Ashton Philip M, Mageiros Leonardos, Meiring James E, Chunga-Chirambo Angeziwa, Khanam Farhana, Dongol Sabina, Banda Happy, Karkey Abhilasha, Preciado-Llanes Lorena, Thomaides-Brears Helena, Gibani Malick, Rajib Nazmul Hasan, Rahman Nazia, Biswas Prasanta Kumar, Bhuiyan Md Amirul Islam, Kay Sally, Auger Kate, Seret Olivier, Thomson Nicholas R, Pollard Andrew J, Baker Stephen, Basnyat Buddha, Clemens John D, Dolecek Christiane, Dunstan Sarah J, Dougan Gordon, Heyderman Robert S, Pitzer Virginia E, Qadri Firdausi, Gordon Melita A, Holt Kathryn E, Darton Thomas C
Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi.
Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
Microbiome. 2025 Jul 22;13(1):168. doi: 10.1186/s40168-025-02125-7.
Typhoid fever is a systemic infection caused by Salmonella enterica serovar Typhi (S. Typhi) invasion from the gut lumen. Transmission between people occurs through ingestion of contaminated food and water, particularly in settings with poor water and sanitation infrastructure, resulting in over 10 million illnesses annually. As the pathogen invades via the gastrointestinal tract, it is plausible that the gut microbiome may influence the outcome of S. Typhi exposure. There is some evidence that bacteria producing short-chain fatty acids (SCFAs) may create an environment unfavourable to invasive Salmonella, but data from humans is limited.
To investigate the association between the gut microbiome and typhoid fever, we analysed samples collected from three all-age cohorts enrolled in a prospective surveillance study conducted across three settings where typhoid fever is endemic (Dhaka, Bangladesh; Blantyre, Malawi; and Kathmandu, Nepal). Cohorts consisted of acute typhoid fever patients (n = 92), asymptomatic household contacts of typhoid fever patients (representing individuals who were likely exposed to S. Typhi but did not develop the disease, n = 97) and asymptomatic serosurvey participants with high Vi antibody titres (representing individuals who were exposed to S. Typhi and may be carriers, n = 69). The stool microbiomes of each cohort were characterised using shotgun metagenomics, and bacterial diversity, composition and function were compared.
We identified 4 bacterial species that were significantly lower in abundance in typhoid fever patients compared with household contacts (i.e. probably exposed), in two of the three participant populations (Bangladesh and Malawi). These bacteria may represent taxa that provide protection against the development of clinical infection upon exposure to S. Typhi and include the inflammation-associated species Prevotella copri clade A and Haemophilus parainfluenzae. Our functional analysis identified 28 specific metabolic gene clusters (MGCs) negatively associated with typhoid fever in Bangladesh and Malawi, including seven MGCs involved in SCFA metabolism. The putative protection provided by microbiome SCFA metabolism was supported by data from a controlled human infection model conducted in a UK population, in which participants who did not develop typhoid fever following ingestion of S. Typhi had a higher abundance of a putative SCFA-metabolising MGC (q-value = 0.22).
This study identified the same protective associations between taxonomic and functional microbiota characteristics and non-susceptibility to typhoid fever across multiple human populations. Future research should explore the potential functional role of SCFAs and inflammation-associated bacteria in resistance to S. Typhi and other enteric infections. Video Abstract.
伤寒热是一种由肠道沙门氏菌血清型伤寒杆菌（伤寒杆菌）从肠腔入侵引起的全身性感染。人与人之间的传播是通过摄入受污染的食物和水发生的，特别是在水和卫生基础设施差的环境中，每年导致超过1000万例疾病。由于病原体通过胃肠道入侵，肠道微生物群可能影响伤寒杆菌暴露的结果是合理的。有一些证据表明，产生短链脂肪酸（SCFAs）的细菌可能会创造一个不利于侵袭性沙门氏菌的环境，但来自人类的数据有限。
为了研究肠道微生物群与伤寒热之间的关联，我们分析了从三个全年龄队列收集的样本，这些队列参与了在伤寒热流行的三个地区（孟加拉国达卡、马拉维布兰太尔和尼泊尔加德满都）进行的前瞻性监测研究。队列包括急性伤寒热患者（n = 92）、伤寒热患者的无症状家庭接触者（代表可能接触过伤寒杆菌但未发病的个体，n = 97）和Vi抗体滴度高的无症状血清学调查参与者（代表接触过伤寒杆菌且可能是携带者的个体，n = 69）。使用鸟枪法宏基因组学对每个队列的粪便微生物群进行表征，并比较细菌多样性、组成和功能。
在三个参与人群中的两个（孟加拉国和马拉维），我们发现与家庭接触者（即可能接触过）相比，伤寒热患者中4种细菌的丰度显著降低。这些细菌可能代表在接触伤寒杆菌后提供针对临床感染发展保护作用的分类群，包括与炎症相关的物种柯氏普雷沃菌A分支和副流感嗜血杆菌。我们的功能分析确定了在孟加拉国和马拉维与伤寒热呈负相关的28个特定代谢基因簇（MGCs），包括7个参与SCFA代谢的MGCs。在英国人群中进行的一项受控人类感染模型的数据支持了微生物群SCFA代谢提供的假定保护作用，在该模型中，摄入伤寒杆菌后未患伤寒热的参与者中，一个假定的SCFA代谢MGC的丰度更高（q值 = 0.22）。
本研究在多个人类群体中确定了分类学和功能性微生物群特征与对伤寒热不敏感之间相同的保护关联。未来的研究应探索SCFAs和与炎症相关的细菌在抵抗伤寒杆菌和其他肠道感染中的潜在功能作用。视频摘要。
