Abstract
Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.
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Data availability
The scRNA data have been deposited in the NCBI Sequence Read Archive (accession no. PRJNA1074271). The bacterial 16S rRNA-sequencing data have been deposited in the NCBI Sequence Read Archive (accession no. PRJNA1073670). The data supporting the findings of this study are available within the Article and its Supplementary Information files. All relevant data are available from the corresponding author. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Institutes of Health (NIH) (R01DK125087, R01DE030691, R01DE026728, R01DE031951, R01NS122536, R01CA210273, R01CA271799, R01CA271369, R01CA227622, R01CA222251, R01CA204969 and P30CA046592 to J.J.M. and U01DE033330 to Y.L.L.). Y. Xie is supported by NIH funding R01HL166508 and an NSF award IOS 2107215. D.N. is supported by a Rogel Cancer Center grant and a Forbes Scholar Award. We thank the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of MHC-I tetramers.
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Contributions
K.H., F.X. and J.J.M. designed the study. K.H. and F.X. performed the experiments. O.A., M.N., F.W., K.O., A.A., S.C. and D.N. assisted with the measurement and analysis of short-chain fatty acids and untargeted metabolomics. O.A. performed the machine learning analysis. J.J.O. assisted with the casein and peanut allergy model studies and provided useful discussion. S.K., Y.K. and N.K. assisted with the small intestine studies. M.T.P., Y.S.C., H.D. and Q.W. provided technical help with immune cell analyses in the colon and lungs. J.X., X.Z., X.H., J.A., M.T.P., X.A., Y. Xu and S.-H.L. provided technical help with flow cytometry, NMR and MALDI-TOF. A.K. assisted in the rheology test. Z.L., W.G., Y. Xie and Y.L.L. assisted with the scRNA-seq experiments and analysis. K.H., F.X. and J.J.M. interpreted the data and wrote the paper.
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Competing interests
Patent applications for inulin-gel-based treatment for allergies and other disorders have been filed in the USA, Europe, Japan, South Korea, China, Australia and Canada (US20230346826, WO2022066825, US20220347294 and WO2021061789), with J.J.M., K.H., F.X., J.X., X.H. and X.Z. as inventors. J.J.M. declares financial interests for board membership, as a paid consultant, for research funding, and/or as an equity holder in EVOQ Therapeutics and Saros Therapeutics. The University of Michigan has a financial interest in EVOQ Therapeutics, Inc. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Biosafety evaluation.
BALB/c mice were treated as in Fig. 1b. The bodyweight changes during OIT (a) and body weight on day 48 (b) were recorded. (c) Blood samples were collected for CBC test on day 48. (d) Serum samples were collected for biochemistry test on day 48. Data represent mean ± s.e.m. (n = 5 for Naive, 7 for Inulin gel/OVA (a), n = 5 for Naive, 8 for all other groups (b,c), n = 5 for Naive, 8 for all other groups in ALT and AST datasets, 3 for Naive, 8 for PBS or 7 for all other groups in BUN dataset, 2 for Naive, 8 for PBS and OVA, or 6 for Inulin gel/OVA in CREA dataset (d) biologically independent samples). ns: not significant. Data were analysed by one-way (b-d) or two-way ANOVA (a) with Bonferroni’s multiple comparisons test.
Extended Data Fig. 2 Inulin gel/OVA OIT protects against OVA challenges.
a, Therapeutic regimen. BALB/c mice were sensitized with alum/OVA on days 0 and 14. From day 29, the mice were orally gavaged with inulin gel (55 mg per dose), or inulin gel (55 mg per dose)/OVA (1 mg per dose). From day 49, mice were intragastrically (i.g.) challenged with OVA (50 mg per dose) on 6 alternating days. Shown are the (b) average body temperature change after the 6th challenge, (c) anaphylactic scores, (d) diarrhea occurrence rate, and (e) diarrhea severity during challenges. f, Diarrhea-induced body weight change after the 6th i.g. challenge. g, OVA-specific IgE levels in serum on days 48 and 55. Data represent mean ± s.e.m. (n = 8 biologically independent samples). Data were analysed by two-way ANOVA (b,c,e) with Bonferroni’s multiple comparisons test, or unpaired, two-sided Student’s t-test (f,g).
Extended Data Fig. 3 DP values of inulin affect OIT efficacy.
a, The DP values of inulin from different vendors were measured by 1HNMR and MALDI-TOF. b, BALB/c mice were treated as in Fig. 1b and received OIT treatments of inulin (DP7)/OVA, inulin gel (DP10)/OVA, and inulin gel (DP23)/OVA, respectively. Mice were i.g. challenged for 6 times. The body temperatures during the 6th i.g. challenge, the anaphylactic symptoms, diarrhea occurrence rate and severity during the challenges were recorded. c, The diarrhea images at the 3rd i.g. challenge. d, Average mast cells and the representative images in ileum. Data represent mean ± s.e.m. (In body temperature, n = 7 for Inulin (DP7)/OVA and Inulin gel (DP10)/OVA, or 8 for Inulin gel (DP23)/OVA, in all other datasets, n = 8 (b), n = 6 for Inulin (DP7)/OVA, Inulin gel (DP10)/OVA, 4 for Inulin gel (DP23)/OVA (d) biologically independent samples). ns, not significant. Data were analysed using two-way ANOVA (b), or one-way ANOVA (d) with Bonferroni’s multiple comparisons test.
Extended Data Fig. 4 In vitro Treg cell differentiation.
BMDCs were treated with inulin gel/OVA or inulin gel/OVA-II peptide for 24 h. BMDCs were washed and co-cultured with CFSE-labeled OT-II CD4+ T cells. Shown are the frequency of Foxp3+CD4+ T cells, proliferating CFSElow cells, and representative flow cytometry plots after 5 days of co-culture. Data represent mean ± s.e.m. (n = 4 biologically independent samples). Data were analysed by one-way ANOVA with Bonferroni’s multiple comparisons test.
Extended Data Fig. 5 Long-term protection.
Alum/OVA-sensitized mice received the indicated OIT treatment, followed by 4 times of i.g. challenges of OVA protein. The doses of inulin and OVA were 55 mg and 1 mg, respectively. All treatments were discontinued from day 55. From day 146, the mice were i.g. challenged with OVA. Shown are the body temperature drop, anaphylactic score, diarrhea score, and body weight change during the 5th i.g. re-challenge. Data represent mean ± s.e.m. (n = 5 for Naive, 7 for Inulin/OVA or 6 for all other groups, biologically independent samples). Data were analysed by one-way or two-way ANOVA with Bonferroni’s multiple comparisons test.
Extended Data Fig. 6 Microbes abundances in ileal contents.
Alum/OVA-sensitized BALB/c mice were treated as in Fig. 1b. Shown are the relative abundances of several genera in the ileal contents. Data represent mean ± s.e.m. (n = 5 for Naive, 7 for OVA or 8 for all other groups, biologically independent samples). Data were analysed by one-way ANOVA with Bonferroni’s multiple comparisons test.
Extended Data Fig. 7 Immunomodulatory guanosine as identified by metabolomics and machine learning based analyses.
Alum/OVA-sensitized BALB/c mice were treated as in Fig. 1b. a-b, Untargeted metabolome analysis in the ileal contents and feces. Shown are the sPL-SDA analysis of the metabolites in the ileal contents on day 49 and feces on day 48 (a), fold changes of metabolites (whose P-value is less than 0.05) in the ileal and fecal contents. The size of the circle denotes the fold change of upregulated metabolites in the inulin gel/OVA group, compared with naïve, PBS, OVA, and inulin/OVA groups. The P-values are unadjusted and are based on a two-sided t-test statistics (b). c-e, Metabolite-induced differentiation of CD4+ T cells in vitro. CD4+ T cells isolated from Foxp3(GFP) reporter mice were cultured with various metabolites in suboptimal Treg-inducing condition (1 µg/mL anti-CD3 antibody, 1 µg/mL anti-CD28 antibody, 5 ng/mL IL-2, and 1 ng/mL TGF-β) and analyzed on day 3 for Foxp3 expression (c). CD4+ T cells isolated from wide-type (WT) C57BL/6 mice were cultured with various metabolites in TH1-inducing condition (1 µg/mL anti-CD3 antibody, 1 µg/mL anti-CD28 antibody, 5 ng/mL IL-2, 10 ng/mL IL-12p40, and 10 μg/mL anti-IL-4 antibody) and analyzed on day 5 for IFN-γ secretion (d). CD4+ T cells isolated from WT C57BL/6 mice were cultured with various metabolites in TH2-inducing condition (1 µg/mL anti-CD3 antibody, 1 µg/mL anti-CD28 antibody, 5 ng/mL IL-2, 10 ng/mL IL-4, and 10 μg/mL anti-IFN-γ antibody) and analyzed on day 5 for IFN-γ secretion (e). f, Machine learning-based association study between ileal metabolomics and microbes at the family level. Only features with significant clusters were shown on the heatmap (Hallagram). g, Spearman’s correlation coefficient analyses between the relative abundances of ileal guanosine and Eggerthellaceae (family) or Enterorhabdus (genus). Data represent the mean ± s.e.m. from one of two independent experiments (n = 5 for Naive or 8 for all other groups (a), n = 6 for PBS and DMSO, or 4 for all other groups (c), n = 6 for PBS and DMSO, or 3 for all other groups (d,e) biologically independent samples). Data were analysed by one-way ANOVA with Bonferroni’s multiple comparisons test (c-e), or two-tailed Spearman’s rank correlation test (g).
Extended Data Fig. 8 OVA/guanosine OIT protects mice against allergen challenges.
a, Schema of the intestinal anaphylaxis and therapeutic regimen of OVA/guanosine OIT. BALB/c mice were sensitized with alum/OVA on days 0 and 14. From day 28, mice were orally gavaged with OVA (1 mg per dose) and provided with normal drinking water either with or without 37.5 µg/mL of guanosine (denoted OVA and OVA/guanosine, respectively). Inulin gel (55 mg per dose)/OVA (1 mg per dose) treated mice that were provided with normal drinking water were included as an additional control. From day 48, mice were i.g. challenged with OVA (50 mg per dose) on 4 alternating days. b, After the 4th i.g. challenge, changes in core body temperature were measured. c-e, Over the 4 consecutive i.g. challenges, animals were analyzed for anaphylactic scores (c), diarrhea severity score (d), and body weight change (e). Data represent the mean ± s.e.m. (n = 8 for Inulin gel/OVA or 7 for all other groups (b), n = 8 (c-e) biologically independent samples). Data were analysed by two-way ANOVA with Bonferroni’s multiple comparisons test.
Extended Data Fig. 9 Less frequent inulin gel/OVA OIT remains protective.
Schema of the intestinal anaphylaxis and therapeutic regimen. BALB/c mice were sensitized with alum/OVA on days 0 and 14. From day 29, mice were orally gavaged with PBS, OVA (1 mg per dose), or inulin gel (55 mg per dose)/OVA (1 mg per dose) every other day. From day 40, mice were i.g. challenged with OVA (50 mg per dose) on 6 alternating days. b, After the 6th i.g. challenge, changes in the average core body temperature were measured. c-f, Over the 6 consecutive i.g. challenges, animals were analyzed for anaphylactic scores (c), diarrhea severity score (d), diarrhea occurrence rate (e), and bodyweight drop (f). Data represent mean ± s.e.m. (n = 5 for Naive, 8 for PBS or 9 for Inulin gel/OVA (alternative) (b-f) biologically independent samples). Data were analysed by two-way ANOVA (b-d,f) with Bonferroni’s multiple comparisons test.
Extended Data Fig. 10 Inulin gel does not induce type 2 inflammatory response.
Naive C57BL/6 mice were fed with high (26%) inulin chow diet, control chow diet (0% inulin, PBS group), control chow diet plus inulin (55 mg/dose, 3 times per 4 days, inulin group), or control chow diet plus inulin gel (55 mg/dose, 3 times per 4 days, inulin gel group). On day 13, the frequencies of immune cells in the colon were detected: (a) eosinophils; (b) neutrophils; (c) Ly6Chigh monocytes; (d) CD64+ macrophages; (e) DCs; (f) B cells; (g) T cells. (h) The frequency of eosinophils in the lung. (i) The representative flow plot of eosinophils in the colon and lung. The concentrations of ω-MCA, CA, TCA, UDCA, DCA, and CDCA in the (j) serum, (k) feces, and (l) cecum on day 13. Data represent mean ± s.e.m. (n = 8 biologically independent samples). ns: not significant. Data were analysed by (a-h) one-way, or (j-l) two-way ANOVA with Bonferroni’s multiple comparisons test.
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Han, K., Xie, F., Animasahun, O. et al. Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy. Nat. Mater. (2024). https://doi.org/10.1038/s41563-024-01909-w
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DOI: https://doi.org/10.1038/s41563-024-01909-w
