Social relationships shape human health and mortality via behavioral, psychosocial, and physiological mechanisms, including inflammatory and immune responses. Though not tested in human studies, recent primate studies indicate that the gut microbiome may also be a biological mechanism linking relationships to health. Integrating microbiota data into the 60-year-old Wisconsin Longitudinal Study, we found that socialness with family and friends is associated with differences in the human fecal microbiota. Analysis of spouse (N = 94) and sibling pairs (N = 83) further revealed that spouses have more similar microbiota and more bacterial taxa in common than siblings, with no observed differences between sibling and unrelated pairs. These differences held even after accounting for dietary factors. The differences between unrelated individuals and married couples was driven entirely by couples who reported close relationships; there were no differences in similarity between couples reporting somewhat close relationships and unrelated individuals. Moreover, married individuals harbor microbial communities of greater diversity and richness relative to those living alone, with the greatest diversity among couples reporting close relationships, which is notable given decades of research documenting the health benefits of marriage. These results suggest that human interactions, especially sustained, close marital relationships, influence the gut microbiota.

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp . and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2 . Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.

26 The microbial communities that inhabit the distal gut of humans and other mammals exhibit large 27 inter-individual variation. While host genetics is a known factor that influences gut microbiota 28 composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) 29 are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as 30 environmental cues and nutrients to microbes, but they can also have antibacterial effects. We 31 hypothesized that host genetic variation in BA metabolism and homeostasis influence gut 32 microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population 33 of genetically distinct mice derived from eight founder strains. We characterized the fecal 34 microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a 35 high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we 36 identified several genomic regions associated with variations in both bacterial and BA profiles.37 Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped 38 to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and 39 subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression 40 associated with the different strains influences levels of both traits and revealed novel interactions 41 between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to 42 generate testable hypotheses and provide insight into host-microbe interactions. 44Author summary 45 Inter-individual variation in the composition of the intestinal microbiota can in part be attributed 46 to host genetics. However, the specific genes and genetic variants underlying differences in the 47 microbiota remain largely unknown. To address this, we profiled the fecal microbiota composition 3 48 of 400 genetically distinct mice, for which genotypic data is available. We identified many loci of 49 the mouse genome associated with changes in abundance of bacterial taxa. One of these loci is 50 also associated with changes in the abundance of plasma bile acidsmetabolites generated by the 51 host that influence both microbiota composition and host physiology. Follow up validation 52 experiments provide mechanistic insights linking host genetic differences, with changes in ileum 53 gene expression, bile acid-bacteria interactions and bile acid homeostasis. Together, this work 54 demonstrates how genetic approaches can be used to generate testable hypothesis to yield novel 55 insight into how host genetics shape gut microbiota composition. 56 57 Introduction 58The intestinal microbiota has profound effects on host physiology and health (1-3). The 59 composition of the gut microbiota is governed by a combination of environmental factors, 60 including diet, drugs, maternal seeding, cohabitation, and host genetics (4-7). Together, these 61 factors cause substantial inter-i...

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe–host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila–host interactions and support the role of host genetics as a determinant of responses to gut microbes.

30Social relationships shape human health and mortality via behavioral, psychosocial, and 31 physiological mechanisms, including inflammatory and immune responses. Though not tested in 32 human studies, recent primate studies indicate that the gut microbiome may also be a biological 33 mechanism linking relationships to health. Integrating microbiota data into the 60-year-old 34Wisconsin Longitudinal Study, we found that socialness with family and friends is associated with 35 differences in the human fecal microbiota. Analysis of spouse (N = 94) and sibling pairs (N = 83) 36 further revealed that spouses have more similar microbiota and more bacterial taxa in common 37 than siblings, with no observed differences between sibling and unrelated pairs. These differences 38 held even after accounting for dietary factors. The differences between unrelated individuals and 39 married couples was driven entirely by couples who reported close relationships; there were no 40 differences in similarity between couples reporting somewhat close relationships and unrelated 41 individuals. Moreover, the microbiota of married individuals, compared to those living alone, has 42 greater diversity and richness, with the greatest diversity among couples reporting close 43 relationships, which is notable given decades of research documenting the health benefits of 44 marriage. These results suggest that human interactions, especially sustained, close marital 45 relationships, influence the gut microbiota. 46 including age, sex, antibiotics, diet (dietary protein), and chronic conditions (diabetes and heart 131 disease) unless stated otherwise. Dietary data reflects the three days prior to the fecal sample 132 collection. We tested a wide array of specific dietary variables, but consumption of dietary protein 133 was the only one robustly associated with microbial composition. 134 135 Social interactions and the human fecal microbiota In the WLS graduate cohort, we have 136 identified factors correlated with gastrointestinal (GI) microbiota. These factors include sex, 137