Reinforcement of the intestinal mucosal barrier via mucus-penetrating PEGylated bacteria – Nature Biomedical Engineering

  • Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Paone, P. & Cani, P. D. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 69, 2232–2243 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, W. et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat. Commun. 11, 4457 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mills, R. H. et al. Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity. Nat. Microbiol. 7, 262–276 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, X. et al. Pathobionts from chemically disrupted gut microbiota induce insulin-dependent diabetes in mice. Microbiome 11, 62 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bischoff, S. C. et al. Intestinal permeability—a new target for disease prevention and therapy. BMC Gastroenterol. 14, 189 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cunningham, K. E. & Turner, J. R. Myosin light chain kinase: pulling the strings of epithelial tight junction function. Ann. N. Y. Acad. Sci. 1258, 34–42 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jin, Y. & Blikslager, A. T. The regulation of intestinal mucosal barrier by myosin light chain kinase/Rho kinases. Int. J. Mol. Sci. 21, 3550 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, S. et al. Mucosal immunity-mediated modulation of the gut microbiome by oral delivery of probiotics into Peyer’s patches. Sci. Adv. 7, eabf0677 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leonardi, I. et al. Mucosal fungi promote gut barrier function and social behavior via type 17 immunity. Cell 185, 831–846 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rubin, D. T., Ananthakrishnan, A. N., Siegel, C. A., Sauer, B. G. & Long, M. D. ACG clinical guideline: ulcerative colitis in adults. Am. J. Gastroenterol. 114, 384–413 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Gong, Z. & Wang, Y. Immune checkpoint inhibitor-mediated diarrhea and colitis: a clinical review. JCO Oncol. Pract. 16, 453–461 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Wang, Y. et al. Soluble epoxide hydrolase is an endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation. Proc. Natl Acad. Sci. USA 117, 8431–8436 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nagata, N. et al. Human gut microbiota and its metabolites impact immune responses in COVID-19 and its complications. Gastroenterology 164, 272–288 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • You, J. S. et al. Commensal-derived metabolites govern Vibrio cholerae pathogenesis in host intestine. Microbiome 7, 132 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Venkatesh, M. et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41, 296–310 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ruas-Madiedo, P., Gueimonde, M., Fernandez-Garcia, M., de los Reyes-Gavilan, C. G. & Margolles, A. Mucin degradation by Bifidobacterium strains isolated from the human intestinal microbiota. Appl. Environ. Microbiol. 74, 1936–1940 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kinnebrew, M. A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duncan, K., Carey-Ewend, K. & Vaishnava, S. Spatial analysis of gut microbiome reveals a distinct ecological niche associated with the mucus layer. Gut Microbes 13, 1874815 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bergstrom, K. et al. Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota. Science 370, 467–472 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, S. M. et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Donaldson, G. P. et al. Spatially distinct physiology of Bacteroides fragilis within the proximal colon of gnotobiotic mice. Nat. Microbiol. 5, 746–756 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. Y. et al. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that ‘slip’ through the human mucus barrier. Angew. Chem. Int. Ed. Engl. 47, 9726–9729 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huckaby, J. T. & Lai, S. K. PEGylation for enhancing nanoparticle diffusion in mucus. Adv. Drug Deliv. Rev. 124, 125–139 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Maisel, K. et al. Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo. Nanomedicine 11, 1337–1343 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lai, S. K. et al. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc. Natl Acad. Sci. USA 104, 1482–1487 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cao, Z., Wang, X., Pang, Y., Cheng, S. & Liu, J. Biointerfacial self-assembly generates lipid membrane coated bacteria for enhanced oral delivery and treatment. Nat. Commun. 10, 5783 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luo, H. et al. Encoding bacterial colonization and therapeutic modality by wrapping with an adhesive drug-loadable nanocoating. Mater. Today 62, 98–110 (2023).

    Article 

    Google Scholar
     

  • Hasegawa, Y., Mark Welch, J. L., Rossetti, B. J. & Borisy, G. G. Preservation of three-dimensional spatial structure in the gut microbiome. PLoS ONE 12, e0188257 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McGuckin, M. A., Linden, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265–278 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miller, B. M. et al. Anaerobic respiration of NOX1-derived hydrogen peroxide licenses bacterial growth at the colonic surface. Cell Host Microbe 28, 789–797 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Giron, J. A., Ho, A. S. & Schoolnik, G. K. An inducible bundle-forming pilus of enteropathogenic Escherichia coli. Science 254, 710–713 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fee, C. J. & Van Alstine, J. M. PEG-proteins: reaction engineering and separation issues. Chem. Eng. Sci. 61, 924–939 (2006).

    Article 
    CAS 

    Google Scholar
     

  • McCallum, G. & Tropini, C. The gut microbiota and its biogeography. Nat. Rev. Microbiol. 22, 105–118 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Johansson, M. E., Thomsson, K. A. & Hansson, G. C. Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 mucin, is strongly bound to the Fcgbp protein. J. Proteome Res. 8, 3549–3557 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, M. Y., Inohara, N. & Nunez, G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 10, 18–26 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van Zyl, W. F., Deane, S. M. & Dicks, L. M. T. Molecular insights into probiotic mechanisms of action employed against intestinal pathogenic bacteria. Gut Microbes 12, 1831339 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Diseases, G. B. D. & Injuries, C. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1204–1222 (2020).

    Article 

    Google Scholar
     

  • Li, J. et al. Polydopamine nanoparticle-mediated dopaminergic immunoregulation in colitis. Adv. Sci. 9, e2104006 (2022).

    Article 

    Google Scholar
     

  • Su, M. et al. Metagenomic analysis revealed differences in composition and function between liquid-associated and solid-associated microorganisms of sheep rumen. Front. Microbiol. 13, 851567 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jia, L. et al. Porphyromonas gingivalis and Lactobacillus rhamnosus GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2. Clin. Transl. Immunol. 9, e1213 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Shi, J. et al. Gut microbiota modulation and anti-inflammatory properties of mixed lactobacilli in dextran sodium sulfate-induced colitis in mice. Food Funct. 12, 5130–5143 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bhatia, R., Sharma, S., Bhadada, S. K., Bishnoi, M. & Kondepudi, K. K. Lactic acid bacterial supplementation ameliorated the lipopolysaccharide-induced gut inflammation and dysbiosis in mice. Front. Microbiol. 13, 930928 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eckstein, M. T., Moreno-Velasquez, S. D. & Perez, J. C. Gut bacteria shape intestinal microhabitats occupied by the fungus Candida albicans. Curr. Biol. 30, 4799–4807 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hwang, I. et al. Tissue-specific expression of occludin, zona occludens-1, and junction adhesion molecule A in the duodenum, ileum, colon, kidney, liver, lung, brain, and skeletal muscle of C57BL mice. J. Physiol. Pharmacol. 64, 11–18 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Duangnumsawang, Y., Zentek, J. & Goodarzi Boroojeni, F. Development and functional properties of intestinal mucus layer in poultry. Front. Immunol. 12, 745849 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wotzka, S. Y., Nguyen, B. D. & Hardt, W. D. Salmonella Typhimurium diarrhea reveals basic principles of enteropathogen infection and disease-promoted DNA exchange. Cell Host Microbe 21, 443–454 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vivinus-Nebot, M. et al. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 63, 744–752 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nagpal, R. & Yadav, H. Bacterial translocation from the gut to the distant organs: an overview. Ann. Nutr. Metab. 71, 11–16 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Galan, J. E. Salmonella Typhimurium and inflammation: a pathogen-centric affair. Nat. Rev. Microbiol. 19, 716–725 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moreno-Indias, I., Cardona, F., Tinahones, F. J. & Queipo-Ortuno, M. I. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front. Microbiol. 5, 190 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roediger, W. E. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 83, 424–429 (1982).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cani, P. D., Depommier, C., Derrien, M., Everard, A. & de Vos, W. M. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat. Rev. Gastroenterol. Hepatol. 19, 625–637 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Wang, L., Wu, J. & Wang, Y. The prevalence and treatment of diabetes in China from 2013 to 2018-reply. JAMA 327, 1706–1707 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Zheng, X. et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metab. 33, 791–803 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, N. et al. Non-alcoholic fatty liver disease and complications in type 1 and type 2 diabetes: a Mendelian randomization study. Diabetes Obes. Metab. 25, 365–376 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, H. et al. Adipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity. Nat. Commun. 10, 3254 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, Y. et al. Therapeutic luminal coating of the intestine. Nat. Mater. 17, 834–842 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Firrman, J. et al. Applying advanced in vitro culturing technology to study the human gut microbiota. J. Vis. Exp. 144, e59054 (2019).


    Google Scholar
     

  • Lock, J. Y., Carlson, T. L. & Carrier, R. L. Mucus models to evaluate the diffusion of drugs and particles. Adv. Drug Deliv. Rev. 124, 34–49 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar