Depletion of core microbiome forms the shared background against diverging dysbiosis patterns in CD and ITB - Insights from an integrated multi-cohort analysis. Gut Micro/Myco-biome in Intestinal Tuberculosis and Crohns' Disease

CD and ITB are GI inflammatory disorders with overlapping clinical presentations, but diverging etilogies. The study aims to decipher CD and ITB-associated gut dysbiosis signature and identify disease-associated co-occurring modules to evaluate whether this dysbiosis signature is a disease-specific trait or is it a shared feature across GI diseases of diverging etiologies. Stool samples from controls, CD and ITB subjects were subjected to 16S(n=57) and ITS1(n=64) sequencing, to compare bacteriome/archaeome/mycobiome dysbiosis, between the two diseases. Co-abundance network analysis was performed on the differentially abundant taxa to identify disease-associated modules, which were re-investigated through meta-network analysis encompassing > 5,400 bacteriomes and ~900 mycobiome profiles. Following this, greater than 1,600 Indian gut microbiomes were analysed to identify an Indian gut microbiome core of 46 members, whose abundances aided in formulation of a Core Gut Microbiome Score (CGMS) to measure the degree of core retention. With respect to controls, the extent of alterations in α and beta diversities of bacteriome/archaeome were similar in CD and ITB, however, the shifts in mycobiome diversity and profiles were more pronounced in ITB. Specific differential bacterial taxa, along with the diverging mycobiome enables distinction between two diseases. Co-abundance network analysis of these taxa, validated by an integrated meta-network analysis, revealed a ‘disease-depleted’ module, consistent across multiple cohorts. Greater than 75% of this module overlapped with the Indian gut microbiome core. CGMS robustly assessed the core microbiome loss across different stages of gut inflammatory disorders, in Indian as well as international cohorts. While diseases-specific gain of detrimental bacteria forms an important component of gut dysbiosis, the loss of the core microbiome is a shared phenomenon contributing to various GI disorders.

克罗恩病（Crohn’s Disease, CD）与肠结核（Intestinal Tuberculosis, ITB）均为胃肠道（Gastrointestinal, GI）炎性疾病，二者临床表现存在重叠，但病因学存在显著差异。本研究旨在解析CD与ITB相关的肠道菌群失调特征谱，并识别疾病相关共现模块，以评估该菌群失调特征究竟是疾病特异性特征，还是不同病因胃肠道疾病共有的特征。研究收集了健康对照、CD及ITB受试者的粪便样本，分别开展16S测序（n=57）与ITS1测序（n=64），以对比两种疾病间细菌组（bacteriome）、古菌组（archaeome）与真菌组（mycobiome）的菌群失调差异。研究对差异丰度类群开展共丰度网络分析（co-abundance network analysis），以识别疾病相关模块；随后通过覆盖超过5400份细菌组样本与约900份真菌组样本的元网络分析（meta-network analysis），对上述模块进行复现验证。在此基础上，研究分析了超过1600份印度人群肠道微生物组样本，鉴定出由46个成员组成的印度人群肠道核心微生物组，并基于其丰度构建了核心肠道微生物组评分（Core Gut Microbiome Score, CGMS），用于量化核心菌群的保留程度。与健康对照相比，CD与ITB患者的细菌组、古菌组的α多样性与β多样性改变程度相似，但ITB患者的真菌组多样性及群落结构的变化更为显著。特定的差异细菌类群结合真菌组的特异性变化，可实现两种疾病的有效区分。对上述类群开展的共丰度网络分析经整合元网络分析验证后，发现了一个‘疾病耗竭型’模块，该模块在多个研究队列中均保持一致。该模块中超过75%的成员与印度人群肠道核心微生物组存在重叠。CGMS可在印度及国际研究队列中，准确评估各类胃肠道炎性疾病不同阶段的核心微生物组丢失情况。研究表明，疾病特异性的有害细菌增殖是肠道菌群失调的重要组成部分，而核心微生物组的丢失则是多种胃肠道疾病共有的发病机制。