How Do Genetics and Diet Shape the Human Microbiome?

The human microbiome is essential for good health. It affects digestion, immune system activity, and how the body regulates metabolism.

The gut microbiota is a complex community of microorganisms, most of which are found in the colon. It is mainly made up of bacteria from the Firmicutes and Bacteroidetes phyla.¹

Many factors shape the gut microbiota, but genetics and diet are especially important. Studying how these two factors interact can help us understand disease risk. It also supports the development of personalized nutrition plans and new microbiome-based treatments.^1,2

Image Credit: PeopleImages.com - Yuri A/Shutterstock.com

Gene–Microbiome Interactions

The interaction between human genetics and the gut microbiota is a growing area of research. Projects like the Microbiome Genome (MiBioGen) consortium are conducting large-scale meta-analyses of genome-wide association studies (GWAS) to identify genetic loci linked to differences in microbial diversity and abundance.³

Variants in the LCT gene, which influence lactase persistence and lactose metabolism, have been associated with increased abundance of Bifidobacterium, a genus that metabolizes lactose. Whereas variants in the toll-like receptor 4 (TLR4) gene, which plays a key role in innate immunity, have been linked to shifts in gut microbial composition associated with egg and milk allergies in infants.^3,4

Genetic variation in the FUT2 gene (which encodes fucosyltransferase 2) determines secretor status by regulating the expression of fucosylated glycans in mucosal secretions. These glycans serve as substrates for gut bacteria, influencing diversity and metabolite production.^3,5

Beyond taxonomic shifts, other studies have explored how genetic variation influences microbial function, including metabolite production. For example, specific single-nucleotide polymorphisms (SNPs) can affect genes involved in receptor activity, transport, and intracellular signaling pathways. These pathways are related to short-chain fatty acids (SCFAs), which are produced when gut bacteria ferment dietary fiber.⁵

Genetic variants in genes encoding G-protein-coupled receptors (e.g., GPR41, GPR43) and SCFA transporters (e.g., monocarboxylate transporters, MCTs) can influence individual responsiveness to SCFAs, affecting their immunomodulatory and metabolic effects. They may alter the expression of enzymes involved in SCFA metabolism in the liver and peripheral tissues, contributing to individual variability in systemic SCFA concentrations and downstream biological processes.⁵

Therefore, host genetic variation plays a significant role in microbiome dynamics, influencing the composition and function of the gut microbiota. In turn, genotype shapes a selective intestinal environment that modulates microbial colonization and activity, highlighting the importance of genetic background and metabolic profile.

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Microbiome Responses to Diet

Alongside genetic factors, dietary composition remains a principal modulator of the gut microbiome’s structure and function. Diet influences host physiology both directly and indirectly through interactions with the gut microbiota and its metabolome, exerting both short- and long-term effects.^1,2

The gut microbiota responds to dietary inputs and contributes to health outcomes, largely through the production of metabolites derived from dietary components that can affect host biology. Macronutrient composition—specifically the intake and type of carbohydrates, proteins, and fats—plays a critical role in shaping the microbial ecosystem of the gastrointestinal (GI) tract.^1,2

The impact of dietary fiber on the gut microbiota is well established. A high-fiber diet is consistently associated with increased microbial diversity and enrichment of saccharolytic bacteria (e.g., Bifidobacterium) supporting digestive health.^1,2

Fermentable fibers, such as pectin and inulin, modulate microbial metabolism toward beneficial compounds such as SCFAs, particularly butyrate, which has anti-inflammatory, gut barrier-supporting, and anti-carcinogenic properties. Fiber also increases beneficial tryptophan-derived metabolites, such as indole-3-propionic acid (IPA) and indole-3-acetic acid (ILA), which support gut barrier integrity, immune regulation, and gut-brain communication.^5,6

In contrast, a low-fiber diet is associated with a reduction in SCFA-producing bacteria and beneficial indole derivatives, alongside a shift toward proteolytic fermentation. This metabolic change can lead to the production of potentially harmful tryptophan metabolites—such as oxindole, tryptamine, and serotonin—that have been linked to gut dysbiosis and other pathophysiological effects.^6,7

Protein intake influences the microbiota directly and via metabolic by-products. Increased dietary protein is associated with greater microbial biomass but reduced diversity, an effect linked to adverse digestive outcomes. Microbial responses also vary by protein source, with animal-based proteins associated with increased Bacteroides and reduced Firmicutes, while plant-derived proteins tend to promote a more beneficial microbial composition.^1,2,8

Undigested proteins that reach the colon undergo bacterial proteolysis, producing metabolites such as branched-chain fatty acids (BCFAs), amines, phenolic compounds, indoles, and hydrogen sulfide. While some of these have signaling or antimicrobial functions, excessive proteolytic fermentation is linked to mucosal irritation, impaired gut barrier function, and pro-inflammatory conditions.^5,8

Dietary fats influence the gut microbiome indirectly by altering bile acid secretion and composition. Bile acids possess antimicrobial properties that selectively shape microbial populations. Diets high in saturated fats—characteristic of Western dietary patterns—are associated with reduced microbial diversity and an increase in pro-inflammatory taxa (e.g., Alistipes, Bacteroides). These shifts may impair the intestinal barrier, increase gut permeability, and promote systemic inflammation.^1,2

In contrast, unsaturated fats—especially omega-3 polyunsaturated fatty acids (PUFAs) found in fish, nuts, and plant oils, which are key components of the Mediterranean diet—promote beneficial butyrate-producing bacteria (e.g., Faecalibacterium, Roseburia) and anti-inflammatory genera (e.g., Bifidobacterium, Lactobacillus), supporting greater microbial diversity and improved intestinal homeostasis.^1,2

For a practical look at at-home microbiome testing and how everyday diet influences gut health, watch this short explainer from The Washington Post:

Implications for Integrative Medicine

New research using multi-omics approaches is helping to reveal how host genetics and diet work together to shape the gut microbiome’s structure and function. By combining genomic data with microbiome and metabolomic profiling, scientists are gaining a clearer understanding of how gene–diet–microbiome interactions influence microbial metabolite production, which influences disease susceptibility and treatment response.

This holistic perspective is driving advances in precision nutrition and microbiome-targeted therapies. For example, personalized dietary interventions aimed at boosting butyrate-producing bacteria can help manage inflammatory bowel diseases (IBD).⁹ Similarly, manipulating microbial metabolites influenced by host genetics is being explored to improve metabolic conditions such as type 2 diabetes (T2D) and obesity.¹⁰

Microbiome modulation using probiotics, prebiotics, or fecal microbiota transplantation (FMT) is also being explored for treating neuroinflammatory disorders, such as multiple sclerosis (MS), where gut-brain axis pathways are implicated.¹¹

Together, these interconnected data approaches inform nutritional and therapeutic strategies tailored to an individual’s genetic and microbial profile, aiming to modulate microbial ecosystems to prevent disease and improve clinical outcomes.

By combining genetic, microbial, and metabolomic insights, researchers develop a multidimensional understanding of host–microbiome biology, uncovering mechanisms fundamental to human health and disease, and laying the foundation for advances in precision medicine and integrative care.

To learn more about recent discoveries in gene–diet–microbiome interactions and their clinical implications, visit:

• Genes may determine how early life exposures shape the gut microbiome
• Study Reveals TRF's Role in Reshaping Gut Microbiome and Metabolism
• Gut Microbiome Offers Clues to Detecting and Treating Gastrointestinal Diseases
• Healthy gut microbiome before chemo could help protect breast cancer patients against cardiotoxicity

References and Further Reading

1. Ma, Z.F., Lee, Y.Y. (2025). The Role of the Gut Microbiota in Health, Diet, and Disease with a Focus on Obesity. Foods, 14(3), 492. doi: 10.3390/foods14030492
2. Perler, B.K., Friedman, E.S., Wu, G.D. (2023). The Role of the Gut Microbiota in the Relationship Between Diet and Human Health. Annual Review of Physiology, 85:449-468. doi: 10.1146/annurev-physiol-031522-092054
3. Kurilshikov, A., et al. (2021). Large-scale association analyses identify host factors influencing human gut microbiome composition. Nature Genetics, 53(2):156-165. doi: 10.1038/s41588-020-00763-1
4. Kılıç, M., Beyazıt, E., Önalan, E.E., Kaymaz, T., Taşkın, E. (2023). Evaluation of toll-like receptors 2 and 4 polymorphism and intestinal microbiota in children with food allergies. The Turkish Journal of Pediatrics, 65(5):758-768. doi: 10.24953/turkjped.2023.389
5. Ramos Meyers, G., Samouda, H., Bohn, T. (2022). Short Chain Fatty Acid Metabolism in Relation to Gut Microbiota and Genetic Variability. Nutrients, 14(24), 5361. doi: 10.3390/nu14245361
6. Huang, Z., Boekhorst, J., Fogliano, V., Capuano, E., Wells, J.M. (2023). Distinct effects of fiber and colon segment on microbiota-derived indoles and short-chain fatty acids. Food Chemistry, 398, 133801. doi: 10.1016/j.foodchem.2022.133801
7. Huang, Z., Boekhorst, J., Fogliano, V., Capuano, E., Wells, J.M. (2023). Impact of High-Fiber or High-Protein Diet on the Capacity of Human Gut Microbiota To Produce Tryptophan Catabolites. Journal of Agricultural and Food Chemistry, 71(18):6956-6966. doi: 10.1021/acs.jafc.2c08953
8. Bartlett, A., Kleiner, M. (2022). Dietary protein and the intestinal microbiota: An understudied relationship. iScience, 25(11):105313. doi: 10.1016/j.isci.2022.105313
9. Lacroix, V., Cassard, A., Mas, E., Barreau, F. (2021). Multi-Omics Analysis of Gut Microbiota in Inflammatory Bowel Diseases: What Benefits for Diagnostic, Prognostic and Therapeutic Tools? International Journal of Molecular Sciences, 22(20), 11255. doi: 10.3390/ijms222011255
10. Jardon, K.M., Canfora, E.E., Goossens, G.H.,& Blaak, E.E. (2022). Dietary macronutrients and the gut microbiome: a precision nutrition approach to improve cardiometabolic health. Gut, 71(6):1214-1226. doi: 10.1136/gutjnl-2020-323715
11. Tsogka, A., Kitsos, D.K., Stavrogianni, K.,Giannopapas, V., Chasiotis, A., Christouli, N., Tsivgoulis, G., Tzartos, J.S., Giannopoulos, S. (2023). Modulating the Gut Microbiome in Multiple Sclerosis Management: A Systematic Review of Current Interventions. Journal of Clinical Medicine, 12(24), 7610. doi.org/10.3390/jcm12247610