When the whole is greater than the sum of it's parts

To begin our exploration of biodiversity it might be helpful to think about the molecular mechanisms acting to generate this divergence. For sexually reproducing organisms, genetic recombination by means of chromosomal crossing over allows allelic genes to transfer across homologous chromosomal pairs during meiosis. This exchange of genetic material to reposition genes in new gene combinations may lead to offspring with potentially divergent phenotypic expression. Beginning about one decade ago came the realization that microbial symbionts of an organism acted to enhance certain host functional capabilities promoting the idea of a ‘meta-organism’, considering the host in combination with those accompanying microorganisms together representing that organism’s functional capability as a larger whole. The term ‘holobiont’ (holo- whole, biont – life), the combination of the all of the cells of the host as well as those of the symbiotic microorganisms, and the hologenome, the analogous combination of all of the genetic material of the holobiont, have been used to further describe this expanded understanding.

Seth Bordenstein, a pioneer in holobiont biology, has written to describe (Science 386, 6723 (2024)) how viewing the combined hologenomic sequences of an organism expands our understanding of a means for generating phenotypic diversity among offspring when compared solely with that of vertical inheritance of the host genome alone. Microorganisms acquired from the environment generate diverse populations through an alternate process of horizontal gene transfer. For microorganisms this is an often used mechanism for responding to environmental selection pressure as it allows a rapid response to such environmental disturbance. Gene transfer may occur by several means  including conjugated transfer of genes through direct contact, through bacteriophage transfer of a gene from one microbe to another or through the microbial release of extracellular vesicles containing genes that may be absorbed by recipient microorganisms. A famous example of this capability is the rapid spread of genetic material promoting antibiotic resistance in response to chronic therapeutic use of antimicrobial drugs.

Genome-wide association studies employ genetic sequencing of a species’ genome searching for genetic variants, typically single nucleotide polymorphisms, which may be associated with phenotypic trait variation of interest. Similarly, quantitative hologenomic analysis seeks to identify genetic variation across the hologenome of an organism that might similarly account for trait variation. Certain phenotypic traits are measurable. A genetic locus in which allelic variation of a gene is found to correspond with an accompanying phenotypic trait variation in that organisms is said to be a quantitative trait locus. Bordenstein illustrates a representative example of such a procedure in which the concurrent sequencing of chromosomes across the hologenome identifies quantitative trait loci present in both the host’s as well as the microbial genome. Importantly, had the analysis for these tell-tale loci been confined solely to the host’s genome alone then a significant additional degree of understanding of the contribution of microbial quantitative trait loci in accounting for phenotypic trait variation in an organism would have been missed.  

That the expression of a genetic locus from the host genome might be affected by that of a microbial gene to account for the variation of a phenotypic trait represents an example of intergenomic epistasis. Gene epistatic effects, one gene affecting that of a second, may act either to enhance or inhibit the expression or function of the associated gene. Like intragenomic epistasis - the influence of one gene upon another’s function within a single genome - intergenomic epistasis represents an analogous means of modifying genomic output to achieve phenotypic diversity from the hologenomic perspective. This provides the holobiont with an expanded repertoire of potential responses to, for example selection pressures from a rapidly changing environment. Intergenomic epistasis thus represents a potential means for enhancing an organism fitness in its environment without the costs to the host in shouldering the entirety of the genomic variants alone.

An emerging and important example of holobiont biology comes from ongoing studies of the gastrointestinal microbiome and its seeming ability to regulate anticancer immune responses. Examples of the gut microbiota affecting cancer range from their effect on the integrity of the gut epithelial barrier, their capability for enhancing the responsiveness of primary and secondary immune organ’s anticancer responses and the ability to modulate the landscape of the tumor microenvironment. Surveying these interactions, Gregory Sepich-Poore et. al, writing in Science 371, eabc4552, (2022) describe a framework for these holobiont-related host-microbiome functional capabilities which they term the immuno-oncology-microbiome axis (IOM).   

Broadly, the authors relate several types of IOM axis activity believed to affect anti-cancer immune responses. A prominent example of this axis is the effects stemming from systemic absorption of microbial derived metabolites and compounds such as microorganism-associated molecular patterns (MAMPS) and short chain fatty acids. These microbial products act to augment the recovery of bone marrow myeloid elements following allogenic marrow transplantation. The gut microbiome also provides important carbohydrate metabolizing enzymes necessary to optimize the energy harvesting from the healing GI tract of the transplant recipient. Prospective studies have demonstrated a correlation between survival following such transplants and the corresponding degree of microbial diversity observed from fecal samples of the recovering individual’s GI tract. That positive relationship suggests a likely role of the gut microbiome in promoting a faciliatory effect on immune recovery. That a diverse microbiota providing an expanded set of genetic information to the allogeneic recipient is consistent with the model of a hologenome to explain that correlation.

Another example of the IOM axis comes from studies which identify the translocation of gut microorganisms to lymphoid organs and the effect some of those organisms are able to exert in priming adaptive immunity. As a routine now in transplant medicine Cyclophosphamide is used as a pretreatment causing epithelial barrier injury and leading to the translocation of Enterococcus Hirae microorganisms to the spleen. There they act to increase the number T17 helper T-cells along with an increase in the ratio of CD8 T-cells over T regulatory cells enhancing anticancer immunity. Similarly, gastrointestinal-associated lymphoid tissue and mesenteric lymph nodes process antigens from the microbiota and by doing so augment dendritic cell maturation. Dendritic cell antigen processing in turn increases the costimulation of dendritic cells and T-cells along with an increased production of anticancer cytokines such as Interferon-gamma.

The gut microbiota may also influence the character of the tumor microenvironment diminishing the inflammatory nature of the environment through release of microbe-derived outer membrane vesicles. Activation of pattern recognition receptors and Toll-like receptors, sensitive to microbial antigens, can change the polarity of tumor-associated macrophages either causing a tolerogenic state or alternatively to a cooperative environment of macrophage directed presence of tumor infiltrating lymphocytes. Microbial antigens from the microbiome may mimic those of the neoantigens of the tumor itself in a process termed molecular mimicry leading to an informed, antigen-primed T-cell immune response.

Holobiont biology then serves as an example of what economists term the division of labor. If we consider the complex task of maintaining ecological fitness across the lifetime of an organism living in an always changing environment and looking for chances to maximize its survival, then a means of efficiently generating phenotypic variation to address those changes would be a survival advantage. By “outsourcing” some of tasks to a symbiotic partner, the host will gain the benefit of increased efficiency that derives from subdividing a task in responding to survival challenges. We can think of the hologenome then as an expanded library of instructions available to the holobiont to complete those tasks.