Host Biology in Light of the MicrobiomeTen Principles of Holobionts and Hologenomes

A single fruit fly sitting on a piece of rotting fruit carries somewhere between ten trillion and one hundred trillion microbial cells. These are not invaders or passengers. They are co-authors of its biology. If that's true — and the evidence now supports this — then almost every major theory in biology was built around the wrong unit of life. This is the argument that Seth Bordenstein and Kevin Theis make in their two thousand fifteen paper laying out ten principles of holobionts and hologenomes. It's a sweeping claim, deliberately structured to be testable and falsifiable. And it starts with a problem that took a long time to name. Biology's foundational frameworks — Darwin's variation among individuals, Mendel's particulate inheritance, and the mid-twentieth century modern synthesis — all share a quiet assumption: that the multicellular organism is the relevant unit. Phenotypes map to the host nuclear genome. Selection acts on autonomous organisms. The field became, as Bordenstein and Theis put it, nucleocentric. And that happened for understandable reasons: microbiology was largely divorced from zoology and botany for most of the era when these theories crystallized. The tools to study microbes in depth simply didn't exist. Now they do. What they are showing is that animals and plants are better described as holobionts — the host plus all of its associated symbiotic microbes, bacteria, archaea, viruses, protists, fungi, and the works — and that their collective genetic content forms a hologenome: the host nuclear genome, organelle genomes, and the microbiome together. The term holobiont traces to Lynn Margulis and the Greek word holos, meaning whole. Bordenstein and Theis are careful about what this term does and doesn't mean. A holobiont is not an organ system — organs are built from cells sharing one genome, while the microbiota is a multispecies consortium with many. It's not a superorganism, a term reserved for same-species colonies like ant or bee colonies. And the hologenome is not a metagenome. That distinction is worth pausing on. A metagenome refers to the genetic inventory of an environmental sample — soil or a water column. It's a catalog. Hologenome implies evolutionary unity: heritable variation that selection and drift can act upon. Removing a bacterial metagenome from soil leaves soil. Removing it from a host leaves something that can no longer survive as itself. That difference — between a catalog and an evolutionary unit — is where the concept gets real traction. Microbial genetic variation, Bordenstein and Theis note, vastly exceeds that of the host genome and accumulates far more rapidly. This means the microbiome isn't background noise. It's an enormous reservoir of raw material for evolution. This brings us to Mendel's uncomfortable moment. Microbes move between generations. Bordenstein and Theis describe two broad routes: vertical transmission, which is from parent to offspring, via internal routes like transovarial passage or external routes like breast milk, and horizontal transmission, which is acquisition from the environment or other hosts. The key insight is that many associations start horizontal and become vertical over evolutionary time. Mitochondria did exactly that. So did insect endosymbionts — bacteria once acquired during a host's lifetime that are now inherited across generations as reliably as any gene. If the host and microbe covary across generations with sufficient fidelity, microbes behave like alleles. They change frequency in populations. They are subject to selection and drift. Bordenstein and Theis introduce a parameter they call Theta — the degree of coinheritance of hologenomic combinations — and argue that when Theta is high, selection can operate on host-microbe combinations much as it does on linked nuclear alleles. This doesn't rewrite Mendel. It extends him, adding microbial players to the pool of heritable variation. The authors call it an "expansive but not revolutionary extension" of evolutionary genetics. The predictions generated are concrete. Offspring microbiota should resemble their parents' microbiota more closely than unrelated adults at comparable ages. Experimentally tagged microbes in parents should appear in offspring organs more often than in peers. Hosts should evolve immune, morphological, or behavioral mechanisms to promote transmission of beneficial microbes. These are testable. Some are already being tested. Now here's where the argument reaches its most ambitious point: natural selection can act on the holobiont as a whole. The central empirical pillar Bordenstein and Theis offer is phylosymbiosis — the pattern in which microbial community relationships change in parallel with the host nuclear phylogeny. Within a generation, intraspecific microbial communities should be more similar to each other than to interspecific communities. Across generations, host genetic divergence should associate with microbial community divergence. Under diet-controlled conditions, evidence for phylosymbiosis exists in Nasonia wasps and Hydra; in the wild, it appears in sponges, ants, and apes. Phylosymbiosis is a pattern. Speciation examples show the process. Bordenstein and Theis walk through several. In Drosophila paulistorum, Lee Ehrman's classic work revealed bacterial infections in testes — later identified as Wolbachia — contributing to infectious hybrid sterility between subspecies. In Nasonia parasitoid wasps, Wolbachia drive first-generation hybrid inviability, and there’s a striking genetic contingency: quantitative trait loci associated with second-generation hybrid lethality are contingent on the presence of the Nasonia gut microbiota. Remove the microbiota, and the genetic effect changes. In Drosophila melanogaster, variation in the gut microbiota alters host odor profiles and causes premating isolation between strains — behavioral isolation driven not by nuclear genes alone, but by microbial passengers. Immune genes sit at the center of this story. Bordenstein and Theis invoke what they call the Large Immune Effect: immune and defense genes evolve rapidly under positive selection and are disproportionately disrupted in hybrids. The number that lands this point is striking. In hybridizations between Drosophila melanogaster and Drosophila simulans, ninety-three percent of immune genes were differentially expressed relative to nonhybrid controls, compared with fifty-seven percent of nonimmune genes. Hybrids in other systems show altered microbiota, increased gut pathology, and misregulated immune expression. These aren't side effects of speciation. They may be drivers of it. The implication that Bordenstein and Theis draw is direct: if host immune genes and microbiota jointly determine holobiont fitness, and if host-microbe covariance persists across generations, then selection can operate on hologenomic combinations in a manner analogous to selection on nuclear gene combinations. Speciation, in this view, is partly a story about symbiosis. All of this, though, only matters scientifically if it generates predictions that can fail. Bordenstein and Theis are explicit about this. They write that the concepts are "subject to refutation" and that they have explained how they can be empirically and experimentally falsified. The ten principles exist precisely to make holobionts and hologenomes into hypotheses rather than metaphors. The methodological anchor they return to repeatedly is microbe-free experimentation — germ-free, gnotobiotic, and transbiotic setups where microbial composition can be controlled or stripped out entirely. The paper argues this should become routine in speciation studies. The principle is simple: if hologenomic variation affects fitness, then manipulating the total microbiota will alter host fitness. Empirical examples support this. Hemipteran insects raised with germ-free or interspecific gut microbiota show reduced survivorship and delayed development. Mice colonized with human gut microbiota develop global immunodeficiency — less T cell proliferation and greater susceptibility to enteric infection. The microbiome isn't decorative. Beyond single experiments, the framework demands quantification: of transmission fidelity, of host-microbe covariance, and of intergenomic epistasis. Are host and microbial genomes coinherited strongly enough for selection to change their combined frequencies across generations? How consistent is microbial transmission? How extensive is the interplay between host genes and microbial genes in shaping fitness? These questions couldn't even be properly framed within a strictly nucleocentric paradigm. Bordenstein and Theis close by being clear about what they are and aren't claiming. Principle ten states explicitly that holobionts and hologenomes do not change the rules of evolutionary biology. Darwin and Mendel aren't casualties here. What changes is the unit: the biological individual is redefined to include the host plus its symbiotic microbes, and that composite — the holobiont — along with its total genetic content becomes a legitimate unit of ecological and evolutionary analysis. Biology built extraordinary power by reducing organisms to their genes. That reductionist approach isn't wrong. It just needs to accommodate the microbial co-authors sitting alongside those genes — co-authors whose combined genetic variation dwarfs the host's own, whose inheritance can be tracked across generations, and whose presence shapes whether hybrids live or die. The question now isn't whether microbes matter to host biology. That's settled. The question is how to build the experimental and theoretical infrastructure to figure out exactly how — and to be willing to be proven wrong about the details. That's what makes this a scientific program rather than a philosophical one. And that's why it matters. This lecture was created by ennepō. Go to https://ennepo.ai to Discover, Create and Follow the latest research in your field. Read when you can. Listen when you want to.