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Engineering Mucus to Study and Influence the Microbiome

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Engineering Mucus to Study and Influence the Microbiome REVIEWS Engineering mucus to study and influence the microbiome Caroline Werlang 1, Gerardo Cárcarmo- Oyarce 1,2 and Katharina Ribbeck 1,2* Abstract | Mucus is a 3D hydrogel that houses the majority of the human microbiome. The mucous environment plays an important role in the differentiation and behaviour of microbial phenotypes and enables the creation of spatial distributions. Dysregulation of mucus is further associated with various diseases. Therefore, mucus is the key ingredient to study the behaviour of commensal and pathogenic microbiota in vitro. Indeed, microorganisms cultured in mucus exhibit phenotypes substantially different from those exhibited in standard laboratory media. In this Review, we discuss the impact of mucus on the microbiome and examine the structure and glycosylation of mucins — the main building blocks of mucus. We investigate the impact of glycans on mucin function and highlight different approaches for the engineering of synthetic mucins, including synthesis of the backbone, the design of mucin- mimetic hydrogels and the engineering of glycans. Finally, mucin mimetics for 3D in vitro cell culture and for modulating microbial community structure and function are discussed. Humans have at least as many bacterial cells as human For decades, human tissue culture models were limi- cells1. The human microbiome (BOx 1) has a profound ted to 2D methods that did not facilitate cell differentia- impact on human health, and changes in the compo- tion and spatial separation. Polymers, such as Matrigel, sition of the microbial community are associated with can provide the 3D spatial scaffolding necessary for cell various diseases, ranging from diabetes to depression2,3. differentiation and enable environmental regulation of The development of rapid and efficient DNA sequencing cell fate15. In such 3D systems, the definition and divi- techniques has revolutionized the study of the human sion of space allow the creation of signal and nutrient microbiome4, enabling the identification, categorization gradients, which can drive progenitor cells to differen- and tracking of human- associated microorganisms5. tiate into a variety of cell types16. Synthetic or natural Many microbial species are commensal and even bene- 3D matrices can also present different biophysical and ficial; however, the microbiome also contains potential biochemical cues, such as growth factors that influence pathogens, and the mechanisms of virulence suppression cellular development and cell fate17. Recognizing the in healthy individuals remain elusive thus far6. importance of the extracellular matrix for in vitro cell High-throughput DNA sequencing of clinical samples culture substantially advanced the study of healthy and enables the identification of groups of microorganisms diseased tissues and enabled the engineering of physio- associated with health and disease7; however, to under- logically relevant models of human tissues18,19, such as stand their function and behaviour, microorganisms organoid systems. need to be cultured in vitro. Cultures of clinical sam- On the basis of lessons learned from human tissue ples are often dominated by certain genera, but incor- culture methods, the 3D context of microorganisms porating the natural mucous environment can help to — mucus — must be considered in the development preserve species diversity8,9. Interaction with the sur- of microbiota culture models. The mucous barrier 1Department of Biological rounding environment and other community mem- (mucous gel) provides the specialized nutrients and Engineering, Massachusetts bers of different species is often crucial for survival spatial differentiation necessary to maintain microbial Institute of Technology, and required to provide access to trace nutrients, meta- species diversity and coexistence20. The incorporation Cambridge, MA, USA. bolites and biochemical and biophysical signals10,11. of mucus into in vitro microbial culture systems has the 2 Research Laboratory for Even microorganisms that are able to survive in tra- potential to facilitate viable multispecies culture systems Electronics, Massachusetts Institute of Technology, ditional in vitro culture methods can exhibit behav- and increase the number of culturable species. Cambridge, MA, USA. iours different from those exhibited in their natural The use of mucus and soluble mucins for in vitro cul- 12,13 *e- mail: [email protected] environment . Therefore, culturing microorganisms ture systems has been limited by the difficulty of acquir- https://doi.org/10.1038/ in a relevant 3D context is essential for understanding ing fresh mucosal samples and of generating a sufficient s41578-018-0079-7 their behaviour14. quantity through the culture of mucus- secreting cells. 134 | FEBRUARY 2019 | VOLUME 4 www.nature.com/natrevmats REVIEWS Box 1 | The microbiome also potentially pathogenic microorganisms, which are kept under control by mucus. The human microbiota constitutes the vast majority of the 10–100 trillion microbial Therefore, a functioning mucous barrier is essential organisms inhabiting the human body. This microbial community is composed of a for health, and mucus dysregulation can lead to disease. variety of different organisms, including bacteria, archaea, fungi and viruses3. It has For example, underproduction of mucus or a change been estimated that 400–1,000 different bacterial species coexist in a delicate equilibrium. However, microorganism–microorganism and microorganism–host in the properties of mucus can result in dry or thick 27 interactions are still poorly understood5,174. Many of the organisms in the microbiota are mucus , which leads to unshielded and dehydrated epi- not cultivable in vitro, that is, they do not grow in standard culture media175,176. Thus far, thelial surfaces that are prone to infection and wounding the microbiota has been mainly characterized using DNA-based analysis of specific (FIG. 1b). Dysregulation of mucus can further result in dry microbial markers, including 16 S ribosomal RNA (rRNA) genes, 18 S rRNA genes or eye syndrome28,29, xerostomia (dry mouth)30 and respira- other marker genes and genomic regions, amplified and sequenced from biological tory diseases, such as cystic fibrosis31,32, asthma33,34 and samples177. chronic obstructive pulmonary disease35,36. Moreover, Microbiota and microbiome mucin dysregulation is implicated in diseases of the In the current literature, the terms microbiota and microbiome are used interchangeably, digestive tract, including Crohn’s disease37, ulcerative even as synonyms168,178–180. However, microbiome has been previously defined as a colitis38 and gastric39 and colorectal40,41 cancer. In general, distinct concept, for example, the pool of genomes of the microbiota members5 or the loss of functionality of the mucin barrier makes the body 181 pool of microbiota organisms and their genes . Owing to the availability of powerful more accessible for environmental toxins and pathogens, genomic technologies, most studies of microbiota are specifically based on their genes which can lead to chronic inflammation or infection. and genomes, and therefore, both terms — microbiota and microbiome — have become In vitro studies with mucous gels, reconstituted operationally similar concepts. from animal sources22, have enabled the discovery that Microorganisms mucus is able to directly influence bacterial behaviour, Microorganism is a catch- all term that includes bacteria, viruses, fungi and other making a fundamental contribution to our understand- microscopic organisms. ing of host–microorganism interactions in health and disease. Indeed, mucus can regulate cross-kingdom Processed mucins isolated from pigs and cows are virulence through its ability to influence how micro- commercially available; however, industrial-scale pro- organisms swim, settle and communicate with each other. tein isolation can damage the structure of mucins and Therefore, mucus can be considered a sophisticated reduce their gel-forming functionality21,22. Alternatively, bioactive material with powerful abilities to manipulate synthetic mucin mimetics can be designed to replicate microbial behaviour and phenotypes. the characteristics of native human mucus. Synthetic mucins can be used to recreate and inves- Mucins tigate how mucus can suppress microbial virulence and Mucins provide mucus with its functional properties. promote species diversity. Well- defined mucin-inspired Mucins are glycoproteins that, when hydrated, form in vitro systems provide powerful tools for the system- the mucous hydrogel. The elongated protein backbone atic analyses of microorganism–mucus interactions, assumes a brush polymer architecture, as it is densely enabling studies of single-species beha viour, community grafted with sugar side chains, called glycans42 (Fig. 2a). interactions and human–microbial co-culture. Broadly, there are two classes of mucins: mucins that remain tethered to cell membranes and mucins that are Mucus houses the microbiota secreted, usually by goblet cells43. Tethered, or trans- The human body produces more than a litre of mucus membrane, mucins are found on many cell surfaces per day, lining all surfaces in the body that are not and play an important role in immune recognition44. covered by skin — over 2,000 ft2 (Fig. 1a). Mucus is a Secreted mucins form the mucosal hydrogel and are hydrogel composed of gel- forming mucins, salts, lipids, found throughout the body (FIg. 1a); for example, in proteins and immunological factors with varying con-
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