Implications of blood type in personalised microbiome therapy

The critical role the gut microbiome can play in personalised medicine is deeply rooted in the symbiotic relationship between the host and gut microorganisms, a relationship shaped by their coevolution and extensive host–microbe metabolic and immune interactions. It is hypothesised that host genetics can determine the chemical and physical environment that gut microorganisms inhabit, including nutrient availability and immune system thresholds, but genetics-based evidence and mechanistic understanding are still lacking. We recently carried out a genome-wide association study between human genetics and gut microbial structural variations (SVs),1 which shed light on how blood type A sugar fuels gut microbes and promotes human health. Here, we summaries our key findings and elaborate on the implications for clinical practice. Heritability of the gut microbiome has been observed in animals and humans. In recent years, genome-wide association studies on microbial species abundance level have yielded several robust associations with host genetic loci. However, the genetic diversity within individual species can complicate mechanistic interpretation.2 Specifically, bacterial SVs, segments of the bacterial genome of different lengths, are an essential microbial adaptive mechanism. SVs have been found to play a crucial role in enhancing microbial survival, carbohydrate utilisation, metabolism and even pathogenic potential.3 We were therefore motivated to identify microbial genes under host control via the lens of microbial SVs. Our study identified striking association between the human ABO locus and a specific SV region in the gut microbe Faecalibacterium prausnitzii. The ABO gene encodes a transferase that determines the terminal sugars of blood type antigens: GalNAc for blood type A and galactose for blood type B. In people who are also FUT2 secretors, these blood type antigens can be freed and released into body fluid, including into intestinal mucus. Interestingly, the SV region of F. prausnitzii that we identified contains a GalNAc utilisation gene cluster, and we further found that the presence rate of this cluster was significantly higher in blood type A/AB individuals with FUT2 secretor status. Our study also revealed mechanistic evidence that gut microbes can utilise blood type-linked sugar as nutrients for growth, and we also found evidence for a beneficial impact on microbial niche and host cardiometabolic health (Figure 1). The study was the first human study to move beyond established associations between host genetics and gut microbial abundance to pinpointing potential causal genes of both human genome and the gut microbiome, bridging the gap from species abundance to functionality. The identified association involves the ABO gene and F. prausnitzii, both of which have been implicated in human health. The ABO genotype has been associated with many diseases and traits, including venous thromboembolism, lipid levels, cardiometabolic phenotypes and susceptibility to infectious diseases such as dengue, malaria and even COVID-19.4, 5 Its pleiotropic effect has also been observed at molecular levels, such as in cardiovascular-disease-related proteins.6 F. prausnitzii is a major fibre fermenter in our intestine that produces a health-promoting short-chain fatty acid called as butyrate. The beneficial role of F. prausnitzii has been reported in all kinds of human diseases, ranging from cardiometabolic, immune and mental diseases to cancers. Pre-clinical experiments have shown it has a beneficial role in shaping the intestinal microbial flora, restoring metabolic homeostasis and alleviating inflammation.7 However, F. prausnitzii is a strictly anaerobic microbe, and development of F. prausnitzii as a next-generation probiotic still faces some technical hurdles.8 Approaches to manipulate its intestinal abundance still largely rely on dietary intervention (e.g., high fibre intake) or faecal microbiota transplantation (FMT). FMT has now been approved as an effective approach in treating Clostridium difficile infections,9 and its application is emerging for the treatment of other diseases and in combination with other treatment to enhance therapeutic outcome. The most notable example thus far is that FMT can enhance efficacy of immunotherapy,10, 11 and F. prausnitzii has been shown to abrogate intestinal toxicity and promote immunity.12 Thus, colonisation with the right F. prausnitzii strain for the patient is crucial. Blood compatibility is critical in solid organ transplantation; our results suggest that it might also be necessary to match blood type to a specific strain of F. prausnitzii to promote engraftment and colonisation of F. prausnitzii. In other ways, our study provides evidence of the need for personalised microbiome-based medicine. This study provides mechanistic insights into microbial utilisation of carbohydrates produced by the human genome, demonstrating a positive health impact in individuals with A blood type and FUT2 secretor status. However, it remains unclear whether their improved health is due to the direct effect of GalNAc utilisation or a secondary effect of the enhanced growth of the beneficial bacterium F. prausnitzii. Future research needs to construct comprehensive in vivo models that can unravel the causal relationship, particularly the interaction between A-antigen, F. prausnitzii, and host health outcomes. In addition to the ABO locus, our study reported >200 suggestive associations with small to modest effect size. Their underlying biological mechanisms and potential physiological value await detailed understanding. Future research thus calls for cross-disciplinary approaches such as the integration of omics technologies and statistical tools in combination with in vivo and in vitro approaches. J.F. supervised the whole writing process and revised the manuscript. Y.Z. wrote the manuscript with critical reading and feedback from R.G. We thank Kate Mc Intyre for English editing. Y.Z. is supported by a joint fellowship from the University Medical Center Groningen and CSC with grant number CSC202006170040. J.F. is supported by the Dutch Heart Foundation IN-CONTROL (CVON2018-27), the European Research Council Consolidator Grant (grant agreement no. 101001678), the Dutch Research Council (NWO) VICI (VI.C.202.022), the 2023 AMMODO Science Award for Biomedical Sciences from Stichting Ammodo, and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation Project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands. All authors have been personally and actively involved in substantial work leading to the paper and will take public responsibility for its content.