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The gut digestive fluid of many invertebrates is acidified by the vesicular-type H+-ATPase (VHA). In contrast, vertebrates generate acidic gut fluids using the gastric H+\/K+-ATPase (HKA), an evolutionary innovation linked with the appearance of a true stomach that greatly improves digestion, absorption and immune function. Hagfishes are the most basal extant vertebrates, and their mechanism of digestive acidification remains unclear. Herein, we report that the stomachless Pacific hagfish (Eptatretus stoutii) acidify their gut using the VHA, and searches of E. stoutii gut transcriptomes and the genome of a closely related hagfish species (E. burgerii) indicate they lack HKA, consistent with its emergence following the 2R whole-genome duplication. Immunostaining revealed prominent VHA presence in the apical membrane of enterocytes and sub-apical expression of both VHA and soluble adenylyl cyclase. Interestingly, akin to vertebrates, VHA was also observed in immature pancreatic-like zymogen granules and was noticeably absent from the mature granules. Furthermore, isolated gut sacs from fed hagfish demonstrate increased VHA-dependent luminal H+ secretion that is stimulated by the cAMP pathway. Overall, these results suggest that the hagfish gut shares the trait of VHA-dependent acidification with invertebrates, while simultaneously performing some roles of the pancreas and intestine of gnathostomes.<\/jats:p>","DOI":"10.1242\/jeb.249641","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T10:46:03Z","timestamp":1738233963000},"source":"Crossref","is-referenced-by-count":4,"title":["Evolutionary insights into gut acidification: invertebrate-like mechanisms in the basal vertebrate hagfish"],"prefix":"10.1242","volume":"228","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5710-0035","authenticated-orcid":false,"given":"Alyssa M.","family":"Weinrauch","sequence":"first","affiliation":[{"name":"University of Alberta 1 Department of Biological Sciences , , 116 St and 85 Ave, Edmonton, AB , , T6G 2R3","place":["Canada"]},{"name":"Bamfield Marine Sciences Centre 2 , 100 Pachena Rd, Bamfield, BC , , V0R 1B0","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-2731","authenticated-orcid":false,"given":"Garfield T.","family":"Kwan","sequence":"additional","affiliation":[{"name":"Scripps Institution of Oceanography, University of California San Diego 3 Marine Biology Research Division , , 9500 Gilman Drive, La Jolla, CA 92093 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Giacomin","sequence":"additional","affiliation":[{"name":"University of Alberta 1 Department of Biological Sciences , , 116 St and 85 Ave, Edmonton, AB , , T6G 2R3","place":["Canada"]},{"name":"Bamfield Marine Sciences Centre 2 , 100 Pachena Rd, Bamfield, BC , , V0R 1B0","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4267-1043","authenticated-orcid":false,"given":"Ian A.","family":"Bouyoucos","sequence":"additional","affiliation":[{"name":"University of Manitoba 4 Department of Biological Sciences , , Winnipeg, MB , , R3T 2N2","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7090-9266","authenticated-orcid":false,"given":"Martin","family":"Tresguerres","sequence":"additional","affiliation":[{"name":"Scripps Institution of Oceanography, University of California San Diego 3 Marine Biology Research Division , , 9500 Gilman Drive, La Jolla, CA 92093 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0786-8868","authenticated-orcid":false,"given":"Greg G.","family":"Goss","sequence":"additional","affiliation":[{"name":"University of Alberta 1 Department of Biological Sciences , , 116 St and 85 Ave, Edmonton, AB , , T6G 2R3","place":["Canada"]},{"name":"Bamfield Marine Sciences Centre 2 , 100 Pachena Rd, Bamfield, BC , , V0R 1B0","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"2025032505535342500_JEB249641C1","first-page":"256","article-title":"Structure and histochemistry of the alimentary canal","volume-title":"The Biology of Myxine","author":"Adam","year":"1963"},{"key":"2025032505535342500_JEB249641C2","doi-asserted-by":"publisher","first-page":"C1071","DOI":"10.1152\/ajpcell.00284.2009","article-title":"Loss of the apical V-ATPase a-subunit VHA-6 prevents acidification of the intestinal lumen during a rhythmic behavior in C. elegans","volume":"297","author":"Allman","year":"2009","journal-title":"Am. 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