High dietary fat intake induces a microbiota signature that promotes food allergy.

BACKGROUND: Diet-induced obesity and food allergies increase in tandem, but a potential cause-and-effect relationship between these diseases of affluence remains to be tested. OBJECTIVE: We sought to test the role of high dietary fat intake, diet-induced obesity, and associated changes in gut microbial community structure on food allergy pathogenesis. METHODS: Mice were fed a high-fat diet (HFD) for 12 weeks before food allergen sensitization on an atopic dermatitis-like skin lesion, followed by intragastric allergen challenge to induce experimental food allergy. Germ-free animals were colonized with a signature HFD or lean microbiota for 8 weeks before induction of food allergy. Food-induced allergic responses were quantified by using a clinical allergy score, serum IgE levels, serum mouse mast cell protease 1 concentrations, and type 2 cytokine responses. Accumulation of intestinal mast cells was examined by using flow cytometry and chloroacetate esterase tissue staining. Changes in the gut microbial community structure were assessed by using high-throughput 16S ribosomal DNA gene sequencing. RESULTS: HFD-induced obesity potentiates food-induced allergic responses associated with dysregulated intestinal effector mast cell responses, increased intestinal permeability, and gut dysbiosis. An HFD-associated microbiome was transmissible to germ-free mice, with the gut microbial community structure of recipients segregating according to the microbiota input source. Independent of an obese state, an HFD-associated gut microbiome was sufficient to confer enhanced susceptibility to food allergy. CONCLUSION: These findings identify HFD-induced microbial alterations as risk factors for experimental food allergy and uncouple a pathogenic role of an HFD-associated microbiome from obesity. Postdieting microbiome alterations caused by overindulgence of dietary fat might increase susceptibility to food allergy.

Tetraspanin-8 sequesters syntaxin-2 to control biphasic release propensity of mucin granules.

Agonist-mediated stimulated pathway of mucin and insulin release are biphasic in which rapid fusion of pre-docked granules is followed by slow docking and fusion of granules from the reserve pool. Here, based on a cell-culture system, we show that plasma membrane-located tetraspanin-8 sequesters syntaxin-2 to control mucin release. Tetraspanin-8 affects fusion of granules during the second phase of stimulated mucin release. The tetraspanin-8/syntaxin-2 complex does not contain VAMP-8, which functions with syntaxin-2 to mediate granule fusion. We suggest that by sequestering syntaxin-2, tetraspanin-8 prevents docking of granules from the reserve pool. In the absence of tetraspanin-8, more syntaxin-2 is available for docking and fusion of granules and thus doubles the quantities of mucins secreted. This principle also applies to insulin release and we suggest a cell type specific Tetraspanin/Syntaxin combination is a general mechanism regulating the fusion of dense core granules.