride). Neither inhibitor had an effect on glucose dissimilation, and NADPH + H+ generation occurred directly from the oxidation of glucose-6-phosphate (to 6-phosphoglucono-δ-lactone) by glucose-6phosphate dehydrogenase. The pentose phosphate pathway subsequently permits the direct oxidative decarboxylation of glucose to pentoses. The capability of this oxidative metabolic system to bypass glycolysis explains the term shunt.
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