Written by Nick Trompeter, Ph.D., Cole Toohey, Payton Olson, Peter Lee, and Ken Dorko
Depiction of the intestine, with a close-up of the intestinal epithelium on the bottom right. Intestinal epithelial cells highlighted in include Goblet Cells, enteroendocrine cells, intestinal stem cells (Crypt Cells), and enterocytes. Created in BioRender.
In the intricate landscape of the human body, the gut and liver engage in a profound dialogue, orchestrating a symphony of signals that impact health and disease. This dynamic interplay, known as the gut-liver axis, is a burgeoning field of research with far-reaching implications. Let's embark on a journey through the inner workings of this fascinating relationship, exploring its key components and implications for health, particularly focusing on non-alcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD).
Mucus: A Protective Barrier
Within the intestinal milieu, a thick layer of mucus serves as the first line of defense, shielding the epithelium from microbial intrusion. The composition and thickness of the mucus changes as you progress distally in the intestinal tracts. However, the glycoprotein Mucin-2 remains the main component of mucus in the small and large intestines. In the small intestine, a single layer of mucus allows for absorption of nutrients, due to its discontinuous and more permeable nature. Meanwhile, the colonic mucosal barrier is comprised of two distinct layers, a thicker inner layer, 40 -240 µm in width, and a thinner outer layer (~50 µm). In the colon, the outer gel-like matrix acts as a habitat for beneficial microbes, while impeding the passage of pathogens within the predominantly sterile inner mucosal barrier.(1)
The outer layer of mucus in the colon and the single layer of mucus within the small intestine provide a carbon rich energy source for the microflora within the gut. The bacteria residing within the intestines are predominantly Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, and Verrucomicrobia, which, secrete proteases to digest the carbohydrate filled mucus as nutrition. The production of galactosidases, glucosaminidases, fucosidases, sialidases, and sulphatases by commensal bacteria allows for consumption of post-translational modification of mucins.(2,4)
While mucus provides a physical and biochemical barrier to the epithelium of the large intestine and colon, the body utilizes other defensive mechanisms to protect itself while promoting a healthy microbiota. Paneth cells, within the epithelium, produce a variety of proteolytic enzymes and proteins as a barrier, such as defensins, lysozymes, regenerating islet-derived 3 peptides and IgA. While these proteins and enzymes protect the intestine from the microbiota, it is also hypothesized the IgA and other factors promote immune tolerance and selection of bacteria for each individual person.(3)
Bile Acids: Masters of Microbial Control
Intestinal epithelial signaling and metabolites from gut microbiota influence the signaling and physiology within the liver. However, the liver can also regulate the microflora through bile acids. Bile acids, traditionally recognized for their role in fat digestion, emerge as central players in shaping the gut microbiota. Through intricate signaling pathways, bile acids exert selective pressure on microbial communities, influencing their composition and function. The role of bile acids to modulate colonic microbiota works both indirectly and directly. Taurine and glycine are conjugated to primary bile acids by hepatocytes through Phase I and Phase II metabolism. These conjugated bile acids (namely cholic acid and chenodeoxycholic acid) are released into the ileum from enterohepatic circulation, with a small portion entering the colon. Once in the colon, microbiota cleave taurine or glycine residues from conjugated primary bile acids to allow thefor metabolism into secondary bile acids. Secondary bile acids produced by the bacteria serve as protectants from pathogenic bacteria, by either limiting availability of primary bile acids or by the antifungal properties innate to secondary bile acids.(4)
In addition to the interaction of bile acids with microbes, intestinal epithelial barrier function is mediated by nuclear bile acid receptors and membrane-bound receptors. Increased intestinal permeability induced by a high fat diet elicits an increase in the conjugated primary bile acid pool. This increase in conjugated bile acids decreases markers of tight junction function of the epithelium, namely zona occludens. In rodent models of bile flow obstruction, increased intestinal permeability can be abrogated by activation of nuclear bile acid receptors. This indicates the importance of bile acids in maintaining a health in the intestine.(4)
Intestinal Barrier: Guardian of Homeostasis
Beneath the mucus layer, a delicate monolayer of epithelial cells forms the intestinal barrier. Tight junctions, maintain the integrity of the epithelial cells. compose of various epithelial cell types. All cells within the intestinal epithelium are derived from intestinal stem cells, but unique cell populations differentiate from these stem cells to provide specific function in digestion, immunity, and homeostasis. Essential to intestinal cell differentiation is Notch signaling, driving cell fate towards the terminal populations of the intestinal epithelium: Paneth cells, Goblet cells, enteroendocrine cells, and enterocytes. In addition to deriving from a single progenitor cell, these various epithelial cells work in concert to ensure homeostasis within the intestine.
Paneth cells , as mentioned previously, secrete various antimicrobial factors from within the crypt villus to prevent small intestinal bacterial overgrowth, which can elicit deleterious effects on the gut and systemic physiology. The mechanisms involved in host-defense extend beyond the breadth of this article but include defensins, lectins, IgGA, and other proteases that can bind and penetrate the bacterial cell wall. Additional mechanisms of action of antimicrobial agents can be found in the studies of Chairatana and Nolan, 2016.(5)
Goblet cells produce mucins to provide a protective barrier within the colon, with the mucus serving as a lubricant and an energy source for commensal bacteria. During the secretion process of mucins, they undergo important post-translational modifications within the Golgi apparatus. The addition of glycan moieties to mucins, such as mannose, xylose, N-acetylgalactosamine, and O-linked glycosylation, allows for integration of de novo mucin synthesis into the mucus layer. Branching of glycans, which comprises 80% of secreted mucins, is terminated with sialic acid, fucose, sulfate, and N-acetylgalactosamine groups. The post-translation modifications of mucins within the Golgi apparatus influences and selects for specific commensal bacteria, as highlighted by the differences in normal microbiota between humans and mice.(6) This selection pressure also drives the specific ability of bacterial to remodel and degrade the mucus and glycans within the mucosal barrier, creating a symbiotic relationship.
Enteroendocrine cells (EECs) are interspersed amongthroughout the other epithelial cells and perform integral functions for intestinal homeostasis by releasingthrough the release of hormones and other factors important for physiological responses to digestion and microbial stimuli. These cells possess villi structures that expand from the apical membrane into the lumen of the intestine. Interestingly, enteroendocrine cells also contain basolateral processes that extend towards neighboring epithelial cells. Secretory granules are a hallmark of enteroendocrine cells characterization, from which hormones and other peptides are secreted. The secretion of serotonin, somatostatin, peptide YY, and glucagon-like peptide 1 and 2, by enteroendocrine cells allows for physiological responses to feeding. These secreted factors of EECs provide feedback to the neurocrine, hepatic, and pancreatic systems. Serotonin release from EECs appears to influence the response to small chain fatty acid metabolites from bacteria and stimulates gastric motility, which may be partially responsible for colonic motility in Inflammatory Bowel Disease (IBD). Somatostatin inhibits digestive hormones, including a self-involved negative feedback mechanism that exert influence on pancreatic cells.(9)
Enterocytes account for a large portion of the intestinal epithelium, which were originally postulated to only provide a barrier against infections and for their absorption properties for nutrients, water, salts, and bile acids. However, in the past two decades, their role in gut microbiota tolerance and immune function has been identified. Differential roles of enterocytes exist across the intestinal tracts, with nutrient absorption occurring within the small intestine and electrolyte, vitamin, and water absorption taking place within the colon. With regards to immunological tolerance evoked by enterocytes, these cells possess and can produce MHC-II-peptide complexes and express neonatal Fc receptors expression, both of which are released from the basolateral membranes of enterocytes.(7)
To form a functional epithelial barrier, the epithelial poles of the various epithelial cells and immune cells embedded within the epithelium utilize more than 50 different proteins to form a junctional barrier. Tight junctions at the apicolateral border connect the cytoskeleton of the cells involved to preserves the morphological characteristics of these various cell types. Zona occludens, junctional adhesion molecule, and claudins are suggested to be the key tight junction proteins responsible for maintenance of intestinal permeability. Regulation of the tight junction occurs through an intracellular signaling cascade that involves modulation of myosin light chains, GTPase signaling, and proteins usually associated with growth factor induction, such as MAPK.(8)
References
1. Herath, M., Hosie, S., Bornstein, J.C., Franks, A.E., and Hill-Yardin, E.L. (2020). The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders. Preprint at Frontiers Media S.A., https://doi.org/10.3389/fcimb.2020.00248 https://doi.org/10.3389/fcimb.2020.00248.
2. Loomba, R., Seguritan, V., Li, W., Long, T., Klitgord, N., Bhatt, A., Dulai, P.S., Caussy, C., Bettencourt, R., Highlander, S.K., et al. (2017). Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab 25, 1054-1062.e5. https://doi.org/10.1016/j.cmet.2017.04.001.
3. Peterson, D.A., Frank, D.N., Pace, N.R., and Gordon, J.I. (2008). Metagenomic Approaches for Defining the Pathogenesis of Inflammatory Bowel Diseases. Preprint, https://doi.org/10.1016/j.chom.2008.05.001 https://doi.org/10.1016/j.chom.2008.05.001.
4. Larabi, A.B., Masson, H.L.P., and Bäumler, A.J. (2023). Bile acids as modulators of gut microbiota composition and function. Preprint at Taylor and Francis Ltd., https://doi.org/10.1080/19490976.2023.2172671 https://doi.org/10.1080/19490976.2023.2172671.
5. Chairatana, P., Chu, H., Castillo, P.A., Shen, B., Bevins, C.L., and Nolan, E.M. (2016). Proteolysis triggers self-assembly and unmasks innate immune function of a human α-defensin peptide. Chem Sci 7, 1738–1752. https://doi.org/10.1039/c5sc04194e.
6. Arike, L., and Hansson, G.C. (2016). The Densely O-Glycosylated MUC2 Mucin Protects the Intestine and Provides Food for the Commensal Bacteria. Preprint at Academic Press, https://doi.org/10.1016/j.jmb.2016.02.010 https://doi.org/10.1016/j.jmb.2016.02.010.
7. Miron, N., and Cristea, V. (2012). Enterocytes: Active cells in tolerance to food and microbial antigens in the gut. Preprint, https://doi.org/10.1111/j.1365-2249.2011.04523.x https://doi.org/10.1111/j.1365-2249.2011.04523.x.
8. Lee, B., Moon, K.M., and Kim, C.Y. (2018). Tight junction in the intestinal epithelium: Its association with diseases and regulation by phytochemicals. Preprint at Hindawi Limited, https://doi.org/10.1155/2018/2645465 https://doi.org/10.1155/2018/2645465.
9. Gunawardene, A.R., Corfe, B.M., and Staton, C.A. (2011). Classification and functions of enteroendocrine cells of the lower gastrointestinal tract. Preprint, https://doi.org/10.1111/j.1365-2613.2011.00767.x https://doi.org/10.1111/j.1365-2613.2011.00767.x.
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