In this work, to explore the relationships between serum metabolome and gut microbiome in the states of anorexia nervosa, we analyzed gut microbiome, fasting serum metabolome and lipidome, and human phenotypes data originally obtained from 77 well-characterized women with Anorexia Nervosa (AN) and 70 age-matched healthy and normal-weight female controls (NC). We also found gut microbiome from AN patients modulate the AN-relevant endophenotypes in fecal microbiota-transplanted germ-free mice. At the genus rank of the gut microbiome, two genus were noticed to be significantly decreased in the AN group. By contrasting Metagenomic Species Pan-genomes (MSPs) between AN and NC participants, our discovery includes diminished relative abundance of a propionate producer, as well as lower abundance of bacteria which is a mucosa-associated species that increases the bioavailability of butyrate as energy source in AN cases. We demonstrated structural variations are highly prevalent in AN microbiome at species level. At the level of microbiome functional potentials, 34 MSP-based modules were significantly changed in the contrast between AN and NC groups. Interestingly, two distinct propionate production pathways showed contrasting trends, one through transferase was higher while the other one through propanediol pathway was lower in AN patients. Moreover, axis gut-brain modules like glutamate degradation (crotonyl-CoA pathway) was higher in NC group and the GABA biosynthesis (eukaryotes, via putrescine => GABA) was higher in AN patients. Estimation of dynamic growth rates demonstrated AN patients are characterized by reduced growth dynamics of the entire microbiota. Untargeted metabolome and lipidomics profiles were generated on fasting serum samples, providing information about 28 polar metabolites and 1027 lipids (191 known, 836 unknown), respectively. After combining measures of gut microbiome, fasting serum metabolome, and host phenotypes, we demonstrated that host BMI correlated with two key species' abundance, two microbial metabolic modules, as well as circulating levels of metabolites. Compared with NCs, female germ-free mice littermates receiving AN fecal microbiota transplants displayed typical AN-relevant phenotype, higher body weight loss, corresponding to enhanced expression of hypothalamic body-weight-lowering genes and adipose thermogenic genes. Collectively, our study suggests dysbiosis in AN microbiome can alter neurologic and adipose function in ways that may be relevant to AN pathophysiology.
