Environmental sensing mechanisms in intestinal homeostasis

The mucosal epithelium has 2 main functions: transport of nutrients and metabolic wastes and exclusion of microbial, chemical, and physical threats. These 2 functions operate at a cost to each other. Whereas the former requires barrier permeability, the latter requires barrier fortification. Thus, design of mucosal barriers must optimize the trade-off between transport and defense. At least 2 strategies have evolved to accommodate this trade-off. First, transport and defensive functions are segregated in different cell types. For example, absorptive enterocytes take up nutrients from the gut lumen, whereas Paneth and goblet cells produce antimicrobial peptides and mucins to protect the epithelium. Second, the performance of the 2 competing functions is adjusted on demand. Alterations in diet and pathogen load, for example, control nutrient processing machinery and antimicrobial response programs of the intestinal epithelium.1von Moltke J. Ji M. Liang H.E. Locksley R.M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit.Nature. 2016; 529: 221-225Crossref PubMed Scopus (723) Google Scholar,2Sullivan Z.A. Khoury-Hanold W. Lim J. Smillie C. Biton M. Reis B.S. et al.γδ T cells regulate the intestinal response to nutrient sensing.Science. 2021; 371eaba8310Crossref PubMed Scopus (50) Google Scholar This adjustment of transport and defensive barrier functions, which relies on the mucosal immune system, enables the organism to meet its nutritional needs when confronted with changes in its surroundings. The programmable nature of mucosal barriers requires systems to (1) detect changes in the environment and (2) initiate adaptive programs to accommodate those changes. Sensory systems, including the olfactory, gustatory, and gut chemosensory systems, detect fluctuations in food availability and quality and can directly influence gut absorptive function.3Florsheim E.B. Sullivan Z.A. Khoury-Hanold W. Medzhitov R. Food allergy as a biological food quality control system.Cell. 2021; 184: 1440-1454Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar On their own, however, these systems are limited in their ability to fortify mucosal barriers against the threat of pathogens and toxins. The mucosal immune system acts downstream of, and in concert with, nonimmune sensory systems to modify barrier function. During parasitic infection, for example, tuft cell secretion of IL-25 induces IL-13 production by type 2 innate lymphoid cells to cause tuft and goblet cell hyperplasia.1von Moltke J. Ji M. Liang H.E. Locksley R.M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit.Nature. 2016; 529: 221-225Crossref PubMed Scopus (723) Google Scholar In another case, γδ T cells promote reprogramming of intestinal epithelium to optimize carbohydrate digestion and absorption.2Sullivan Z.A. Khoury-Hanold W. Lim J. Smillie C. Biton M. Reis B.S. et al.γδ T cells regulate the intestinal response to nutrient sensing.Science. 2021; 371eaba8310Crossref PubMed Scopus (50) Google Scholar Thus, the mucosal immune system fine-tunes gut barrier function in response to a dynamic environment. The contents of the intestinal lumen can be divided into 3 types of variables: nutrients, pathogens and toxins, and commensals. Nutrients include both macronutrients (carbohydrates, proteins, and fats) and micronutrients (vitamins and minerals) and have a positive valence, whereas toxins and pathogens have a negative valence. The commensal microbiota, on the other hand, can have either a positive or negative valence depending on the dynamics of the commensal niche. To the benefit of the host, commensal microbes enhance nutrient extraction from the environment by breaking down otherwise nondigestible polysaccharides and synthesizing vitamins.4Jandhyala S.M. Talukdar R. Subramanyam C. Vuyyuru H. Sasikala M. Nageshwar Reddy D. Role of the normal gut microbiota.World J Gastroenterol. 2015; 21: 8787-8803Crossref PubMed Scopus (1308) Google Scholar They can also supplement host defense by producing antimicrobial compounds and outcompeting pathogens for resources. In exchange, the host maintains the commensal niche, but this alliance creates a vulnerability to microbes that can take advantage of the host’s provisions. By monitoring food compounds, commensal composition, and metabolic products, the organism can adjust gut barrier function in a context-dependent fashion. Compartmentalization of intestinal function further optimizes nutrient extraction. The small intestine absorbs macronutrients, whereas the colon hosts an abundance of commensal microbes. These functions are facilitated by distinct barrier properties: a thin mucus layer in the small intestine and a thick mucus layer in the colon. Nutrients, commensals, and their metabolites vary along the length of the intestine and promote distinct immune populations within each intestinal compartment.5Brown H. Esterházy D. Intestinal immune compartmentalization: implications of tissue specific determinants in health and disease.Mucosal Immunol. 2021; 14: 1259-1270Crossref PubMed Scopus (16) Google Scholar This immune regionalization, together with chemosensory systems, likely helps fine-tune barrier function in a location-dependent manner to maintain the ecosystem of the gut. How are dietary and commensal metabolites monitored, and what specific features are sensed? Several receptors can detect breakdown products of macronutrients, nonnutrient and micronutrient food chemicals, and microbial metabolites. The aryl hydrocarbon receptor (Ahr) binds ligands that derive from tryptophan (released subsequent to protein digestion) and plant secondary metabolites.6Stockinger B. Shah K. Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function.Nat Rev Gastroenterol Hepatol. 2021; 18: 559-570Crossref PubMed Scopus (71) Google Scholar Other plant-derived and steroid molecules are natural ligands for retinoic acid receptor–related orphan receptors,7Ladurner A. Schwarz P.F. Dirsch V.M. Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs).Nat Prod Rep. 2021; 38: 757-781Crossref PubMed Google Scholar and metabolites of vitamin A are detected by retinoic acid receptors and retinoid X receptors.8Hall J.A. Grainger J.R. Spencer S.P. Belkaid Y. The role of retinoic acid in tolerance and immunity.Immunity. 2011; 35: 13-22Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar At least 5 G protein–coupled receptors recognize short-chain fatty acids, which are produced by both commensal and pathogenic microbial fermentation of dietary fibers.9Liu P. Wang Y. Yang G. Zhang Q. Meng L. Xin Y. et al.The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis.Pharmacol Res. 2021; 165105420Crossref Scopus (127) Google Scholar For some of these sensors, the same receptor may detect multiple natural ligands, and the molecules that are sensed can be produced by distinct metabolic processes. Ligands of Ahr, for example, form from acid-catalyzed condensation reactions or microbial breakdown of dietary proligands.6Stockinger B. Shah K. Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function.Nat Rev Gastroenterol Hepatol. 2021; 18: 559-570Crossref PubMed Scopus (71) Google Scholar In addition to sensing microbial metabolites, the host can produce “molecular probes” that are metabolized by gut bacteria, thus providing information about specific metabolic activities of resident bacteria. Primary bile acids secreted into the duodenum for dietary lipid emulsification are converted into secondary bile acids by colonic bacteria if not reabsorbed in the ileum. Both primary and secondary bile acids are detected by host receptors and can have an immunomodulatory function.10Chen M.L. Takeda K. Sundrud M.S. Emerging roles of bile acids in mucosal immunity and inflammation.Mucosal Immunol. 2019; 12: 851-861Crossref PubMed Scopus (141) Google Scholar Although dedicated sensors have been identified for only a fraction of the compounds naturally present in the intestinal lumen, these examples illustrate multiple mechanisms to monitor luminal contents and microbial activity. What consequences do intestinal sensors have on host physiology? The available evidence supports a role in barrier maintenance and defense, with significant contribution of the mucosal immune system. Ahr ligands and short-chain fatty acids can act directly on intestinal epithelial cells to affect epithelial barrier integrity, turnover, and antimicrobial function.6Stockinger B. Shah K. Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function.Nat Rev Gastroenterol Hepatol. 2021; 18: 559-570Crossref PubMed Scopus (71) Google Scholar,9Liu P. Wang Y. Yang G. Zhang Q. Meng L. Xin Y. et al.The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis.Pharmacol Res. 2021; 165105420Crossref Scopus (127) Google Scholar Otherwise, environmental sensors can affect mucosal barriers indirectly by modulating mucosal immunity. Retinoic acid receptor–related orphan receptors and Ahr are critical for TH17 cell differentiation and innate lymphoid cell development,6Stockinger B. Shah K. Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function.Nat Rev Gastroenterol Hepatol. 2021; 18: 559-570Crossref PubMed Scopus (71) Google Scholar,7Ladurner A. Schwarz P.F. Dirsch V.M. Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs).Nat Prod Rep. 2021; 38: 757-781Crossref PubMed Google Scholar and Ahr-dependent IL-22 production by these cells supports the intestinal epithelium. In addition, retinoic acid promotes B-cell class switching to IgA,8Hall J.A. Grainger J.R. Spencer S.P. Belkaid Y. The role of retinoic acid in tolerance and immunity.Immunity. 2011; 35: 13-22Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar which is the major antibody isotype in mucosal secretions. Deficiency in environmental sensing and response machinery is often associated with intestinal inflammation.6Stockinger B. Shah K. Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function.Nat Rev Gastroenterol Hepatol. 2021; 18: 559-570Crossref PubMed Scopus (71) Google Scholar,7Ladurner A. Schwarz P.F. Dirsch V.M. Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs).Nat Prod Rep. 2021; 38: 757-781Crossref PubMed Google Scholar,10Chen M.L. Takeda K. Sundrud M.S. Emerging roles of bile acids in mucosal immunity and inflammation.Mucosal Immunol. 2019; 12: 851-861Crossref PubMed Scopus (141) Google Scholar Although not exhaustive, these examples highlight the ability of environmental sensing pathways to regulate mucosal barriers, both directly and through the immune system. Environmental sensors of mucosal tissues detect nutrients and nonnutrients and initiate programs to modify barrier function. This programming requires coordinated activity of epithelial and mucosal immune cells, both of which can participate as sensors, signal transducers, or responders (Fig 1). Many receptors have been identified as environmental sensors with the capacity to bind multiple natural ligands. These findings raise questions about how the host prioritizes information received from different sensors and the physiologic relevance of sensor promiscuity. Can environmental sensors distinguish ligand source (microbial or dietary) and influence barrier function accordingly? Absorptive and defensive barrier functions must be tightly regulated to minimize the respective risks of threat exposure and nutrient deficiency. How does the host decide to prioritize absorption versus defense? Presumably, this decision is based on some metric reflecting the chemical composition of the intestinal lumen, as well as the metabolic status of the host (such that deficiency in some metabolites may promote the appropriate absorptive functions, whereas malaise may promote defensive functions). Ultimately, the trade-off between absorption and defense is optimized by monitoring key signatures of chemical composition of the intestine. Deciphering the language of chemical communication at mucosal barriers is a challenge for future studies.