We demonstrate, for the first time that we are aware of, that taste function is altered in an animal model of IBD. Chronic colitis reduced sweet taste transmission to the brain, in parallel with the downregulation of the Tas1r2 sweet receptor subunit in oral taste receptor cells. DSS treatment suppressed neural responses to a wide range of natural and artificial sweeteners. Only the two lowest concentrations of sucrose and aceK were unaffected by DSS (Fig. 4a, c), likely because responses were near zero creating a “floor effect”. Chronic DSS also modestly elevated responses to 0.3M MSG and upregulated expression of the Tas1r1 subunit that transduces umami stimuli in taste cells. While we did not perform behavioral taste testing, we previously showed that milder, chronic gut inflammation suppressed brief-access licking and 23-hr licking in addition to CT responses to sweet stimuli24. Thus, reduced neural responsiveness could potentially impair behavioral sensitivity to sweet tastants.
Several studies indicate that sweet taste may also be dysregulated in IBD patients. Patients with Crohn’s disease exhibit higher taste thresholds for sucrose compared to control subjects, which may lead to overconsumption of sugar7,34. In other studies, however, IBD patients exhibited lower sensitivity to multiple taste modalities11, reduced sensitivity to bitter, salty, umami and fat but increased sour sensitivity12, or reduced sensitivity to multiple modalities except sour10. Others report no taste changes in patients13. Studies on IBD-induced taste dysfunction may lack consensus because of the inclusion of patients with both Crohn’s disease and ulcerative colitis, patients in different stages of flare-up and remission, varied dietary and environmental conditions, sex differences and the use of different methods to test taste sensitivity1,2,7,8,10–13. In the current chronic study, we used male mice because acute disease symptoms were more pronounced, likely due to more robust inflammatory responses and protective effects of estrogen in the DSS model31,35. Additional studies will determine whether female mice with colitis exhibit similar changes in sweet and umami taste function. Nonetheless, these results highlight the value of DSS-induced colitis in revealing mechanisms underlying taste changes in animals with defined environmental conditions and genetic backgrounds.
In addition to DSS, dietary and gut manipulations can alter peripheral taste function in rodents. Acute or chronic oral LPS gavage increased neutrophils in the colon, as shown here, and suppressed neural and behavioral responses to sweet stimuli24,25. LPS also reduced CT nerve and behavioral responses to NaCl, but treated mice did not exhibit weight loss or sickness behavior unlike DSS suggesting divergent mechanisms24. Dietary manipulations with and without changes in body weight can also affect taste. Rats chronically consuming 30% sucrose solution did not gain significantly more weight compared to groups fed solid high-sucrose or control food, but CT nerve taste responses to sweet and salty stimuli decreased36. Fewer taste receptor cells responded to sweet stimuli and behavioral detection of sucrose and aceK was impaired in obese mice fed a high-fat diet 37. The same investigators showed that a high-fat diet, with and without weight gain, reduced the expression of gustducin and PLCβ2 downstream from sweet, umami and bitter receptor signaling as a mechanism for dampened taste responses38. The regulation of downstream taste transduction molecules in colitis, in addition to the decrease in sweet subunit expression identified here, will be of interest in future studies.
Mechanisms by which the inflamed colon affect taste buds remain to be determined. DSS is unlikely to damage taste buds directly since the lingual tissue structure is intact. The taste cell marker gene, K8, was also expressed at similar levels in DSS and control groups, indicating that taste buds do not undergo significant degeneration in mice with colitis. Though inflammation can regulate taste function39,40, we found no evidence of increased immune cell responses near taste buds in DSS-treated vs. control mice. IBD can cause zinc deficiency41,42, which impairs behavioral and neural taste responsiveness in rodents43–45. In previous studies, however, zinc deficiency suppressed CT responses to multiple taste qualities (i.e. NaCl, QHCl, HCl, NH4Cl, and glutamic acid)44. We did not measure serum zinc levels here, but found more restricted changes in neural responses to sweet stimuli and MSG. Malnourishment is a common symptom of IBD, and DSS-treated mice lost weight in the current study. Yet, CT responses to sodium were specifically impaired in rats maintained on a protein-deficient diet prenatally through adulthood46. Thus, there are mismatches in the taste modalities affected by dietary zinc and protein deficiency compared to mice with colitis.
DSS-induced colitis alters cytokine levels in serum as well as colon, providing a potential route of communication between the inflamed gut and taste buds. Circulating Th1-Th17 responses (i.e. TNF-α, IL-6, IL-17, CXCL-1) dominate in the acute phase after DSS treatment, while Th2 cytokines (i.e. IL-4 and IL-10) are chronically upregulated in mice with colitis47,48. Oral taste bud cells express receptors for cytokines including TNF, IL-1, IL-6, and IL-10, which can also affect their function and life span49–54. Yet, the specific changes in sweet and umami taste observed in mice with chronic colitis limit potential upstream mechanisms. The Th2 cytokine, IL-10, is important for mucosal homeostasis55, and IL-10Rα (IL-10R1), the ligand-binding subunit of the IL-10 receptor, is co-localized to T1R3 + sweet- and umami-sensing taste cells50. However, serum IL-10 levels are elevated in mice with chronic DSS-induced colitis, while taste bud number and size decreased in the absence of IL-1047,48,50. The microbiota of the tongue, saliva and the GI tract is dysregulated in mice with colitis and patients with IBD56–58, which also could alter taste function. Type II taste cells express a genetic signature and possibly functions similar to microfold (M) cells that surveil mucosal-associated lymphoid tissues (MALT)59. Mice deficient in Spib, a transcription factor critical for M cell development, displayed increased licking responses to sucrose and MPG59,60. While the parallels are imperfect, since neural responses to sweet and umami stimuli were inversely altered here, taste changes in colitis could depend on inflammatory or microbial dysregulation60,61.
In conclusion, we report novel taste changes in male mice with chronic colitis. Tas1r2 expression is suppressed and Tas1r1 elevated in taste buds, mediating decreased sweet and heightened umami neural inputs to the brain. Chemosensory cells and receptor proteins in the gut and airway act as sentinels for microbes and coordinate inflammatory and neural responses20,62–65. These results, together with previous studies24,25, indicate that taste buds are also modulated by gut inflammation, which may in turn affect diet and nutrition. Changes in taste function could lead to excess consumption of palatable foods or nutritional deficits further exacerbating IBD, warranting further investigation66–69.