Correction: GerAB residues predicted to interact with water based on MD simulations mediate germinosome stability in Bacillus subtilis spores

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In the first paper of this Series, we discussed the temporal dynamics of the human gut microbiome across multiple timescales, ranging from diurnal rhythms and seasonal fluctuations to lifelong progression, all of which are associated with host homoeostasis, health, and disease susceptibility. In this second Series paper, we focus on the spatial signatures of the human gut microbiome, synthesising knowledge of its biogeographical architecture, underlying factors, and clinical implications, alongside cutting-edge approaches to investigate this spatial ecology.Beyond displaying temporal dynamics, the human gut microbiome also shows distinct spatial patterns along the gastrointestinal tract, from the small intestine to the colon, 1,2 reflecting niche-specific adaptations to local physiological and chemical conditions. Moreover, due to the complex network of host cells and unique microenvironments (eg, oxygen, pH, immune factors) in each region of the gastrointestinal tract, the host mucosal layer and lumen each sustain a specialised microbiome, which maintains protective niches along the transverse axis. This spatial organisation therefore shapes the host-microbiome interface, making it a crucial determinant of human health. 1,3 However, a fundamental challenge in advancing the understanding of the gut microbial spatial organisation lies in the conceptual and methodological distinction between autochthonous (adherent, resident) microbiome and allochthonous (transient) microbiome. Faecal samples, which have been the mainstay of gut microbiome research, predominantly represent the luminal and allochthonous communities. Consequently, they are inherently devoid of biogeographical information on the adherent, site-specific autochthonous populations that directly interact with the host epithelium. This limitation is further exacerbated by the current underdevelopment of in-situ sequencing techniques capable of directly profiling microbial communities within specific regions of the gastrointestinal tract. 4,5 In this Series paper, we first synthesise the varied and unique microbiomes observed along the human gastrointestinal tract and the factors that influence their biogeographical architecture. We further explore how microbial metabolites, such as short-chain fatty acids and modified bile acids, serve as key communicators between the microbes and the host, particularly in regulating immune and metabolic pathways. The clinical relevance of spatial gut microbiome variation is also discussed, underscoring its diagnostic, therapeutic, and prognostic potential. Advances in molecular techniques, from high-resolution imaging and single-cell sequencing to non-invasive sampling devices, are now enabling fine-grained mapping of microbial communities across the gut niches of each region. These tools have evolved to capture everything from individual strains to complex consortia, offering unprecedented insights into the functional roles of biogeography.activity differ significantly between gastrointestinal tract regions, such as the small and large intestine. As a result, relying on samples from only one or a few regions of the gastrointestinal tract cannot provide a complete view of the gut microbiome as a whole. To date, most studies investigating the dynamics of the gut microbiome have relied on faecal samples due to their non-invasive and convenient sampling. 6 Despite offering valuable insights into the microbial communities of the distal colon, faecal samples do not fully capture the diversity and functional nuances of microbial populations in other regions of the gastrointestinal tract. This limitation underscores the need for more sophisticated sampling methods and technologies to explore the spatial heterogeneity of the gut microbiome across its entire length and breadth.Access to specific regions of the gastrointestinal tract for microbiome sampling can be achieved through endoscopy, typically performed on individuals who are either fasting or under sedation. 6 This approach has allowed researchers to glimpse distinct microbial signatures of the small and large intestine, revealing substantial differences in microbial composition and function between these regions. 7 In addition to variations along the longitudinal axis of the gastrointestinal tract (from the stomach to the colon), the microbiome also shows differences along the transverse axis, such as between the lumen (the inner cavity of the gut) and the mucosal layer (the gut lining). 8 Generally, the gut lumen is characterised by a core member of Enterobacteriaceae, Bifidobacterium, Bacteroides, Streptococcus, Clostridium, Enterococcus, Lactobacillus, and Ruminococcus, whereas mucin consumers, such as species of Clostridium, Lactobacillus, Enterococcus, and Verrucomicrobia reside closer to the epithelium. 9 By clustering antibiotic resistance genes (ARGs) of the microbes sampled from luminal aspirates (including the terminal ileum, caecum, and descending colon) and mucosal samples (eg, the caecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum), researchers have found that ARGs can distinguish between samples from different regions and layers of the gut. 10 Additionally, the mucosal viral community shows a distinct composition from the stool virome, characterised by a high abundance of crAss-like phages that remain undetectable through faecal sampling, as shown by analysis of proximal colon, distal colon, and faecal samples from three children with inflammatory bowel disease. 11 These findings underscore the spatially heterogeneous functional variability of the gut microbiome, reflecting its adaptation to distinct microhabitats along both the longitudinal and transverse axes of the gastrointestinal tract (figure 1).Although few studies have focused on the microbial composition of the human small intestine, current findings have identified a core set of microbial taxa that consistently colonise this region, including Streptococcus, Veillonella, Fusobacterium, Prevotella, and Haemophilus. 12 In characterising the microbial composition in each segment of the small intestine (ie, the duodenum, jejunum, and ileum), Neisseria, Granulicatella, Rothia, and Gemella were uniquely found in the duodenum, and Actinomyces was only found in the jejunum. By contrast, the ileum was found to be dominated by taxa such as Lactobacillus, Bifidobacterium, Clostridium, Ruminococcus, Escherichia, and Bacteroides. 12 The microbial ecosystem of the human small intestine is characterised by rapid nutrient turnover, primarily driven by the efficient consumption of simple carbohydrates. 13 A comparative analysis of microbial communities across the transverse axis of the small intestine revealed clear differentiation between the mucosal and luminal microbiomes. In a study on the mucosal layer of 33 deceased Chinese transplant donors, Coprococcus and Clostridium were the dominant genera, with Akkermansia and Bifidobacterium present as notable secondary colonisers. 7 Balloon-assisted enteroscopy data from 29 Japanese individuals showed that Bacillota overwhelmingly dominated the small-intestinal microbiome, accounting for 50-56% of the total microbial community. 14 Within this phylum, Veillonella and Streptococcus were especially enriched in the upper gastrointestinal tract-including the stomach, duodenum, and jejunum-in which Veillonella constituted approximately 15-20% of the community and Streptococcus comprised approximately 20-29%. 14 Notably, Veillonella is particularly efficient in metabolising lactate as a primary substrate. This trait is evidenced by the observed increase in the abundance of this genus in the faecal sample of athletes after a marathon, coupled with an increased expression of genes responsible for converting lactate to propionate. These observations suggest Veillonella might contribute to lactate level management and metabolic recovery. 15 The prevalence of Bacillota has been re