Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105302
Thomas A Russo, Ulrike Carlino-MacDonald, Zachary J Drayer, Connor J Davies, Cassandra L Alvarado, Alan Hutson, Ting L Luo, Melissa J Martin, Patrick T McGann, Francois Lebreton
Background: Quantitating the contribution of phenotype-responsible elements in hypervirulent Klebsiella pneumoniae is needed.
Methods: Isogenic mutants of four hypervirulent clinical isolates that produced K1 (ST23), K2 (ST86), K20 (ST1544), or K54 (ST29) capsules (mean 2.2 log10 LD50 (range 1.5-2.9)) were created to measure the effects on LD50 in a murine model of the hypervirulence-associated plasmid (pVir), iucA, prmpA, prmpA2 (truncated), irp2, and clbBC.
Findings: Curing pVir had the greatest increase in survival (mean LD50 to 7.6 (range 7.0-9.0, p ≤ 0.0001), a dosage comparable to classical K. pneumoniae. Results also showed increased mean LD50s for ΔprmpA (5.9, p ≤ 0.0001), ΔiucA (3.6, p ≤ 0.0001), Δirp2 (3.4), ΔrmpAΔiucA (6.3, p ≤ 0.0001), and ΔpVirΔirp2 (8.7, p ≤ 0.0001). Notably ΔpVir had an additional mean LD50 increase of 1.3 compared to the pVir-encoded ΔprmpAΔiucA (p ≤ 0.01), suggesting presence of additional pVir-virulence genes. Truncated pRmpA2 did not contribute to virulence. Odd ratios in the absence of pVir/yersiniabactin, pVir, pRmpA/aerobactin, pRmpA, aerobactin, yersiniabactin, and colibactin demonstrated a 250-fold, 67-fold, 20-fold, 16.7-fold, 9.6-fold, and 1.7-fold decrease in lethality respectively.
Interpretation: These data can guide countermeasure development.
Funding: This work was supported by NIH R21 AI123558-01 and 1R21AI141826-01A1 (Dr. Russo) and the Department of Veterans Affairs VA Merit Review (I01 BX004677-01) (Dr. Russo). This study was also partially funded by the U.S. Defense Health Program (DHP) Operations and Maintenance.
{"title":"Deciphering the relative importance of genetic elements in hypervirulent Klebsiella pneumoniae to guide countermeasure development.","authors":"Thomas A Russo, Ulrike Carlino-MacDonald, Zachary J Drayer, Connor J Davies, Cassandra L Alvarado, Alan Hutson, Ting L Luo, Melissa J Martin, Patrick T McGann, Francois Lebreton","doi":"10.1016/j.ebiom.2024.105302","DOIUrl":"10.1016/j.ebiom.2024.105302","url":null,"abstract":"<p><strong>Background: </strong>Quantitating the contribution of phenotype-responsible elements in hypervirulent Klebsiella pneumoniae is needed.</p><p><strong>Methods: </strong>Isogenic mutants of four hypervirulent clinical isolates that produced K1 (ST23), K2 (ST86), K20 (ST1544), or K54 (ST29) capsules (mean 2.2 log<sub>10</sub> LD<sub>50</sub> (range 1.5-2.9)) were created to measure the effects on LD<sub>50</sub> in a murine model of the hypervirulence-associated plasmid (pVir), iucA, <sub>p</sub>rmpA, <sub>p</sub>rmpA2 (truncated), irp2, and clbBC.</p><p><strong>Findings: </strong>Curing pVir had the greatest increase in survival (mean LD<sub>50</sub> to 7.6 (range 7.0-9.0, p ≤ 0.0001), a dosage comparable to classical K. pneumoniae. Results also showed increased mean LD<sub>50</sub>s for Δ<sub>p</sub>rmpA (5.9, p ≤ 0.0001), ΔiucA (3.6, p ≤ 0.0001), Δirp2 (3.4), ΔrmpAΔiucA (6.3, p ≤ 0.0001), and ΔpVirΔirp2 (8.7, p ≤ 0.0001). Notably ΔpVir had an additional mean LD<sub>50</sub> increase of 1.3 compared to the pVir-encoded Δ<sub>p</sub>rmpAΔiucA (p ≤ 0.01), suggesting presence of additional pVir-virulence genes. Truncated <sub>p</sub>RmpA2 did not contribute to virulence. Odd ratios in the absence of pVir/yersiniabactin, pVir, <sub>p</sub>RmpA/aerobactin, <sub>p</sub>RmpA, aerobactin, yersiniabactin, and colibactin demonstrated a 250-fold, 67-fold, 20-fold, 16.7-fold, 9.6-fold, and 1.7-fold decrease in lethality respectively.</p><p><strong>Interpretation: </strong>These data can guide countermeasure development.</p><p><strong>Funding: </strong>This work was supported by NIH R21 AI123558-01 and 1R21AI141826-01A1 (Dr. Russo) and the Department of Veterans Affairs VA Merit Review (I01 BX004677-01) (Dr. Russo). This study was also partially funded by the U.S. Defense Health Program (DHP) Operations and Maintenance.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046465","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 : 2024-08-21DOI: 10.1016/j.ebiom.2024.105272
Silvia Calvo, Jose Manuel Rodrigo-Muñoz, Raquel Tarancón, Santiago Uranga, Carlos Martín, Victoria Del Pozo, Nacho Aguiló
Background: MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs.
Methods: Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens.
Findings: IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5.
Interpretation: Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure.
Funding: MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.
背景:MTBVAC 是一种减毒的结核病活疫苗,目前正在进行预防结核病的 III 期评估。在之前的临床前研究中,我们发现通过鼻内途径在局部肺部注射 MTBVAC 对哮喘有很强的治疗效果。这种效果与肺部过敏原特异性 Th2 反应的减弱有关:方法:我们利用不同的哮喘小鼠模型,研究了通过静脉注射(IV)途径给药的 MTBVAC 的效果及其作为免疫治疗剂在系统水平上诱导过敏原特异性反应脱敏的潜力。我们探讨了这一过程对不同过敏原诱发的气道高反应性(AHR)的疗效:结果:静脉注射 MTBVAC 能高效降低不同过敏原诱发的气道高反应性。此外,IV MTBVAC 还具有良好的耐受性,可从分析的不同器官中逐渐排出。从机理的角度来看,我们观察到 MTBVAC 静脉注射(而非鼻内注射)会损害肺部和脾脏的过敏原特异性 Th2 反应。这种全身水平的降低与针对过敏原暴露的长期治疗保护相关。我们的研究结果还揭示了支配全身和局部肺部过敏原脱敏过程的不同免疫机制。值得注意的是,在一组对屋尘螨(HDM)敏感的哮喘患者中,用 MTBVAC 体外培养外周血单核细胞(PBMCs)可阻止过敏原特异性产生 Th2 细胞因子 IL-4 和 IL-5:总之,我们的研究结果表明,静脉注射 MTBVAC 可能是治疗哮喘的一种可行的过敏原脱敏方法,并可在接触过敏原时提供长期保护:基金:MCIN/AEI/10.13039/501100011033[资助编号RTI2018-097625-B-I00和PID2022-138624OB-I00];卡洛斯三世健康研究所Consorcio Centro de Investigación Biomédica en Red-(CB06/06/0020和CB06/06/0013组)。
{"title":"Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC.","authors":"Silvia Calvo, Jose Manuel Rodrigo-Muñoz, Raquel Tarancón, Santiago Uranga, Carlos Martín, Victoria Del Pozo, Nacho Aguiló","doi":"10.1016/j.ebiom.2024.105272","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105272","url":null,"abstract":"<p><strong>Background: </strong>MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs.</p><p><strong>Methods: </strong>Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens.</p><p><strong>Findings: </strong>IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5.</p><p><strong>Interpretation: </strong>Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure.</p><p><strong>Funding: </strong>MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035458","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}
Background: Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes.
Methods: We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients).
Findings: The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022).
Interpretation: We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity.
Funding: JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.
背景:乳腺癌细胞可抑制宿主免疫系统,从而有效入侵淋巴结;然而,人们对其深层机制仍不甚了解。在此,我们旨在全面描述乳腺癌对淋巴结免疫细胞的影响:方法:我们收集了 6 名淋巴结转移的乳腺癌患者的非转移性和转移性淋巴结样本。我们对所获得的淋巴结进行了批量转录组学、空间转录组学和成像质谱分析。此外,我们还对更大的患者群体(来自 58 名患者的 474 张切片)进行了组织学分析:结果:对同一患者有转移和无转移的配对淋巴结进行比较后发现,转移淋巴结中CD169+淋巴结窦巨噬细胞的数量减少(36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2,p = 0.0087),而其他主要免疫细胞类型的数量没有变化。我们还发现,CD169+巨噬细胞在转移癌组织中的浸润因肿瘤切片位置而异,这表明CD169+巨噬细胞在抗癌反应后逐渐减少。此外,CD169+巨噬细胞的消除在主要的乳腺癌亚型中普遍存在,并与乳腺癌分期相关(p = 0.022):我们的结论是,乳腺癌转移淋巴结中的 CD169+ 巨噬细胞较少,这可能不利于抗癌免疫的活性:基金:JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd., Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.
{"title":"Intra-patient spatial comparison of non-metastatic and metastatic lymph nodes reveals a reduction in CD169<sup>+</sup> macrophages within metastatic breast cancers.","authors":"Yurina Maeshima, Tatsuki R Kataoka, Alexis Vandenbon, Masahiro Hirata, Yasuhide Takeuchi, Yutaka Suzuki, Yukiko Fukui, Masahiro Kawashima, Masahiro Takada, Yumiko Ibi, Hironori Haga, Satoshi Morita, Masakazu Toi, Shinpei Kawaoka, Kosuke Kawaguchi","doi":"10.1016/j.ebiom.2024.105271","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105271","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes.</p><p><strong>Methods: </strong>We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients).</p><p><strong>Findings: </strong>The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169<sup>+</sup> lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm<sup>2</sup>, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169<sup>+</sup> macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169<sup>+</sup> macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169<sup>+</sup> macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022).</p><p><strong>Interpretation: </strong>We concluded that lymph nodes with breast cancer metastases have fewer CD169<sup>+</sup> macrophages, which may be detrimental to the activity of anti-cancer immunity.</p><p><strong>Funding: </strong>JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035461","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 : 2024-08-21DOI: 10.1016/j.ebiom.2024.105292
Carlos Alberto Montenegro-Quiñonez, Valérie R Louis, Olaf Horstick, Raman Velayudhan, Peter Dambach, Silvia Runge-Ranzinger
{"title":"Corrigendum to: interventions against Aedes/dengue at the household level: a systematic review and meta-analysis. EBioMedicine, 93. https://doi.org/10.1016/j.ebiom.2023.104660.","authors":"Carlos Alberto Montenegro-Quiñonez, Valérie R Louis, Olaf Horstick, Raman Velayudhan, Peter Dambach, Silvia Runge-Ranzinger","doi":"10.1016/j.ebiom.2024.105292","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105292","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035460","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 : 2024-08-21DOI: 10.1016/j.ebiom.2024.105282
Thomas Edward Conley, Rachael Slater, Stephen Moss, David Colin Bulmer, Juan de la Revilla Negro, Umer Zeeshan Ijaz, David Mark Pritchard, Miles Parkes, Chris Probert
Background: Irritable bowel syndrome (IBS) is a common and debilitating disorder manifesting with abdominal pain and bowel dysfunction. A mainstay of treatment is dietary modification, including restriction of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). A greater response to a low FODMAP diet has been reported in those with a distinct IBS microbiome termed IBS-P. We investigated whether this is linked to specific changes in the metabolome in IBS-P.
Methods: Solid phase microextraction gas chromatography-mass spectrometry was used to examine the faecal headspace of 56 IBS cases (each paired with a non-IBS household control) at baseline, and after four-weeks of a low FODMAP diet (39 pairs). 50% cases had the IBS-P microbial subtype, while the others had a microbiome that more resembled healthy controls (termed IBS-H). Clinical response to restriction of FODMAPs was measured with the IBS-symptom severity scale, from which a pain sub score was calculated.
Findings: Two distinct metabotypes were identified and mapped onto the microbial subtypes. IBS-P was characterised by a fermentative metabolic profile rich in short chain fatty acids (SCFAs). After FODMAP restriction significant reductions in SCFAs were observed in IBS-P. SCFA levels did not change significantly in the IBS-H group. The magnitude of pain and overall symptom improvement were significantly greater in IBS-P compared to IBS-H (p = 0.016 and p = 0.026, respectively). Using just five metabolites, a biomarker model could predict microbial subtype with accuracy (AUROC 0.797, sensitivity 78.6% (95% CI: 0.78-0.94), specificity 71.4% (95% CI: 0.55-0.88).
Interpretation: A metabotype high in SCFAs can be manipulated by restricting fermentable carbohydrate, and is associated with an enhanced clinical response to this dietary restriction. This implies that SCFAs harbour pro-nociceptive potential when produced in a specific IBS niche. By ascertaining metabotype, microbial subtype can be predicted with accuracy. This could allow targeted FODMAP restriction in those seemingly primed to respond best.
Funding: This research was co-funded by Addenbrooke's Charitable Trust, Cambridge University Hospitals and the Wellcome Sanger Institute, and supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
{"title":"Microbiome-driven IBS metabotypes influence response to the low FODMAP diet: insights from the faecal volatome.","authors":"Thomas Edward Conley, Rachael Slater, Stephen Moss, David Colin Bulmer, Juan de la Revilla Negro, Umer Zeeshan Ijaz, David Mark Pritchard, Miles Parkes, Chris Probert","doi":"10.1016/j.ebiom.2024.105282","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105282","url":null,"abstract":"<p><strong>Background: </strong>Irritable bowel syndrome (IBS) is a common and debilitating disorder manifesting with abdominal pain and bowel dysfunction. A mainstay of treatment is dietary modification, including restriction of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). A greater response to a low FODMAP diet has been reported in those with a distinct IBS microbiome termed IBS-P. We investigated whether this is linked to specific changes in the metabolome in IBS-P.</p><p><strong>Methods: </strong>Solid phase microextraction gas chromatography-mass spectrometry was used to examine the faecal headspace of 56 IBS cases (each paired with a non-IBS household control) at baseline, and after four-weeks of a low FODMAP diet (39 pairs). 50% cases had the IBS-P microbial subtype, while the others had a microbiome that more resembled healthy controls (termed IBS-H). Clinical response to restriction of FODMAPs was measured with the IBS-symptom severity scale, from which a pain sub score was calculated.</p><p><strong>Findings: </strong>Two distinct metabotypes were identified and mapped onto the microbial subtypes. IBS-P was characterised by a fermentative metabolic profile rich in short chain fatty acids (SCFAs). After FODMAP restriction significant reductions in SCFAs were observed in IBS-P. SCFA levels did not change significantly in the IBS-H group. The magnitude of pain and overall symptom improvement were significantly greater in IBS-P compared to IBS-H (p = 0.016 and p = 0.026, respectively). Using just five metabolites, a biomarker model could predict microbial subtype with accuracy (AUROC 0.797, sensitivity 78.6% (95% CI: 0.78-0.94), specificity 71.4% (95% CI: 0.55-0.88).</p><p><strong>Interpretation: </strong>A metabotype high in SCFAs can be manipulated by restricting fermentable carbohydrate, and is associated with an enhanced clinical response to this dietary restriction. This implies that SCFAs harbour pro-nociceptive potential when produced in a specific IBS niche. By ascertaining metabotype, microbial subtype can be predicted with accuracy. This could allow targeted FODMAP restriction in those seemingly primed to respond best.</p><p><strong>Funding: </strong>This research was co-funded by Addenbrooke's Charitable Trust, Cambridge University Hospitals and the Wellcome Sanger Institute, and supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035462","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 : 2024-08-20DOI: 10.1016/j.ebiom.2024.105286
Dan He, Ling Li, Huasong Zhang, Feiyi Liu, Shaoying Li, Xuehao Xiu, Cong Fan, Mengling Qi, Meng Meng, Junping Ye, Matthew Mort, Peter D Stenson, David N Cooper, Huiying Zhao
Background: Genome-wide association studies (GWAS) have revealed many brain disorder-associated SNPs residing in the noncoding genome, rendering it a challenge to decipher the underlying pathogenic mechanisms.
Methods: Here, we present an unsupervised Bayesian framework to identify disease-associated genes by integrating risk SNPs with long-range chromatin interactions (iGOAT), including SNP-SNP interactions extracted from ∼500,000 patients and controls from the UK Biobank, and enhancer-promoter interactions derived from multiple brain cell types at different developmental stages.
Findings: The application of iGOAT to three psychiatric disorders and three neurodegenerative/neurological diseases predicted sets of high-risk (HRGs) and low-risk (LRGs) genes for each disorder. The HRGs were enriched in drug targets, and exhibited higher expression during prenatal brain developmental stages than postnatal stages, indicating their potential to affect brain development at an early stage. The HRGs associated with Alzheimer's disease were found to share genetic architecture with schizophrenia, bipolar disorder and major depressive disorder according to gene co-expression module analysis and rare variants analysis. Comparisons of this method to the eQTL-based method, the TWAS-based method, and the gene-level GWAS method indicated that the genes identified by our method are more enriched in known brain disorder-related genes, and exhibited higher precision. Finally, the method predicted 205 risk genes not previously reported to be associated with any brain disorder, of which one top-risk gene, MLH1, was experimentally validated as being schizophrenia-associated.
Interpretation: iGOAT can successfully leverage epigenomic data, phenotype-genotype associations, and protein-protein interactions to advance our understanding of brain disorders, thereby facilitating the development of new therapeutic approaches.
Funding: The work was funded by the National Key Research and Development Program of China (2024YFF1204902), the Natural Science Foundation of China (82371482), Guangzhou Science and Technology Research Plan (2023A03J0659) and Natural Science Foundation of Guangdong (2024A1515011363).
{"title":"Accurate identification of genes associated with brain disorders by integrating heterogeneous genomic data into a Bayesian framework.","authors":"Dan He, Ling Li, Huasong Zhang, Feiyi Liu, Shaoying Li, Xuehao Xiu, Cong Fan, Mengling Qi, Meng Meng, Junping Ye, Matthew Mort, Peter D Stenson, David N Cooper, Huiying Zhao","doi":"10.1016/j.ebiom.2024.105286","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105286","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies (GWAS) have revealed many brain disorder-associated SNPs residing in the noncoding genome, rendering it a challenge to decipher the underlying pathogenic mechanisms.</p><p><strong>Methods: </strong>Here, we present an unsupervised Bayesian framework to identify disease-associated genes by integrating risk SNPs with long-range chromatin interactions (iGOAT), including SNP-SNP interactions extracted from ∼500,000 patients and controls from the UK Biobank, and enhancer-promoter interactions derived from multiple brain cell types at different developmental stages.</p><p><strong>Findings: </strong>The application of iGOAT to three psychiatric disorders and three neurodegenerative/neurological diseases predicted sets of high-risk (HRGs) and low-risk (LRGs) genes for each disorder. The HRGs were enriched in drug targets, and exhibited higher expression during prenatal brain developmental stages than postnatal stages, indicating their potential to affect brain development at an early stage. The HRGs associated with Alzheimer's disease were found to share genetic architecture with schizophrenia, bipolar disorder and major depressive disorder according to gene co-expression module analysis and rare variants analysis. Comparisons of this method to the eQTL-based method, the TWAS-based method, and the gene-level GWAS method indicated that the genes identified by our method are more enriched in known brain disorder-related genes, and exhibited higher precision. Finally, the method predicted 205 risk genes not previously reported to be associated with any brain disorder, of which one top-risk gene, MLH1, was experimentally validated as being schizophrenia-associated.</p><p><strong>Interpretation: </strong>iGOAT can successfully leverage epigenomic data, phenotype-genotype associations, and protein-protein interactions to advance our understanding of brain disorders, thereby facilitating the development of new therapeutic approaches.</p><p><strong>Funding: </strong>The work was funded by the National Key Research and Development Program of China (2024YFF1204902), the Natural Science Foundation of China (82371482), Guangzhou Science and Technology Research Plan (2023A03J0659) and Natural Science Foundation of Guangdong (2024A1515011363).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016677","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}
Background: Multiplexed immunofluorescence (mIF) staining, such as CODEX and MIBI, holds significant clinical value for various fields, such as disease diagnosis, biological research, and drug development. However, these techniques are often hindered by high time and cost requirements.
Methods: Here we present a Multimodal-Attention-based virtual mIF Staining (MAS) system that utilises a deep learning model to extract potential antibody-related features from dual-modal non-antibody-stained fluorescence imaging, specifically autofluorescence (AF) and DAPI imaging. The MAS system simultaneously generates predictions of mIF with multiple survival-associated biomarkers in gastric cancer using self- and multi-attention learning mechanisms.
Findings: Experimental results with 180 pathological slides from 94 patients with gastric cancer demonstrate the efficiency and consistent performance of the MAS system in both cancer and noncancer gastric tissues. Furthermore, we showcase the prognostic accuracy of the virtual mIF images of seven gastric cancer related biomarkers, including CD3, CD20, FOXP3, PD1, CD8, CD163, and PD-L1, which is comparable to those obtained from the standard mIF staining.
Interpretation: The MAS system rapidly generates reliable multiplexed staining, greatly reducing the cost of mIF and improving clinical workflow.
Funding: Stanford 2022 HAI Seed Grant; National Institutes of Health 1R01CA256890.
{"title":"Virtual multiplexed immunofluorescence staining from non-antibody-stained fluorescence imaging for gastric cancer prognosis.","authors":"Zixia Zhou, Yuming Jiang, Zepang Sun, Taojun Zhang, Wanying Feng, Guoxin Li, Ruijiang Li, Lei Xing","doi":"10.1016/j.ebiom.2024.105287","DOIUrl":"10.1016/j.ebiom.2024.105287","url":null,"abstract":"<p><strong>Background: </strong>Multiplexed immunofluorescence (mIF) staining, such as CODEX and MIBI, holds significant clinical value for various fields, such as disease diagnosis, biological research, and drug development. However, these techniques are often hindered by high time and cost requirements.</p><p><strong>Methods: </strong>Here we present a Multimodal-Attention-based virtual mIF Staining (MAS) system that utilises a deep learning model to extract potential antibody-related features from dual-modal non-antibody-stained fluorescence imaging, specifically autofluorescence (AF) and DAPI imaging. The MAS system simultaneously generates predictions of mIF with multiple survival-associated biomarkers in gastric cancer using self- and multi-attention learning mechanisms.</p><p><strong>Findings: </strong>Experimental results with 180 pathological slides from 94 patients with gastric cancer demonstrate the efficiency and consistent performance of the MAS system in both cancer and noncancer gastric tissues. Furthermore, we showcase the prognostic accuracy of the virtual mIF images of seven gastric cancer related biomarkers, including CD3, CD20, FOXP3, PD1, CD8, CD163, and PD-L1, which is comparable to those obtained from the standard mIF staining.</p><p><strong>Interpretation: </strong>The MAS system rapidly generates reliable multiplexed staining, greatly reducing the cost of mIF and improving clinical workflow.</p><p><strong>Funding: </strong>Stanford 2022 HAI Seed Grant; National Institutes of Health 1R01CA256890.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999591","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}
Pub Date : 2024-08-17DOI: 10.1016/j.ebiom.2024.105279
Daniele Bizzarri, Marcel J T Reinders, Lieke Kuiper, Marian Beekman, Joris Deelen, Joyce B J van Meurs, Jenny van Dongen, René Pool, Dorret I Boomsma, Mohsen Ghanbari, Lude Franke, Pieternella E Slagboom, Erik B van den Akker
Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals.
Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors.
Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates.
Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal.
Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.
背景:血液中的 1H-NMR 代谢组学和 DNA 甲基化是众所周知的预测与年龄相关的生理衰退和死亡率的生物标志物,但它们却发出相互独立的死亡率和虚弱信号:利用四项荷兰人口研究(N = 5238,其中男性占 40%)中的多组学数据,我们研究了 1H-NMR 代谢组学捕获的死亡率信号能否指导构建基于 DNA 甲基化的死亡率预测指标:我们对 64 种代谢组学分析物进行了基于 DNA 甲基化的替代物训练,发现利用 DNA 甲基化检测可以准确重建炎症、体液平衡或高密度脂蛋白/低密度脂蛋白代谢的分析物。有趣的是,以前报道过的一种显示死亡风险的多分析物评分(MetaboHealth)也可以准确地重建。在我们得出的代用指标中,包括MetaboHealth代用指标在内的16个指标都显示与死亡率有显著关联,且不受相关协变量的影响:解释:将我们的代谢分析物衍生代用指标添加到成熟的表观遗传时钟 GrimAge 中,表明我们的代用指标可能代表有价值的死亡率信号:BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.
{"title":"NMR metabolomics-guided DNA methylation mortality predictors.","authors":"Daniele Bizzarri, Marcel J T Reinders, Lieke Kuiper, Marian Beekman, Joris Deelen, Joyce B J van Meurs, Jenny van Dongen, René Pool, Dorret I Boomsma, Mohsen Ghanbari, Lude Franke, Pieternella E Slagboom, Erik B van den Akker","doi":"10.1016/j.ebiom.2024.105279","DOIUrl":"10.1016/j.ebiom.2024.105279","url":null,"abstract":"<p><strong>Background: </strong><sup>1</sup>H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals.</p><p><strong>Methods: </strong>Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by <sup>1</sup>H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors.</p><p><strong>Findings: </strong>We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates.</p><p><strong>Interpretation: </strong>The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal.</p><p><strong>Funding: </strong>BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999590","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}
Pub Date : 2024-08-16DOI: 10.1016/j.ebiom.2024.105285
Kai Fu, Shucheng Si, Xinzhong Jin, Yan Zhang, Vicky Duong, Qianying Cai, Guangyi Li, Win Min Oo, Xianyou Zheng, Cindy G Boer, Yuqing Zhang, Xiaojuan Wei, Changqing Zhang, Youshui Gao, David J Hunter
Background: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly.
Methods: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised.
Findings: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50-2.84, P < 3 × 10-4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48-0.76, P < 3 × 10-4), finger (OR: 0.50, 95% CI: 0.35-0.73, P < 3 × 10-4), and thumb (OR: 0.49, 95% CI: 0.34-0.71, P < 3 × 10-4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype.
Interpretation: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs.
Funding: This study was funded by the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (2022), the Shanghai Municipal Health Commission Health Industry Clinical Research Project (Grant No. 20224Y0139), Beijing Natural Science Foundation (Grant No. 7244458), and the Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation (Grant No. GZC20230130).
{"title":"Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis.","authors":"Kai Fu, Shucheng Si, Xinzhong Jin, Yan Zhang, Vicky Duong, Qianying Cai, Guangyi Li, Win Min Oo, Xianyou Zheng, Cindy G Boer, Yuqing Zhang, Xiaojuan Wei, Changqing Zhang, Youshui Gao, David J Hunter","doi":"10.1016/j.ebiom.2024.105285","DOIUrl":"10.1016/j.ebiom.2024.105285","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly.</p><p><strong>Methods: </strong>We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised.</p><p><strong>Findings: </strong>Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50-2.84, P < 3 × 10<sup>-4</sup>), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48-0.76, P < 3 × 10<sup>-4</sup>), finger (OR: 0.50, 95% CI: 0.35-0.73, P < 3 × 10<sup>-4</sup>), and thumb (OR: 0.49, 95% CI: 0.34-0.71, P < 3 × 10<sup>-4</sup>) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype.</p><p><strong>Interpretation: </strong>Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs.</p><p><strong>Funding: </strong>This study was funded by the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (2022), the Shanghai Municipal Health Commission Health Industry Clinical Research Project (Grant No. 20224Y0139), Beijing Natural Science Foundation (Grant No. 7244458), and the Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation (Grant No. GZC20230130).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995494","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}