Quantifying and Engineering Mucus Adhesion of Probiotics

Mays, Zachary J. S.; Chappell, Todd C.; Nair, Nikhil U.

doi:10.1021/acssynbio.9b00356

Cited by 35 publications

(21 citation statements)

References 112 publications

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“…The importance of ligand presentation was also suggested for mucin coatings, which interacted differently with bacteria depending on the site by which the molecule was attached to the surface. [28,29] Thus, we hypothesize that the architecture of the hydrogel could affect its bioactivity by affecting ligand density, adding or removing steric hindrances to interactions, or allowing the co-presentations of new ligands. The architecture of a hydrogel can be tuned by the details of the chemical crosslinking of the components.…”

Section: Introductionmentioning

confidence: 99%

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Jiang

Yan

Rickert

et al. 2021

Adv Funct Materials

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Hydrogels made of crosslinked macromolecules used in regenerative medicine technologies can be designed to affect the fate of surrounding cells and tissues in defined ways. Their function typically depends on the type and number of bioactive moieties such as receptor ligands present in the hydrogel. However, the detail in how such moieties are presented to cells can also be instrumental. In this work, how the crosslinking architecture of a hydrogel can affect its bioactivity is explored. It is shown that bovine submaxillary mucins, a highly glycosylated and immune‐modulating protein, exhibit strikingly different bioactivities whether they are crosslinked through their glycans or their protein domains. Both the susceptibility to enzymatic degradation and macrophage response are affected, while rheological properties and barrier to diffusion are mostly unaffected. The results suggest that crosslinking architecture affects the accessibility of the substrate to proteases and the pattern of sialic acid residues exposed to the macrophages. Thus, modulating the accessibility of binding sites through the choice of the crosslinking strategy appears as a useful parameter to tune the bioactivity of hydrogel‐based systems.

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Section: Introductionmentioning

confidence: 99%

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Jiang

Yan

Rickert

et al. 2021

Adv Funct Materials

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“…Unfortunately, the physiology of the gut does not lend to metabolic intervention easily, and each age group had plasma phe ubiquitously increase to unsafe levels (Figure 4). As a countering tactical measure, drug formulations for living therapeutics include microencapsulation to survive the stomach (39), surface modification to improve mucoadhesion and increase residence time or cell population (16), bacterial chassis selection to target regional success (40, 41), and enzyme choice and expression to increase specific activity per cell (40, 41). Effectively, the agenda in each case is to increase the level of therapeutic intervention at earlier stages of digestion.…”

Section: Resultsmentioning

confidence: 99%

A quantitative model for metabolic intervention using gut microbes

Mays

Nair

2020

Preprint

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5As medicine shifts toward precision-based and personalized therapeutics, utilizing more complex biomolecules to 6 treat increasingly difficult and rare conditions, microorganisms provide an avenue for realizing the production and 7 processing necessary for novel drug pipelines. More so, probiotic microbes can be co-opted to deliver therapeutics 8 by oral administration as living drugs, able to survive and safely transit the digestive tract. As living therapeutics are 9 in their nascency, traditional pharmacokinetic-pharmacodynamic (PK-PD) models for evaluating drug candidates 10 are not appropriate for this novel platform. Using a living therapeutic in late-stage clinical development for 11 phenylketonuria (PKU) as a case study, we adapt traditional oral drug delivery models to properly evaluate and 12 inform the engineering of living therapeutics. We develop the adapted for living therapeutics compartmental 13 absorption and transit (ALT-CAT) model to provide metrics for drug efficacy across nine age groups of PKU patients 14 and evaluate model parameters that are influenced by patient physiology, microbe selection and therapeutic 15 production, and dosing formulations. 16 Importance 17This work describes a kinetic model to study the behavior of orally delivered living therapeutics. Such therapeutics 18 are becoming increasingly relevant and are an exciting mode of drug delivery that stems from the growing interest 19 through the convergence of advances in synthetic biology of probiotics and gut microbes as well as microbiome 20 science. In particular, this work describes the development of a mathematical framework (pharmacokinetic-21 pharmacodynamic, PK-PD) called ALT-CAT to model the behavior of orally delivered engineered bacteria that act as 22 living therapeutics by adapting similar methods that have been developed and widely-used for small molecular drug 23 delivery and absorption. 24 2 Introduction 25The most common and practical route of drug delivery is oral ingestion, pairing patient convenience and high 26 compliance with ease of administration and stability. While a simple initial assessment of a drug's biochemical 27 feasibility for oral delivery can be predicted using the biopharmaceutical classification system (BCS) (1) or rule of 28 five (Ro5) (2), these evaluations do not inform the further complexities of selecting lead candidates, developing a 29 dosage or release strategy, effective bioavailability, and pharmacokinetics. Accordingly, a range of models -in vitro 30(3) and in vivo (4), static (5) and dynamic (6, 7), molecular (8) and system environment (9) -are used extensively in 31 drug development to evaluate and hone desired features. 32 33 An economically appealing alternative, trading human capital and consumables for computational resources (time 34 and power), is the modeling of drug absorption in the gastrointestinal tract (GIT). In silico models have been 35 developed for both molecular interactions (10), such as receptor binding or transport, and physiology-based 36 pharmacokinetics...

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“…Lactobacillus and Bifidobacterium are the most important gram-positive lactic acid bacteria that have common surface molecules such as surface layer proteins, Mub, and lipoteichoic acid, which have a crucial role in interacting with mucosal constituents [ 141 , 142 ]. Intestinal surface bacterial adhesion can be initially induced by nonspecific contacts such as hydrophobic interactions, accompanied by the second phase of adhesion by specific cell wall constituents [ 143 ]. Surface adhesive proteins, including MucBP and Mub [ 144 ], are mucus-binding proteins.…”

Section: Adhesion Mechanisms Of Probiotics To Intestinal Mucosa and S...mentioning

confidence: 99%

Evaluation of the Function of Probiotics, Emphasizing the Role of their Binding to the Intestinal Epithelium in the Stability and their Effects on the Immune System

et al. 2021

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Due to the importance of using cost-effective methods for therapeutic purposes, the function of probiotics as safe microorganisms and the study of their relevant functional mechanisms have recently been in the spotlight. Finding the mechanisms of attachment and stability and their beneficial effects on the immune system can be useful in identifying and increasing the therapeutic effects of probiotics. In this review, the functional mechanisms of probiotics were comprehensively investigated. Relevant articles were searched in scientific sources, documents, and databases, including PubMed, NCBI, Bactibace, OptiBac, and Bagel4. The most important functional mechanisms of probiotics and their effects on strengthening the epithelial barrier, competitive inhibition of pathogenic microorganisms, production of antimicrobials, binding and interaction with the host, and regulatory effects on the immune system were discussed.In this regard, the attachment of probiotics to the epithelium is very important because the prerequisite for their proper functioning is to establish a proper connection to the epithelium. Therefore, more attention should be paid to the binding effect of probiotics, including sortase A, a significant factor involved in the expression of sortase-dependent proteins (SDP), on their surface as mediators of intestinal epithelial cell binding. In general, by investigating the functional mechanisms of probiotics, it was concluded that the mechanism by which probiotics regulate the immune system and adhesion capacity can directly and indirectly have preventive and therapeutic effects on a wide range of diseases. However, further study of these mechanisms requires extensive research on various aspects.

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Quantifying and Engineering Mucus Adhesion of Probiotics

Cited by 35 publications

References 112 publications

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

A quantitative model for metabolic intervention using gut microbes

Evaluation of the Function of Probiotics, Emphasizing the Role of their Binding to the Intestinal Epithelium in the Stability and their Effects on the Immune System

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