Chapter 1 : Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology

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The gastrointestinal tract (GIT) is a diverse and complex ecosystem shaped by continual interactions between host cells, nutrients, and the gut microbiota. The gut microbiome is estimated to contain approximately 10 bacterial cells and is dominated by the major phyla Firmicutes, Bacteriodetes, Actinobacteria, Proteobacteria, and Verrucomicrobia ( ). Early colonizers of the GIT include bifidobacteria from the phylum . These commensal microbes colonize immediately after birth and are speculated to prime the GIT and influence the gut-brain axis ( ). The infant microbiota is considered to be relatively unstable. Despite dramatic changes in the microbiome structure during early life, the gut microbiota increases in diversity and stability over the first 3 years of life ( ). Following this initial establishment, the microbiomes of children are generally enriched in spp., spp., and compared to adults ( ). During adulthood, the gut microbiome is considered to be stable and is dominated by the phyla Firmicutes and Bacteriodetes. While bacterial populations vary between individuals, the fecal microbiota of adults is highly stable through time ( ). This stability is maintained until older age (>65), when the microbiome stability and function begin to decline ( ).

Citation: Engevik M, Versalovic J. 2018. Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology, p 3-47. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0012-2016
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Figure 1

Methods utilized by commensal bacteria to beneficially modulate the intestinal environment. (A) Commensal bacteria secrete molecules which can alter the gut microbiota. By selectively inhibiting resident microbes, commensal bacteria establish an intestinal bacterial niche. Production of antimicrobial factors has also been shown to exclude pathogens. (B) Select commensal bacteria also secrete compounds which can modulate immune cells such as macrophages, dendritic cells, and lymphocytes such as T cells. These compounds decrease intestinal inflammation by dampening proinflammatory cytokines and promoting anti-inflammatory factors such as IL-10. (C) Commensal bacteria can secrete factors which modulate the functions of the epithelial barrier by enhancing the secretion of the protective mucus layer, upregulating tight junctions, and promoting secretion of molecules such as IgA.

Citation: Engevik M, Versalovic J. 2018. Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology, p 3-47. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0012-2016
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Figure 2

A depiction of secreted metabolites from commensal bacteria and their interactions with the microbiome or host. Lactic acid, hydrogen peroxide, short-chain fatty acids (SCFAs), and bacteriocins are all capable of serving as quorum-sensing molecules and/or directly modulating the composition of the microbiome. SCFAs, long-chain fatty acids (LCFAs), outer membrane vesicles, vitamins, lactocepins, serpins, and biogenic amines have all been demonstrated to beneficially modulate the host. Together, these bacterial products shape the intestinal environment and the host.

Citation: Engevik M, Versalovic J. 2018. Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology, p 3-47. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0012-2016
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Figure 3

Mechanisms by which commensal secreted products beneficially modulate the host. (A) Epithelial cells. Vitamins produced by bacteria provide essential nutrients to the host. Likewise, short-chain fatty acids (SCFAs) such as butyrate are known to serve as energy sources for intestinal epithelial cells. The SCFA acetate has also been shown to inhibit IL-8 production and increase tubulin-α acetylation. Lactobacilli-produced p40 and p75 inhibit TNF-induced apoptosis and enhance tight junctions, which attenuates intestinal barrier disruption. (B) Goblet cells. p40 is known to transactivate the epidermal growth factor receptor, activating the downstream target Akt and stimulating Muc2 gene expression and mucin production. Acetate produced by bacteria has also been shown to increase goblet cell differentiation and expression of mucus-related genes. (C) Immune cells. Vitamins, outer membrane vesicles (OMVs), SCFAs, and long-chain fatty acids (LCFAs) are known to directly influence the development and function of immune cells. In general, these molecules modulate T cell and dendritic cell homeostasis and cytokine production, promoting production of anti-inflammatory IL-10 and inhibiting proinflammatory cytokines such as TNF. Biogenic amines such as histamine have also been shown to suppress proinflammatory cytokines such as TNF in immune cells, thereby ameliorating intestinal inflammation. Bacterial enzymes such as lactocepin selectively degrade lymphocyte-recruiting chemokine IP-10 and other proinflammatory chemokines such as I-TAC and eotaxin. The protease inhibitor serpin has been shown to suppress inflammatory responses by binding and inactivating neutrophil elastase. Using the highlighted mechanism, commensal bacteria produce signals that reduce intestinal inflammation and promote health.

Citation: Engevik M, Versalovic J. 2018. Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology, p 3-47. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0012-2016
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Figure 4

Schematic representation of the molecular mechanisms of commensal secreted products on a Gram-negative bacterium. Bacteriocins are classified based on their structure. Bacteriocins such as nisin bind to a peptidoglycan subunit transporter, thereby preventing cell wall synthesis and resulting in cell death. Furthermore, bacteriocins can initiate pore formation. Pore formation depletes the bacterial transmembrane potential (Δψ) and/or the pH gradient, resulting in membrane disruption and cellular leakage that lead to rapid cell death. Other bacteriocins insert themselves directly or degrade the target membrane, leading to depolarization and death. Bacteriocins have also been shown to serve as quorum-sensing molecules for other microbes. Lactic acid decreases local pH and suppresses the growth and survival of pathogens. Additionally, undissociated lactic acid can traverse the outer membrane via water-filled porins and penetrate the cytoplasmic membrane. This shift lowers the intracellular pH, disrupts the transmembrane proton motive force, and generates oxidative stress. Hydrogen peroxide and select bacteriocins such as microcins damage bacterial DNA and inhibit cell growth. Together, these compounds secreted by select members of the microbiota effectively target pathogens.

Citation: Engevik M, Versalovic J. 2018. Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology, p 3-47. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0012-2016
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