Overcoming the Mucus Barrier

Abstract Background Recent accumulating evidence suggests that amino acids have crucial roles in the maintenance of intestinal homeostasis. In inflammatory bowel disease (IBD), amino acid metabolism is changed in both host and the gut microbiota. Among amino acids, L-serine plays a central role in several metabolic processes that are essential for the growth and survival of both mammalian and bacterial cells. However, the role of L-serine in intestinal homeostasis and IBD remains incompletely understood. In this study, we investigated the effect of dietary L-serine on intestinal inflammation in a murine model of colitis. Methods Specific pathogen-free (SPF) mice were fed either a control diet (amino acid-based diet) or an L-serine-deficient diet (SDD). Colitis was induced by the treatment of dextran sodium sulfate (DSS). The gut microbiome was analyzed by 16S rRNA sequencing. We also evaluate the effect of dietary L-serine in germ-free mice and gnotobiotic mice that were colonized by a consortium of non-mucolytic bacterial strains or the consortium plus mucolytic bacterial strains. Results We found that the SDD exacerbated experimental colitis in SPF mice. However, the severity of colitis in SDD-fed mice was comparable to control diet-fed mice in germ-free condition, suggesting that the gut microbiota is required for exacerbation of colitis caused by the restriction of dietary L-serine. The gut microbiome analysis revealed that dietary L-serine restriction fosters the blooms of a mucus-degrading bacterium Akkermansia muciniphila and adherent-invasive Escherichia coli in the inflamed gut. Consistent with the expansion of mucolytic bacteria, SDD-fed mice showed a loss of the intestinal mucus layer. Dysfunction of the mucus barrier resulted in increased intestinal permeability, thereby leading to bacterial translocation to the intestinal mucosa, which subsequently increased the severity of colitis. The increased intestinal permeability and subsequent bacterial translocation were observed in SDD-fed gnotobiotic mice that colonized by mucolytic bacteria. In contrast, dietary L-serine restriction did not alter intestinal barrier integrity in gnotobiotic mice that colonized only by non-mucolytic bacteria. Conclusion Our results suggest that dietary L-serine regulates the integrity of the intestinal mucus barrier during inflammation by limiting the expansion of mucus degrading bacteria.

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The role of KPI-121 0.25% in the treatment of dry eye disease: penetrating the mucus barrier to treat periodic flares

Therapeutic Advances in Ophthalmology ◽

10.1177/25158414211012797 ◽

2021 ◽

Vol 13 ◽

pp. 251584142110127

Author(s):

Preeya K. Gupta ◽

Nandini Venkateswaran

Keyword(s):

Drug Delivery ◽

Dry Eye ◽

Ocular Surface ◽

Dry Eye Disease ◽

Eye Disease ◽

Eye Drops ◽

Short Term ◽

Short Term Treatment ◽

Loteprednol Etabonate ◽

Mucus Barrier

The tear film, which includes mucins that adhere to foreign particles, rapidly clears allergens and pathogens from the ocular surface, protecting the underlying tissues. However, the tear film’s ability to efficiently remove foreign particles during blinking can also pose challenges for topical drug delivery, as traditional eye drops (solutions and suspensions) are cleared from the ocular surface before the drug can penetrate into the conjunctival and corneal epithelium. In the past 15 years, there has been an increase in the development of nanoparticles with specialized coatings that have reduced affinity to mucins and are small enough in size to pass through the mucus barrier. These mucus-penetrating particles (MPPs) have been shown to efficiently penetrate the mucus barrier and reach the ocular surface tissues. Dry eye disease (DED) is a common inflammatory ocular surface disorder that often presents with periodic flares (exacerbations). However, currently approved immunomodulatory treatments for DED are intended for long-term use. Thus, there is a need for effective short-term treatments that can address intermittent flares of DED. Loteprednol etabonate, an ocular corticosteroid, was engineered to break down rapidly after administration to the ocular surface tissues and thereby reduce risks associated with other topical steroids. KPI-121 is an ophthalmic suspension that uses the MPP technology to deliver loteprednol etabonate more efficiently to the ocular tissues, achieving in animal models a 3.6-fold greater penetration of loteprednol etabonate to the cornea than traditional loteprednol etabonate ophthalmic suspensions. In clinical trials, short-term treatment with KPI-121 0.25% significantly reduced signs and symptoms of DED compared with its vehicle (placebo). Recently approved KPI-121 0.25%, with its novel drug delivery design and ease of use, has the potential to effectively treat periodic flares of DED experienced by many patients.

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Some effects of tripotassium dicitrato bismuthate on gastric secretion and the mucus barrier

Alimentary Pharmacology & Therapeutics ◽

10.1111/j.1365-2036.1990.tb00500.x ◽

2007 ◽

Vol 4 (5) ◽

pp. 535-546 ◽

Cited By ~ 2

Author(s):

R. L. SIDEBOTHAM ◽

J. J. BATTEN ◽

K. LI ◽

J. SPENCER ◽

J. H. BARON

Keyword(s):

Gastric Secretion ◽

Mucus Barrier

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SEDDS facilitate cinnamaldehyde crossing the mucus barrier: the perspective of mucus and Caco-2/HT29 co-culture models

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2022.121461 ◽

2022 ◽

pp. 121461

Author(s):

Ye Cai ◽

Liu Liu ◽

Mengqiu Xia ◽

Chunling Tian ◽

Wenqing Wu ◽

...

Keyword(s):

Culture Models ◽

Mucus Barrier

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13 ASTROVIRUS ALTERS THE GUT MUCUS BARRIER AND REDUCES COLONIZATION TO ENTEROPATHOGENIC E. COLI

Gastroenterology ◽

10.1053/j.gastro.2019.11.130 ◽

2020 ◽

Vol 158 (3) ◽

pp. S45

Author(s):

Valerie Cortez ◽

Bridgett Sharp ◽

Brandi Livingston ◽

Hannah Rowe ◽

Ramzi Alsallaq ◽

...

Keyword(s):

E Coli ◽

Mucus Barrier

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Drug and gene delivery to mucosal tissues: the mucus barrier

Advanced Drug Delivery Reviews ◽

10.1016/j.addr.2009.01.002 ◽

2009 ◽

Vol 61 (2) ◽

pp. 73-74 ◽

Cited By ~ 12

Author(s):

Justin Hanes ◽

Jo Demeester

Keyword(s):

Gene Delivery ◽

Mucosal Tissues ◽

Mucus Barrier ◽

Drug And Gene Delivery

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Frontline defenders: goblet cell mediators dictate host-microbe interactions in the intestinal tract during health and disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00181.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. G360-G377 ◽

Cited By ~ 17

Author(s):

Joannie M. Allaire ◽

Vijay Morampudi ◽

Shauna M. Crowley ◽

Martin Stahl ◽

Hongbing Yu ◽

...

Keyword(s):

Host Defense ◽

Current Evidence ◽

Gi Tract ◽

Intestinal Mucus ◽

Mucin 2 ◽

Microbe Interactions ◽

Noxious Stimuli ◽

Sense And Respond ◽

Mucus Barrier ◽

Host Microbe Interactions

Goblet cells (GCs) are the predominant secretory epithelial cells lining the luminal surface of the mammalian gastrointestinal (GI) tract. Best known for their apical release of mucin 2 (Muc2), which is critical for the formation of the intestinal mucus barrier, GCs have often been overlooked for their active contributions to intestinal protection and host defense. In part, this oversight reflects the limited tools available to study their function but also because GCs have long been viewed as relatively passive players in promoting intestinal homeostasis and host defense. In light of recent studies, this perspective has shifted, as current evidence suggests that Muc2 as well as other GC mediators are actively released into the lumen to defend the host when the GI tract is challenged by noxious stimuli. The ability of GCs to sense and respond to danger signals, such as bacterial pathogens, has recently been linked to inflammasome signaling, potentially intrinsic to the GCs themselves. Moreover, further work suggests that GCs release Muc2, as well as other mediators, to modulate the composition of the gut microbiome, leading to both the expansion as well as the depletion of specific gut microbes. This review will focus on the mechanisms by which GCs actively defend the host from noxious stimuli, as well as describe advanced technologies and new approaches by which their responses can be addressed. Taken together, we will highlight current insights into this understudied, yet critical, aspect of intestinal mucosal protection and its role in promoting gut defense and homeostasis.

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The Cervicovaginal Mucus Barrier

International Journal of Molecular Sciences ◽

10.3390/ijms21218266 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8266

Author(s):

Guillaume Lacroix ◽

Valérie Gouyer ◽

Frédéric Gottrand ◽

Jean-Luc Desseyn

Keyword(s):

Bacterial Vaginosis ◽

Preterm Delivery ◽

Physiological State ◽

Preterm Births ◽

Cervical Mucus ◽

Cervical Canal ◽

Current State ◽

Mucus Plug ◽

Mucus Barrier ◽

Cervicovaginal Mucus

Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to preterm delivery, but uterine infections appear to be a major cause. The vaginal epithelium is covered by the cervicovaginal mucus, which is essential to health because of its direct involvement in reproduction and functions as a selective barrier by sheltering the beneficial lactobacilli while helping to clear pathogens. During pregnancy, the cervical canal is sealed with a cervical mucus plug that prevents the vaginal flora from ascending toward the uterine compartment, which protects the fetus from pathogens. Abnormalities of the cervical mucus plug and bacterial vaginosis are associated with a higher risk of preterm delivery. This review addresses the current understanding of the cervicovaginal mucus and the cervical mucus plug and their interactions with the microbial communities in both the physiological state and bacterial vaginosis, with a focus on gel-forming mucins. We also review the current state of knowledge of gel-forming mucins contained in mouse cervicovaginal mucus and the mouse models used to study bacterial vaginosis.

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