The composition of the intestinal microbiome varies considerably between individuals and is correlated with health 1 . Understanding the extent to which, and how, host genetics contributes to this variation is essential yet has proved to be difficult, as few associations have been replicated, particularly in humans 2 . Here we study the effect of host genotype on the composition of the intestinal microbiota in a large mosaic pig population. We show that, under conditions of exacerbated genetic diversity and environmental uniformity, microbiota composition and the abundance of specific taxa are heritable. We map a quantitative trait locus affecting the abundance of Erysipelotrichaceae species and show that it is caused by a 2.3 kb deletion in the gene encoding N -acetyl-galactosaminyl-transferase that underpins the ABO blood group in humans. We show that this deletion is a ≥3.5-million-year-old trans-species polymorphism under balancing selection. We demonstrate that it decreases the concentrations of N -acetyl-galactosamine in the gut, and thereby reduces the abundance of Erysipelotrichaceae that can import and catabolize N -acetyl-galactosamine. Our results provide very strong evidence for an effect of the host genotype on the abundance of specific bacteria in the intestine combined with insights into the molecular mechanisms that underpin this association. Our data pave the way towards identifying the same effect in rural human populations.

Background Antimicrobial resistance (AMR) has been regarded as a major threat to global health. Pigs are considered an important source of antimicrobial resistance genes (ARGs). However, there is still a lack of large-scale quantitative data on the distribution of ARGs in the pig production industry. The bacterial species integrated ARGs in the gut microbiome have not been clarified. Results In the present study, we used deep metagenomic sequencing data of 451 samples from 425 pigs including wild boars, Tibetan pigs, and commercial or cross-bred experimental pigs under different rearing modes, to comprehensively survey the diversity and distribution of ARGs and detect the bacteria integrated in these ARGs. We identified a total of 1295 open reading frames (ORFs) recognized as antimicrobial resistance protein-coding genes. The ORFs were clustered into 349 unique types of ARGs, and these could be further classified into 69 drug resistance classes. Tetracycline resistance was most enriched in pig feces. Pigs raised on commercial farms had a significantly higher AMR level than pigs under semi-free ranging conditions or wild boars. We tracked the changes in the composition of ARGs at different growth stages and gut locations. There were 30 drug resistance classes showing significantly different abundances in pigs between 25 and 240 days of age. The richness of ARGs and 41 drug resistance classes were significantly different between cecum lumen and feces in pigs from commercial farms, but not in wild boars. We identified 24 bacterial species that existed in almost all tested samples (core bacteria) and were integrated 128 ARGs in their genomes. However, only nine ARGs of these 128 ARGs were core ARGs, suggesting that most of the ARGs in these bacterial species might be acquired rather than constitutive. We selected three subsets of ARGs as indicators for evaluating the pollution level of ARGs in samples with high accuracy (r = 0.73~0.89). Conclusions This study provides a primary overview of ARG profiles in various farms under different rearing modes, and the data serve as a reference for optimizing the use of antimicrobials and evaluating the risk of pollution by ARGs in pig farms.

Gut microbiota plays important roles in host metabolism. Whether and how much the gut microbiota in different gut locations contributes to the variations of host serum metabolites are largely unknown, because it is difficult to obtain microbial samples from different gut locations on a large population scale. Here, we quantified the gut microbial compositions using 16S rRNA gene sequencing for 1070 samples collected from the ileum, cecum and faeces of 544 F6 pigs from a mosaic pig population. Untargeted metabolome measurements determined serum metabolome profiles. We found 1671, 12,985 and 103,250 significant correlations between circulating serum metabolites and bacterial ASVs in the ileum, cecum, and faeces samples. We detected nine serum metabolites showing significant correlations with gut bacteria in more than one gut location. However, most metabolite-microbiota pairwise associations were gut location-specific. Targeted metabolome analysis revealed that CDCA, taurine, L-leucine and N-acetyl-L-alanine can be used as biomarkers to predict porcine fatness. Enriched taxa in fat pigs, for example Prevotella and Lawsonia intracellularis were positively associated with L-leucine, while enriched taxa in lean pigs, such as Clostridium butyricum, were negatively associated with L-leucine and CDCA, but positively associated with taurine and N-acetyl-L-alanine. These results suggested that the contributions of gut microbiota in each gut location to the variations of serum metabolites showed spatial heterogeneity.

Background: Excessive fat accumulation of pigs is undesirable, as it severely affects economic returns in the modern pig industry. Studies in humans and mice have examined the role of the gut microbiome in host energy metabolism. Commercial Duroc pigs are often fed formula diets with high energy and protein contents. Whether and how the gut microbiome under this type of diet regulates swine fat accumulation is largely unknown.Results: In the present study, we systematically investigated the correlation of gut microbiome with pig lean meat percentage (LMP) in 698 commercial Duroc pigs and found that P. copri was significantly associated with pig fat accumulation. Fat pigs had significantly higher abundance of P. copri in the gut. High abundance of P. copri was correlated with increased concentrations of serum metabolites related to chronic inflammation, e.g., lipopolysaccharides, branched chain amino acids, aromatic amino acids, and the metabolites of arachidonic acid. Host intestinal barrier permeability and chronic inflammation response were increased. A gavage experiment using germ-free mice confirmed that the P. copri isolated from experimental pigs was a causal species increasing host fat accumulation and altering serum metabolites. Colon, adipose tissue, and muscle transcriptomes in gavage mice indicated that P. copri colonization activated host chronic inflammatory responses through the TLR4 and mTOR signaling pathways and significantly upregulated the expression of the genes related to lipogenesis and fat accumulation, but attenuated the genes associated with lipolysis, lipid transport, and muscle growth.Conclusions: Taken together, the results identified and confirmed that P. copri in the gut microbial communities of pigs fed by commercial formula diets results in significantly increased host fat deposition. We propose a possible mechanism of P. copri affecting fat accumulation. The results provide fundamental knowledge for reducing pig fat accumulation through regulating the gut microbial composition.

Background: Excessive fat accumulation of pigs is undesirable. It severely affects economic return of modern pig industry. Studies in humans and mice have examined the role of the gut microbiome in host energy metabolism. Commercial Duroc pigs are often fed formula diets with high energy and protein. Whether and how the gut microbiome under this type of diets regulates swine fat accumulation is largely unknown.Results: In the present study, we systematically investigated the correlation of gut microbiome with pig lean meat percentage (LMP) in a total of 698 commercial Duroc pigs. We demonstrate that the gut microbiome of fat pigs was dominated by P. copri which occupied 23.53% and 5.76% of relative abundance in average in the discovery and validation cohort, respectively. High abundance of P. copri in the gut resulted in a higher abundance of serum metabolites associated with chronic inflammation, e.g., branched chain amino acids, aromatic amino acids, the metabolites of arachidonic acid metabolism and lipopolysaccharides. Host intestinal barrier permeability and chronic inflammation response were increased. A gavage experiment using germ-free mice confirmed that the P. copri isolated from experimental pigs was a causal species increasing host fat accumulation. Host colon, adipose tissue, and muscle transcriptomes indicated that P. copri colonization significantly upregulated the expression of the genes related to immune and inflammatory responses, lipogenesis, and fat accumulation, but attenuated the genes associated with lipolysis, lipid transport, and muscle growth.Conclusions: Taken together, we identified and confirmed that P. copri in the gut microbial communities of pigs fed by commercial formula diets results in the significantly increased fat deposition of pigs, and proposed a possible mechanism of P. copri affecting fat accumulation. The results provided fundamental knowledges for reducing pig fat accumulation through regulating the gut microbial composition in pig industry.