Estimating the magnitude and scope of disability-related direct costs: a systematised review.

Trillions of microbes inhabit the human body, particularly in mucosal tissues such as the gut (You et al., 2025). The microbial population in the gut is considerably denser than in other bodily regions (Sender et al., 2016; Thursby and Juge, 2017), comprising approximately 100 distinct species. The gastrointestinal microbiota, which includes bacteria, archaea, and eukaryotes, has co-evolved with its host over millennia to establish a mutually beneficial relationship (Bäckhed et al., 2005). Remarkably, this microscopic ecosystem is estimated to contain 10 individual microbes. Recent evidence suggests that microbial numbers are roughly equivalent to human cell counts (Sender et al., 2016), although earlier estimates proposed a tenfold greater ratio (Gill et al., 2006). The predominant phyla in the gut include , , , and (Korf et al., 2022). Colonization of the gastrointestinal tract begins at birth, with microorganisms acquired from the mother and the surrounding environment (Thursby and Juge, 2017). The gut microbiota protects against pathogens by promoting intestinal epithelium regeneration (Li et al., 2025; Zhang et al., 2025a), strengthening barrier functions, competing for resources, producing antimicrobial substances such as hydrogen peroxide, and creating an acidic environment that inhibits pathogenic bacteria (Thursby and Juge, 2017). It also plays a vital nutritional role by fermenting complex carbohydrates (e.g., cellulose, pectin, and starch) and proteins to produce short- and branched-chain fatty acids, which serve as essential energy sources for colon cells (den Besten et al., 2013). Lactic acid bacteria synthesize vitamin B12, a nutrient that neither plants nor animals can produce (LeBlanc et al., 2013). In parallel, serve as primary producers of folate involved in DNA metabolism and generate essential nutrients such as vitamin K and the B-complex vitamins (Pompei et al., 2007). Clinical findings indicate that patients with inflammatory depression exhibit gut microbiota imbalances, including increased , reduced , and dysregulated short-chain fatty acid-producing species characterized by abnormal butyrate metabolism (Liu et al., 2024a). Animal studies further demonstrate that transplanting fecal microbiota from these patients induces depressive- and anxiety-like behaviors in recipient mice, along with elevated peripheral and central inflammatory markers. Notably, supplementation with restores microbial composition, reduces inflammatory parameters, and exerts antidepressant effects (Liu et al., 2024a). A recent study has confirmed that gut microbiota and its metabolites influence central nervous system (CNS) function by modulating the brain’s biochemical microenvironment and blood–brain barrier (BBB) permeability (Mayerhofer et al., 2017). Over the past two decades, research has increasingly emphasized the critical role of microbiome in maintaining health and its link to neurodegeneration through the microbe-gut-brain axis. The intestinal epithelial permeability increases with age (Tran and Greenwood-Van Meerveld, 2013), allowing gut microbiota and its metabolites to cross the intestinal barrier into the somatic circulation, including the CNS. The gut microbiota communicates with the CNS through producing neuroactive substances, metabolites, and hormones that regulate the immune system, vagus nerve, enteric nervous system, neuroendocrine system, and circulatory system, forming a bidirectional regulatory network with the brain (El Aidy et al., 2015; Bistoletti et al., 2020; Silva et al., 2020). Based on differences in pathology propagation, two disease subtypes have been proposed: brain-first (), where pathology originates in the CNS and extends to the peripheral autonomic nervous system, and body-first (), in which pathology begins in the gut or peripheral autonomic nervous system and progresses to the CNS (Arotcarena et al., 2020; Leclair-Visonneau et al., 2020).