{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:12:32Z","timestamp":1784686352395,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T00:00:00Z","timestamp":1728864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Council of Taiwan","award":["MOST 107-2321-B-003-001-"],"award-info":[{"award-number":["MOST 107-2321-B-003-001-"]}]},{"name":"National Science Council of Taiwan","award":["MOST 108-2321-B-003-001-"],"award-info":[{"award-number":["MOST 108-2321-B-003-001-"]}]},{"name":"National Science Council of Taiwan","award":["MOST 109-2321-B-003-001-"],"award-info":[{"award-number":["MOST 109-2321-B-003-001-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>During the growth process of weaned piglets, digestive problems such as gastrointestinal disorders and diarrhea are common. Farmers usually use antibiotics to help piglets grow smoothly. However, the overuse of antibiotics can lead to antibiotic resistance issues. Therefore, this study chose to use plant extracts as feed additives to explore their potential as alternatives to antibiotics. Additionally, Tilmicosin was used as the antibiotic because it is widely used in treating respiratory infections in piglets. Since traditional Chinese medicine often uses natural products, we selected Guizhi Li-Zhong (GLZ) extract as an alternative to antibiotics. The experiment involved 126 piglets, each 4 weeks old, which were randomly assigned to one of four groups: the sham group (basal diet without supplements, 10.3 \u00b1 0.4 kg, n = 31), the low-dose GLZ group (basal diet with 0.05% GLZ, 10.9 \u00b1 0.4 kg, n = 32), the regular-dose GLZ group (basal diet with 0.2% GLZ, 10.6 \u00b1 0.4 kg, n = 32), and the regular-dose Tilmicosin antibiotic group (basal diet with 0.2% Tilmicosin, 10.2 \u00b1 0.3 kg, n = 31). We recorded and compared the survival rate, growth rate, feed conversion ratio, and diarrhea incidence among four groups of weaned piglets from the 4th to the 10th weeks of age. Then, we examined the oxidative stress, inflammation, and apoptosis in small intestine tissue (jejunum and ileum) through immunohistochemistry and Western blot and compared the gut microbiota in large intestine tissue (colon and rectum) through a next-generation sequencing (NGS) analysis. Our results showed that weaned piglets supplemented with 0.05% and 0.2% GLZ had better survival rates, growth rates (p &lt; 0.01), and feed conversion ratios (p &lt; 0.01) compared to those receiving sham treatment. Even weaned piglets supplemented with 0.2% GLZ performed better than those supplemented with 0.2% Tilmicosin antibiotics (p &lt; 0.05). Furthermore, the incidence of diarrhea and small intestine injury (indicated by oxidative stress-, inflammation-, and apoptosis-related proteins) in piglets supplemented with 0.05% and 0.2% GLZ was lower than in piglets receiving sham treatment (p &lt; 0.05). Even piglets supplemented with 0.2% GLZ had less injury than those supplemented with 0.2% Tilmicosin antibiotics (p &lt; 0.05). The NGS results further showed that GLZ treatment significantly improved beneficial bacteria in weaned piglets (p &lt; 0.05), while antibiotic treatment reduced beneficial bacteria (p &lt; 0.05). In summary, we recommend adding GLZ to the feed as an alternative to antibiotics. This not only effectively reduces intestinal damage but also improves the gut microbiota, thereby promoting the growth of weaning piglets.<\/jats:p>","DOI":"10.3390\/ijms252011034","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T12:44:31Z","timestamp":1728909871000},"page":"11034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chinese Herbal Medicines as Natural Alternative Products to Antibiotics in Weaned Piglets through Intestinal Microbiota Regulation"],"prefix":"10.3390","volume":"25","author":[{"given":"Che-Hsuan","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Science, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kou-Toung","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Health Nutrition and Chemical Engineering, Army Academy of ROC, Taoyuan City 320, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yu","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, National Taiwan University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Jhen","family":"Wu","sequence":"additional","affiliation":[{"name":"Graduate Program for Nanotechnology, Department of Materials Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Hwa","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chung","family":"Lee","sequence":"additional","affiliation":[{"name":"Brion Research Institute of Taiwan, New Taipei City 231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szu-Chuan","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Life Science, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4470-2448","authenticated-orcid":false,"given":"Chung-Hsin","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Life Science, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0301-6226(97)00057-2","article-title":"Factors influencing the structure and function of the small intestine in the weaned pig: A review","volume":"51","author":"Pluske","year":"1997","journal-title":"Livest. Prod. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.2527\/jas.2012-5796","article-title":"Early weaning increases intestinal permeability, alters expression of cytokine and tight junction proteins, and activates mitogen-activated protein kinases in pigs","volume":"91","author":"Hu","year":"2013","journal-title":"J. Anim. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0301-6226(94)90052-3","article-title":"Effects of climatic conditions on the performance, metabolism and health status of weaned piglets: A review","volume":"38","author":"Herpin","year":"1994","journal-title":"Livest. Prod. Sci."},{"key":"ref_4","first-page":"2838","article-title":"Diet-dependent and diet-independent metabolic responses underlie growth stasis of pigs at weaning","volume":"125","author":"McCracken","year":"1995","journal-title":"J. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1093\/jn\/129.3.613","article-title":"Weaning anorexia may contribute to local inflammation in the piglet small intestine","volume":"129","author":"McCracken","year":"1999","journal-title":"J. Nutr."},{"key":"ref_6","first-page":"355","article-title":"Behavioural perspectives on piglet survival","volume":"40","author":"Fraser","year":"1990","journal-title":"J. Reprod. Fertil. Suppl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.2527\/jas1978.4651447x","article-title":"The role of growth promotion by antibiotics","volume":"46","author":"Visek","year":"1978","journal-title":"J. Anim. Sci."},{"key":"ref_8","first-page":"6","article-title":"Role of subtherapeutic antimicrobials in pig production","volume":"62","author":"Zimmerman","year":"1986","journal-title":"J. Anim. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.5713\/ajas.17.0418","article-title":"Current status and prospects for in-feed antibiotics in the different stages of pork production\u2014A review","volume":"30","author":"Li","year":"2017","journal-title":"Asian-Australas. J. Anim. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1081\/ABIO-120005767","article-title":"Why and how antibiotics are used in swine production","volume":"13","author":"Cromwell","year":"2002","journal-title":"Anim. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Xiong, X., Tan, B., Song, M., Ji, P., Kim, K., Yin, Y., and Liu, Y. (2019). Nutritional Intervention for the Intestinal Development and Health of Weaned Pigs. Front. Vet. Sci., 6.","DOI":"10.3389\/fvets.2019.00046"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1097\/00042737-199612000-00018","article-title":"Herbs-useful plants. Their role in history and today","volume":"8","author":"Jones","year":"1996","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1046\/j.1365-2672.1997.00153.x","article-title":"Bioactivity of selected plant essential oils against Listeria monocytogenes","volume":"82","author":"Deans","year":"1997","journal-title":"J. Appl. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1046\/j.1365-2672.1999.00780.x","article-title":"Antimicrobial activity of essential oils and other plant extracts","volume":"86","author":"Hammer","year":"1999","journal-title":"J. Appl. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1046\/j.1472-765X.1998.00303.x","article-title":"Antimicrobial properties of plant essential oils and essences against five important food-borne pathogens","volume":"26","author":"Stewart","year":"1998","journal-title":"Lett. Appl. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48863","DOI":"10.18632\/oncotarget.16458","article-title":"Gut microbiota drives the attenuation of dextran sulphate sodium-induced colitis by Huangqin decoction","volume":"8","author":"Yang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112979","DOI":"10.1016\/j.jep.2020.112979","article-title":"Traditional Chinese Medicine Li-Zhong-Tang accelerates the healing of indomethacin-induced gastric ulcers in rats by affecting TLR-2\/MyD88 signaling pathway","volume":"259","author":"Song","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","first-page":"3548740","article-title":"Efficacy and Safety of Guizhi Decoction AssociatedFormulas for Allergic Rhinitis: A Systematic Review","volume":"2021","author":"Yang","year":"2021","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"ref_19","first-page":"4978783","article-title":"Chinese Herbal Medicine Formula Guizhi Li-Zhong Tang as an Alternative to Antibiotic Feed Additives for Preventing Pneumonia in Piglets through Antioxidant, Anti-Inflammatory, and Antiapoptotic Protection","volume":"2021","author":"Wang","year":"2021","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s11684-020-0754-0","article-title":"Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection","volume":"14","author":"Zou","year":"2020","journal-title":"Front Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/fsn3.2089","article-title":"Alternative antibiotic feed additives alleviate pneumonia with inhibiting ACE-2 expression in the respiratory system of piglets","volume":"9","author":"Lu","year":"2020","journal-title":"Food Sci. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1248\/bpb.b14-00609","article-title":"Anti-inflammatory effect of cinnamaldehyde in Helicobacter pylori induced gastric inflammation","volume":"38","author":"Muhammad","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jdermsci.2019.11.001","article-title":"Antioxidant cinnamaldehyde attenuates UVB-induced photoaging","volume":"96","author":"Tanaka","year":"2019","journal-title":"J. Dermatol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1055\/s-2004-827230","article-title":"Cinnamaldehyde and 2-methoxycinnamaldehyde as NF-kappaB inhibitors from Cinnamomum cassia","volume":"70","author":"Reddy","year":"2004","journal-title":"Planta Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1172\/JCI11891","article-title":"Series introduction: The transcription factor NF-kappaB and human disease","volume":"107","author":"Baldwin","year":"2001","journal-title":"J. Clin. Invest."},{"key":"ref_26","first-page":"158","article-title":"Role of NF-kappa B in liver ischemia reperfusion injury of rats","volume":"23","author":"Xu","year":"2003","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.2174\/1389557520666200429101053","article-title":"Psoralen: A Biologically Important Coumarin with Emerging Applications","volume":"20","author":"Thakur","year":"2020","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_28","first-page":"232","article-title":"Cinnamic acid shortens the period of the circadian clock in mice","volume":"9","author":"Oishi","year":"2017","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1631\/jzus.B1400204","article-title":"Ginsenoside Rg1 ameliorates oxidative stress and myocardial apoptosis in streptozotocin-induced diabetic rats","volume":"16","author":"Yu","year":"2015","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.micpath.2019.05.003","article-title":"Ginsenoside Rb1 ameliorates Staphylococcus aureus-induced Acute Lung Injury through attenuating NF-\u03baB and MAPK activation","volume":"132","author":"Shaukat","year":"2019","journal-title":"Microb. Pathog."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.foodchem.2012.04.145","article-title":"In vitro antioxidant and anti-inflammatory activities of 1-dehydro-[6]-gingerdione, 6-shogaol, 6-dehydroshogaol and hexahydrocurcumin","volume":"135","author":"Li","year":"2012","journal-title":"Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Jeong, Y.H., Li, W., Go, Y., and Oh, Y.C. (2019). Atractylodis Rhizoma Alba Attenuates Neuroinflammation in BV2 Microglia upon LPS Stimulation by Inducing HO-1 Activity and Inhibiting NF-\u03baB and MAPK. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20164015"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.biopha.2016.10.036","article-title":"The protective role of liquiritin in high fructose-induced myocardial fibrosis via inhibiting NF-\u03baB and MAPK signaling pathway","volume":"84","author":"Zhang","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.phrs.2019.04.025","article-title":"Natural products in licorice for the therapy of liver diseases: Progress and future opportunities","volume":"144","author":"Li","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1093\/ajcn\/55.1.299s","article-title":"Physiology and pathophysiology of intestinal absorption","volume":"55","author":"Caspary","year":"1992","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/jn\/134.3.641","article-title":"Weaning is associated with an upregulation of expression of inflammatory cytokines in the intestine of piglets","volume":"134","author":"Pie","year":"2004","journal-title":"J. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tao, S., Zou, H., Li, J., and Wei, H. (2022). Landscapes of Enteric Virome Signatures in Early-Weaned Piglets. Microbiol. Spectr., 10.","DOI":"10.1128\/spectrum.01698-22"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8787","DOI":"10.3748\/wjg.v21.i29.8787","article-title":"Role of the normal gut microbiota","volume":"21","author":"Jandhyala","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1039\/D1NP00072A","article-title":"Bioactive natural products from Bacteroidetes","volume":"39","author":"Brinkmann","year":"2022","journal-title":"Nat. Prod. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Magne, F., Gotteland, M., Gauthier, L., Zazueta, A., Pesoa, S., Navarrete, P., and Balamurugan, R. (2020). The Firmicutes\/Bacteroidetes Ratio: A Relevant Marker of Gut Dysbiosis in Obese Patients?. Nutrients, 12.","DOI":"10.3390\/nu12051474"},{"key":"ref_41","first-page":"E246","article-title":"Polyphenols and Lactobacillus reuteri in oral health","volume":"63","author":"Naureen","year":"2022","journal-title":"J. Prev. Med. Hyg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13073-017-0490-5","article-title":"A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients","volume":"9","author":"Hall","year":"2017","journal-title":"Genome Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Nie, K., Ma, K., Luo, W., Shen, Z., Yang, Z., Xiao, M., Tong, T., Yang, Y., and Wang, X. (2021). Roseburia intestinalis: A Beneficial Gut Organism From the Discoveries in Genus and Species. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.757718"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Badal, V.D., Vaccariello, E.D., Murray, E.R., Yu, K.E., Knight, R., Jeste, D.V., and Nguyen, T.T. (2020). The Gut Microbiome, Aging, and Longevity: A Systematic Review. Nutrients, 12.","DOI":"10.3390\/nu12123759"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2249152","DOI":"10.1080\/19490976.2023.2249152","article-title":"The curious case of Prevotella copri","volume":"15","author":"Abdelsalam","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Uzal, F.A., Navarro, M.A., Asin, J., Boix, O., Ballar\u00e0-Rodriguez, I., and Gibert, X. (2023). Clostridial diarrheas in piglets: A review. Vet. Microbiol., 280.","DOI":"10.1016\/j.vetmic.2023.109691"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"104405","DOI":"10.1016\/j.fitote.2019.104405","article-title":"A review of cinnamaldehyde and its derivatives as antibacterial agents","volume":"139","author":"Doyle","year":"2019","journal-title":"Fitoterapia"},{"key":"ref_48","first-page":"1735803","article-title":"In Vitro Transformation of Protopanaxadiol Saponins in Human Intestinal Flora and Its Effect on Intestinal Flora","volume":"2021","author":"Zhang","year":"2021","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1002\/ptr.2473","article-title":"Antibacterial activity of [10]-gingerol and [12]-gingerol isolated from ginger rhizome against periodontal bacteria","volume":"22","author":"Park","year":"2008","journal-title":"Phytother. Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Yuan, T., Wang, J., Chen, L., Shan, J., and Di, L. (2020). Lactobacillus murinus Improved the Bioavailability of Orally Administered Glycyrrhizic Acid in Rats. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.00597"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Abd El-Hack, M.E., Alagawany, M., Abdel-Moneim, A.E., Mohammed, N.G., Khafaga, A.F., Bin-Jumah, M., Othman, S.I., Allam, A.A., and Elnesr, S.S. (2020). Cinnamon (Cinnamomum zeylanicum) Oil as a Potential Alternative to Antibiotics in Poultry. Antibiotics, 9.","DOI":"10.3390\/antibiotics9050210"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/nmeth.2604","article-title":"UPARSE: Highly accurate OTU sequences from microbial amplicon reads","volume":"10","author":"Edgar","year":"2013","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11034\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:13:06Z","timestamp":1760112786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,14]]},"references-count":52,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252011034"],"URL":"https:\/\/doi.org\/10.3390\/ijms252011034","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,14]]}}}