The composition of the gut microbiota in patients with bronchiectasis has been proven to be distinct from that of healthy individuals, and this disrupted gut microbiota can exacerbate lung infections. However, the responsible microbes and mechanisms in the “gut-lung” axis in bronchiectasis remain unknown. Here, we report that Eggerthella lenta was enriched in the gut, and taurine ursodeoxycholic acid (TUDCA) was enriched in both the guts and sera of patients with bronchiectasis, with both being associated with disease severity. Fecal microbiota transfer from patients with bronchiectasis as well as administration of E. lenta independently exacerbated pulmonary Pseudomonas aeruginosa infections in murine models. E. lenta –associated TUDCA bound adenosine monophosphate–activated protein kinase (AMPK) within neutrophils and interfered with the interaction between liver kinase B1 and AMPK, with a consequential decrease in AMPK phosphorylation. This ultimately reduced ATP production in neutrophils, inhibited their function, and compromised P. aeruginosa elimination from the lung, aggravating tissue injury. Metformin treatment improved disease severity and outcome in the mouse models. In sum, the gut bacterium E. lenta raises the stakes of bacterial lung infection because it causes dysfunction of neutrophils circulated from serum to lung via the metabolite TUDCA. Interventions targeting E. lenta or AMPK phosphorylation may serve as adjunctive strategies to complement existing approaches for managing chronic pulmonary infection in bronchiectasis and other chronic respiratory disease states.
{"title":"A gut Eggerthella lenta –derived metabolite impairs neutrophil function to aggravate bacterial lung infection","authors":"Le-Le Wang, Xiyue Shen, Yingzhou Xie, Ai Ge, Haiwen Lu, Shuyi Gu, Lingxin Kong, Jayanth Kumar Narayana, Jochen Mattner, Sanjay H. Chotirmall, Jin-Fu Xu","doi":"10.1126/scitranslmed.adq4409","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq4409","url":null,"abstract":"The composition of the gut microbiota in patients with bronchiectasis has been proven to be distinct from that of healthy individuals, and this disrupted gut microbiota can exacerbate lung infections. However, the responsible microbes and mechanisms in the “gut-lung” axis in bronchiectasis remain unknown. Here, we report that <jats:italic>Eggerthella lenta</jats:italic> was enriched in the gut, and taurine ursodeoxycholic acid (TUDCA) was enriched in both the guts and sera of patients with bronchiectasis, with both being associated with disease severity. Fecal microbiota transfer from patients with bronchiectasis as well as administration of <jats:italic>E. lenta</jats:italic> independently exacerbated pulmonary <jats:italic>Pseudomonas aeruginosa</jats:italic> infections in murine models. <jats:italic>E. lenta</jats:italic> –associated TUDCA bound adenosine monophosphate–activated protein kinase (AMPK) within neutrophils and interfered with the interaction between liver kinase B1 and AMPK, with a consequential decrease in AMPK phosphorylation. This ultimately reduced ATP production in neutrophils, inhibited their function, and compromised <jats:italic>P. aeruginosa</jats:italic> elimination from the lung, aggravating tissue injury. Metformin treatment improved disease severity and outcome in the mouse models. In sum, the gut bacterium <jats:italic>E. lenta</jats:italic> raises the stakes of bacterial lung infection because it causes dysfunction of neutrophils circulated from serum to lung via the metabolite TUDCA. Interventions targeting <jats:italic>E. lenta</jats:italic> or AMPK phosphorylation may serve as adjunctive strategies to complement existing approaches for managing chronic pulmonary infection in bronchiectasis and other chronic respiratory disease states.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"27 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Binbin Ying, Kewang Nan, Qing Zhu, Tom Khuu, Hana Ro, Sophia Qin, Shubing Wang, Karen Jiang, Yonglin Chen, Guangyu Bao, Josh Jenkins, Andrew Pettinari, Johannes Kuosmanen, Keiko Ishida, Niora Fabian, Aaron Lopes, Flavia Codreanu, Joshua Morimoto, Jason Li, Alison Hayward, Robert Langer, Giovanni Traverso
Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.
{"title":"An electroadhesive hydrogel interface prolongs porcine gastrointestinal mucosal theranostics","authors":"Binbin Ying, Kewang Nan, Qing Zhu, Tom Khuu, Hana Ro, Sophia Qin, Shubing Wang, Karen Jiang, Yonglin Chen, Guangyu Bao, Josh Jenkins, Andrew Pettinari, Johannes Kuosmanen, Keiko Ishida, Niora Fabian, Aaron Lopes, Flavia Codreanu, Joshua Morimoto, Jason Li, Alison Hayward, Robert Langer, Giovanni Traverso","doi":"","DOIUrl":"","url":null,"abstract":"<div >Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 787","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shishodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang
Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA−/− HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha−/− and Bckdhb−/− mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
{"title":"BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease","authors":"Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shishodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang","doi":"","DOIUrl":"","url":null,"abstract":"<div >Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the <i>branched-chain α-ketoacid dehydrogenase E1</i>α (<i>BCKDHA</i>), <i>E1</i>β (<i>BCKDHB</i>), or <i>dihydrolipoamide branched-chain transacylase</i> (<i>DBT</i>) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized <i>BCKDHA</i> and <i>BCKDHB</i> (rAAV9.h<i>A</i>-BiP-h<i>B</i>) to the liver, muscle, heart, and brain. rAAV9.h<i>A</i>-BiP-h<i>B</i> restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in <i>BCKDHA<sup>−/−</sup></i> HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 10<sup>14</sup> vector genomes per kilogram. In two models of severe MSUD (<i>Bckdha<sup>−/−</sup></i> and <i>Bckdhb<sup>−/−</sup></i> mice) and a newborn calf homozygous for <i>BCKDHA</i> c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time <i>BCKDHA-BCKDHB</i> systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 787","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liana Hatoum, Hannah Song, David Alexander, Victor O. Omojola, Hannah Moore, Julia N. Frank, Edward A. Botchwey, Manu O. Platt
Sickle cell disease (SCD) is a hereditary blood disorder that causes sickling of red blood cells under deoxygenation, which stiffens and damages the cells. Individuals homozygous for the mutant β-globin S allele (SS) endure complications including progressive arterial damage and heightened risk of stroke. The effectiveness of bone marrow transplantation (BMT), now the only curative treatment for SCD, in halting or reversing SCD-mediated arteriopathy remains unclear. This study used two distinct conditioning regimens, x-ray irradiation and chemotherapy, in a Townes humanized murine model of SCD. Mice homozygous for the SS allele underwent BMT at 2 or 4 months of age, time points that we deemed early or late, respectively. Label-free magnetic resonance angiography (MRA) was performed to longitudinally monitor common carotid artery luminal areas in living mice pre- and repeatedly post-BMT, followed by histological analysis of the arteries at euthanasia. Myeloablative chemotherapy demonstrated higher survivability in SS mice compared with x-ray irradiation. SS mice exhibited arterial outward expansion by 3 months and thinning of the medial layer at 5 months, which are characteristics of a weakened arterial wall. BMT at 2 months effectively halted this expansion, maintaining smaller luminal areas in SS mice. However, BMT at 4 months did not reverse arteriopathy, indicating the importance of early intervention. This work emphasizes how MRA can be used as a noninvasive method for assessing arteriopathy progression and demonstrates that the timing of BMT is crucial in mitigating sickle cell–induced large artery remodeling.
{"title":"Bone marrow transplant protects mice from sickle cell–mediated large artery remodeling","authors":"Liana Hatoum, Hannah Song, David Alexander, Victor O. Omojola, Hannah Moore, Julia N. Frank, Edward A. Botchwey, Manu O. Platt","doi":"","DOIUrl":"","url":null,"abstract":"<div >Sickle cell disease (SCD) is a hereditary blood disorder that causes sickling of red blood cells under deoxygenation, which stiffens and damages the cells. Individuals homozygous for the mutant β-globin S allele (SS) endure complications including progressive arterial damage and heightened risk of stroke. The effectiveness of bone marrow transplantation (BMT), now the only curative treatment for SCD, in halting or reversing SCD-mediated arteriopathy remains unclear. This study used two distinct conditioning regimens, x-ray irradiation and chemotherapy, in a Townes humanized murine model of SCD. Mice homozygous for the SS allele underwent BMT at 2 or 4 months of age, time points that we deemed early or late, respectively. Label-free magnetic resonance angiography (MRA) was performed to longitudinally monitor common carotid artery luminal areas in living mice pre- and repeatedly post-BMT, followed by histological analysis of the arteries at euthanasia. Myeloablative chemotherapy demonstrated higher survivability in SS mice compared with x-ray irradiation. SS mice exhibited arterial outward expansion by 3 months and thinning of the medial layer at 5 months, which are characteristics of a weakened arterial wall. BMT at 2 months effectively halted this expansion, maintaining smaller luminal areas in SS mice. However, BMT at 4 months did not reverse arteriopathy, indicating the importance of early intervention. This work emphasizes how MRA can be used as a noninvasive method for assessing arteriopathy progression and demonstrates that the timing of BMT is crucial in mitigating sickle cell–induced large artery remodeling.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 787","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1126/scitranslmed.ads0539
Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shishodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang
Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1 α ( BCKDHA ), E1 β ( BCKDHB ), or dihydrolipoamide branched-chain transacylase ( DBT ) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.h A -BiP-h B ) to the liver, muscle, heart, and brain. rAAV9.h A -BiP-h B restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA −/− HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 10 14 vector genomes per kilogram. In two models of severe MSUD ( Bckdha −/− and Bckdhb −/− mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
{"title":"BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease","authors":"Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shishodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang","doi":"10.1126/scitranslmed.ads0539","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads0539","url":null,"abstract":"Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the <jats:italic>branched-chain α-ketoacid dehydrogenase E1</jats:italic> α ( <jats:italic>BCKDHA</jats:italic> ), <jats:italic>E1</jats:italic> β ( <jats:italic>BCKDHB</jats:italic> ), or <jats:italic>dihydrolipoamide branched-chain transacylase</jats:italic> ( <jats:italic>DBT</jats:italic> ) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized <jats:italic>BCKDHA</jats:italic> and <jats:italic>BCKDHB</jats:italic> (rAAV9.h <jats:italic>A</jats:italic> -BiP-h <jats:italic>B</jats:italic> ) to the liver, muscle, heart, and brain. rAAV9.h <jats:italic>A</jats:italic> -BiP-h <jats:italic>B</jats:italic> restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in <jats:italic> BCKDHA <jats:sup>−/−</jats:sup> </jats:italic> HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 10 <jats:sup>14</jats:sup> vector genomes per kilogram. In two models of severe MSUD ( <jats:italic> Bckdha <jats:sup>−/−</jats:sup> </jats:italic> and <jats:italic> Bckdhb <jats:sup>−/−</jats:sup> </jats:italic> mice) and a newborn calf homozygous for <jats:italic>BCKDHA</jats:italic> c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time <jats:italic>BCKDHA-BCKDHB</jats:italic> systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"28 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The composition of the gut microbiota in patients with bronchiectasis has been proven to be distinct from that of healthy individuals, and this disrupted gut microbiota can exacerbate lung infections. However, the responsible microbes and mechanisms in the “gut-lung” axis in bronchiectasis remain unknown. Here, we report that Eggerthella lenta was enriched in the gut, and taurine ursodeoxycholic acid (TUDCA) was enriched in both the guts and sera of patients with bronchiectasis, with both being associated with disease severity. Fecal microbiota transfer from patients with bronchiectasis as well as administration of E. lenta independently exacerbated pulmonary Pseudomonas aeruginosa infections in murine models. E. lenta–associated TUDCA bound adenosine monophosphate–activated protein kinase (AMPK) within neutrophils and interfered with the interaction between liver kinase B1 and AMPK, with a consequential decrease in AMPK phosphorylation. This ultimately reduced ATP production in neutrophils, inhibited their function, and compromised P. aeruginosa elimination from the lung, aggravating tissue injury. Metformin treatment improved disease severity and outcome in the mouse models. In sum, the gut bacterium E. lenta raises the stakes of bacterial lung infection because it causes dysfunction of neutrophils circulated from serum to lung via the metabolite TUDCA. Interventions targeting E. lenta or AMPK phosphorylation may serve as adjunctive strategies to complement existing approaches for managing chronic pulmonary infection in bronchiectasis and other chronic respiratory disease states.
{"title":"A gut Eggerthella lenta–derived metabolite impairs neutrophil function to aggravate bacterial lung infection","authors":"Le-Le Wang, Xiyue Shen, Yingzhou Xie, Ai Ge, Haiwen Lu, Shuyi Gu, Lingxin Kong, Jayanth Kumar Narayana, Jochen Mattner, Sanjay H. Chotirmall, Jin-Fu Xu","doi":"","DOIUrl":"","url":null,"abstract":"<div >The composition of the gut microbiota in patients with bronchiectasis has been proven to be distinct from that of healthy individuals, and this disrupted gut microbiota can exacerbate lung infections. However, the responsible microbes and mechanisms in the “gut-lung” axis in bronchiectasis remain unknown. Here, we report that <i>Eggerthella lenta</i> was enriched in the gut, and taurine ursodeoxycholic acid (TUDCA) was enriched in both the guts and sera of patients with bronchiectasis, with both being associated with disease severity. Fecal microbiota transfer from patients with bronchiectasis as well as administration of <i>E. lenta</i> independently exacerbated pulmonary <i>Pseudomonas aeruginosa</i> infections in murine models. <i>E. lenta</i>–associated TUDCA bound adenosine monophosphate–activated protein kinase (AMPK) within neutrophils and interfered with the interaction between liver kinase B1 and AMPK, with a consequential decrease in AMPK phosphorylation. This ultimately reduced ATP production in neutrophils, inhibited their function, and compromised <i>P. aeruginosa</i> elimination from the lung, aggravating tissue injury. Metformin treatment improved disease severity and outcome in the mouse models. In sum, the gut bacterium <i>E. lenta</i> raises the stakes of bacterial lung infection because it causes dysfunction of neutrophils circulated from serum to lung via the metabolite TUDCA. Interventions targeting <i>E. lenta</i> or AMPK phosphorylation may serve as adjunctive strategies to complement existing approaches for managing chronic pulmonary infection in bronchiectasis and other chronic respiratory disease states.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 787","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adq4409","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chih-Chun Lin, Ke-Chu Fang, Ilaria Balbo, Ting-Yu Liang, Chia-Wei Liu, Wen-Chuan Liu, Yi-Mei Wang, Yen-Ling Hung, Kai-Chien Yang, Scott Kun Geng, Chun-Lun Ni, Christopher P. Driscoll, David S. Ruff, Ami Kumar, Nadia Amokrane, Natasha Desai, Phyllis L. Faust, Elan D. Louis, Sheng-Han Kuo, Ming-Kai Pan
Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell–specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.
{"title":"Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients","authors":"Chih-Chun Lin, Ke-Chu Fang, Ilaria Balbo, Ting-Yu Liang, Chia-Wei Liu, Wen-Chuan Liu, Yi-Mei Wang, Yen-Ling Hung, Kai-Chien Yang, Scott Kun Geng, Chun-Lun Ni, Christopher P. Driscoll, David S. Ruff, Ami Kumar, Nadia Amokrane, Natasha Desai, Phyllis L. Faust, Elan D. Louis, Sheng-Han Kuo, Ming-Kai Pan","doi":"","DOIUrl":"","url":null,"abstract":"<div >Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell–specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 787","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1126/scitranslmed.adq1975
Binbin Ying, Kewang Nan, Qing Zhu, Tom Khuu, Hana Ro, Sophia Qin, Shubing Wang, Karen Jiang, Yonglin Chen, Guangyu Bao, Josh Jenkins, Andrew Pettinari, Johannes Kuosmanen, Keiko Ishida, Niora Fabian, Aaron Lopes, Flavia Codreanu, Joshua Morimoto, Jason Li, Alison Hayward, Robert Langer, Giovanni Traverso
Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.
{"title":"An electroadhesive hydrogel interface prolongs porcine gastrointestinal mucosal theranostics","authors":"Binbin Ying, Kewang Nan, Qing Zhu, Tom Khuu, Hana Ro, Sophia Qin, Shubing Wang, Karen Jiang, Yonglin Chen, Guangyu Bao, Josh Jenkins, Andrew Pettinari, Johannes Kuosmanen, Keiko Ishida, Niora Fabian, Aaron Lopes, Flavia Codreanu, Joshua Morimoto, Jason Li, Alison Hayward, Robert Langer, Giovanni Traverso","doi":"10.1126/scitranslmed.adq1975","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq1975","url":null,"abstract":"Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1126/scitranslmed.adp7690
Liana Hatoum, Hannah Song, David Alexander, Victor O. Omojola, Hannah Moore, Julia N. Frank, Edward A. Botchwey, Manu O. Platt
Sickle cell disease (SCD) is a hereditary blood disorder that causes sickling of red blood cells under deoxygenation, which stiffens and damages the cells. Individuals homozygous for the mutant β-globin S allele (SS) endure complications including progressive arterial damage and heightened risk of stroke. The effectiveness of bone marrow transplantation (BMT), now the only curative treatment for SCD, in halting or reversing SCD-mediated arteriopathy remains unclear. This study used two distinct conditioning regimens, x-ray irradiation and chemotherapy, in a Townes humanized murine model of SCD. Mice homozygous for the SS allele underwent BMT at 2 or 4 months of age, time points that we deemed early or late, respectively. Label-free magnetic resonance angiography (MRA) was performed to longitudinally monitor common carotid artery luminal areas in living mice pre- and repeatedly post-BMT, followed by histological analysis of the arteries at euthanasia. Myeloablative chemotherapy demonstrated higher survivability in SS mice compared with x-ray irradiation. SS mice exhibited arterial outward expansion by 3 months and thinning of the medial layer at 5 months, which are characteristics of a weakened arterial wall. BMT at 2 months effectively halted this expansion, maintaining smaller luminal areas in SS mice. However, BMT at 4 months did not reverse arteriopathy, indicating the importance of early intervention. This work emphasizes how MRA can be used as a noninvasive method for assessing arteriopathy progression and demonstrates that the timing of BMT is crucial in mitigating sickle cell–induced large artery remodeling.
{"title":"Bone marrow transplant protects mice from sickle cell–mediated large artery remodeling","authors":"Liana Hatoum, Hannah Song, David Alexander, Victor O. Omojola, Hannah Moore, Julia N. Frank, Edward A. Botchwey, Manu O. Platt","doi":"10.1126/scitranslmed.adp7690","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp7690","url":null,"abstract":"Sickle cell disease (SCD) is a hereditary blood disorder that causes sickling of red blood cells under deoxygenation, which stiffens and damages the cells. Individuals homozygous for the mutant β-globin S allele (SS) endure complications including progressive arterial damage and heightened risk of stroke. The effectiveness of bone marrow transplantation (BMT), now the only curative treatment for SCD, in halting or reversing SCD-mediated arteriopathy remains unclear. This study used two distinct conditioning regimens, x-ray irradiation and chemotherapy, in a Townes humanized murine model of SCD. Mice homozygous for the SS allele underwent BMT at 2 or 4 months of age, time points that we deemed early or late, respectively. Label-free magnetic resonance angiography (MRA) was performed to longitudinally monitor common carotid artery luminal areas in living mice pre- and repeatedly post-BMT, followed by histological analysis of the arteries at euthanasia. Myeloablative chemotherapy demonstrated higher survivability in SS mice compared with x-ray irradiation. SS mice exhibited arterial outward expansion by 3 months and thinning of the medial layer at 5 months, which are characteristics of a weakened arterial wall. BMT at 2 months effectively halted this expansion, maintaining smaller luminal areas in SS mice. However, BMT at 4 months did not reverse arteriopathy, indicating the importance of early intervention. This work emphasizes how MRA can be used as a noninvasive method for assessing arteriopathy progression and demonstrates that the timing of BMT is crucial in mitigating sickle cell–induced large artery remodeling.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"2 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1126/scitranslmed.adl6758
Sofie Lundgren, Jani Huuhtanen, Mikko Keränen, Xingmin Feng, Bhavisha A. Patel, Georgina L. Ryland, Lucy C. Fox, Carlos Bravo-Perez, Michael Clemente, Cassandra Kerr, Gunilla Walldin, Olli Dufva, Yoshitaka Zaimoku, Tiina Tuononen, Mikko Myllymäki, Freja Ebeling, Emmi Jokinen, Markus Heinonen, Tiina Kasanen, Jay Klievink, Hanna Lähteenmäki, Taina Jaatinen, Sari Kytölä, Sanna Siitonen, Alina Dulau-Florea, Raul Braylan, Merja Heinäniemi, Shinji Nakao, Eva Hellström-Lindberg, Jaroslaw P. Maciejewski, Piers Blombery, Neal S. Young, Harri Lähdesmäki, Satu Mustjoki
Immune aplastic anemia (AA) is a life-threatening bone marrow failure disorder driven by an autoimmune T cell attack against hematopoietic stem and progenitor cells (HSPCs). However, the exact autoantigen targets and role of other immune cells in the pathogenesis of AA are unknown. Here, we analyzed a cohort of 218 patients with AA using single-cell RNA and T cell receptor (TCR) αβ sequencing, TCRβ sequencing, flow cytometry, and plasma cytokine profiling. We identified natural killer (NK) cells and CD8 + terminally differentiated effector T (T EMRA ) cells expressing NK receptors with AA-associated TCRβ motifs as the most dysregulated immune cell populations in AA bone marrow. Functional coculture experiments using primary HSPCs and immune cells showed that NK cells cannot kill HSPCs alone but may sensitize HSPCs to CD8 + T cell–mediated killing through production of interferons. Furthermore, HSPCs induced activation of T cell clones with CD8 + T EMRA NK-like phenotype in coculture. Our results reveal a convergent phenotype of innate and adaptive immune cells that may drive AA.
{"title":"Single-cell analysis of aplastic anemia reveals a convergence of NK and NK-like CD8 + T cells with a disease-associated TCR signature","authors":"Sofie Lundgren, Jani Huuhtanen, Mikko Keränen, Xingmin Feng, Bhavisha A. Patel, Georgina L. Ryland, Lucy C. Fox, Carlos Bravo-Perez, Michael Clemente, Cassandra Kerr, Gunilla Walldin, Olli Dufva, Yoshitaka Zaimoku, Tiina Tuononen, Mikko Myllymäki, Freja Ebeling, Emmi Jokinen, Markus Heinonen, Tiina Kasanen, Jay Klievink, Hanna Lähteenmäki, Taina Jaatinen, Sari Kytölä, Sanna Siitonen, Alina Dulau-Florea, Raul Braylan, Merja Heinäniemi, Shinji Nakao, Eva Hellström-Lindberg, Jaroslaw P. Maciejewski, Piers Blombery, Neal S. Young, Harri Lähdesmäki, Satu Mustjoki","doi":"10.1126/scitranslmed.adl6758","DOIUrl":"https://doi.org/10.1126/scitranslmed.adl6758","url":null,"abstract":"Immune aplastic anemia (AA) is a life-threatening bone marrow failure disorder driven by an autoimmune T cell attack against hematopoietic stem and progenitor cells (HSPCs). However, the exact autoantigen targets and role of other immune cells in the pathogenesis of AA are unknown. Here, we analyzed a cohort of 218 patients with AA using single-cell RNA and T cell receptor (TCR) αβ sequencing, TCRβ sequencing, flow cytometry, and plasma cytokine profiling. We identified natural killer (NK) cells and CD8 <jats:sup>+</jats:sup> terminally differentiated effector T (T <jats:sub>EMRA</jats:sub> ) cells expressing NK receptors with AA-associated TCRβ motifs as the most dysregulated immune cell populations in AA bone marrow. Functional coculture experiments using primary HSPCs and immune cells showed that NK cells cannot kill HSPCs alone but may sensitize HSPCs to CD8 <jats:sup>+</jats:sup> T cell–mediated killing through production of interferons. Furthermore, HSPCs induced activation of T cell clones with CD8 <jats:sup>+</jats:sup> T <jats:sub>EMRA</jats:sub> NK-like phenotype in coculture. Our results reveal a convergent phenotype of innate and adaptive immune cells that may drive AA.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"66 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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