Exploring Mucin as Adjunct to Phage Therapy

Abstract

Conventional phage therapy using bacteriophages (phages) for specific targeting of pathogenic bacteria is not always useful as a therapeutic for gastrointestinal (GI) dysfunction. Complex dysbiotic GI disorders such as small intestinal bowel overgrowth (SIBO), ulcerative colitis (UC), or Crohn’s disease (CD) are even more difficult to treat as these conditions have shifts in multiple populations of bacteria within the microbiome. Such community-level structural changes in the gut microbiota may require an alternative to conventional phage therapy such as fecal virome transfer or a phage cocktail capable of targeting multiple bacterial species. Additionally, manipulation of the GI microenvironment may enhance beneficial bacteria–phage interactions during treatment. Mucin, produced along the entire length of the GI tract to protect the underlying mucosa, is a prominent contributor to the GI microenvironment and may facilitate bacteria–phage interactions in multiple ways, potentially serving as an adjunct during phage therapy. In this review, we will describe what is known about the role of mucin within the GI tract and how its facilitation of bacteria–phage interactions should be considered in any effort directed at optimizing effectiveness of a phage therapy for gastrointestinal dysbiosis.

MUC1: Structure, Function, and Clinic Application in Epithelial Cancers

“…The family of mucins to which MUC1 belongs is that of large, highly glycosylated proteins [ 7 ]. There are three types of mucins: trans-membrane (e.g., MUC1, MUC4, and MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, and MUC6), and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, and MUC20) [ 17 , 18 , 19 ]. MUC1, the best-characterized transmembrane mucin, has a variable number of highly glycosylated, 20-amino acid tandem repeats (VNTR), a sperm protein-enterokinase-agarin (SEA) domain (extracellular), a transmembrane domain, and a 72-amino acid cytoplasmic tail domain that extends up to 200–500 nm out of the cell surface ( Figure 1 A) [ 20 , 21 , 22 , 23 ].…”

Phage-encoded carbohydrate-interacting proteins in the human gut

“…For instance, Dong and colleagues identified that the major coat protein (p8) of the coliphage M13, strongly binds to elemental sulfur, in the context of a bioengineering approach (increasing the discharge capacity of lithium batteries by the self-assembly of nanostructured materials; in this case, phage; Dong et al, 2013). Given that some glycan residues in mucus mucins are sulfated (Robbe et al, 2003;Luis et al, 2021), it was proposed by Carroll-Portillo and Lin that M13 could potentially have mucus mucinbinding properties (Carroll-Portillo and Lin, 2021). Similarly, phage P35 has been shown to bind to the N-acetyl group in GlcNAc residues on the cell wall of Listeria monocytogenes, via the carbohydrate-binding domain P35 (CBDP35; Eugster et al, 2011).…”

Special Issue: Bacteriophage Treatment as an Alternative Technology to Inactivate Pathogenic Bacteria: A Generalized Worldwide Growing Acceptance

“…Two of the papers [11,17] focus on the development of phage-resistant mutants after phage therapy, which is an important aspect for both clinical and non-clinical applications. Five of the published papers in this Special Issue refer to some strategies to prevent the development of phage-resistant mutants, namely by the use of combined approaches, such as the use of antibiotics [12,20], fatty acids [18], essential oil [19], and mucin [21] during phage treatment. Four of the papers include in vivo studies in animals [14,15,22] and plants [23].…”

“…Some strategies have been established for preventing the development of phageresistant mutants by the use of combined approaches, including antibiotics [12,20], fatty acids [18], essential oil [19], and mucin [21], which were addressed in this Special Issue.…”

“…The combined treatment, with both phages and carvacrol (2.0 mg/mL), showed a higher efficacy, preventing Psa regrowth for more than 40 h. The authors concluded that the combined treatment with phages and carvacrol may be a promising, environmentally friendly and cost-effective approach to controlling Psa in the kiwifruit industry. Carrol-Portilo & Lin [21] reviewed the effect of mucin combined with phages as a therapy for gastrointestinal (GI) dysfunction. The authors concluded that the community-level structural changes in the gut microbiota may require an alternative to conventional phage therapy, such as a phage cocktail capable of targeting multiple bacterial species.…”