2026-03-28 Scientific reference on holobiont biology: history, cell counts, microbiome function, germ-free studies, coral holobionts, hologenome theory, and recent research.

Table of contents

Holobionts: Scientific Reference

Companion to holobiont.md, which treats the concept relationally. This file compiles specific empirical data, researcher names, and citations.

1. Definition and History of the Term

The word “holobiont” has a contested etymology with at least three origin points.

Adolf Meyer-Abich (1943) used the German term “Holobiont” in his work on symbiosis and organismic philosophy, referring to composite organisms formed by symbiotic partnerships. Meyer-Abich was a proponent of holistic biology influenced by Jakob von Uexkull and Hans Driesch. His usage appeared in the context of arguing that symbiotic associations could constitute genuine biological individuals. This is the earliest documented use of the term, but it had essentially no influence on anglophone biology and was largely forgotten until historians of science recovered it.

Lynn Margulis is frequently credited with introducing the term into modern English-language biology. Margulis used “holobiont” beginning in the 1990s to describe the composite organism formed by symbiotic association, consistent with her broader theory of symbiogenesis (the idea that eukaryotic organelles – mitochondria, plastids – originated as endosymbiotic bacteria). In Margulis’s usage, the holobiont was a natural extension of the principle that symbiosis is a major evolutionary force, not merely a marginal ecological phenomenon. Her key works include Symbiosis in Cell Evolution (1981, revised 1993) and Symbiotic Planet (1998).

Forest Rohwer and colleagues popularized “holobiont” specifically in the context of coral biology in the early 2000s. Rohwer, Seguritan, Azam, and Knowlton (2002, in FEMS Microbiology Ecology) used “coral holobiont” to designate the unit composed of the coral animal, its endosymbiotic dinoflagellates (then called zooxanthellae, now classified as family Symbiodiniaceae), associated bacteria, archaea, fungi, and viruses. This usage was influential because it framed the holobiont not as a philosophical concept but as an operational unit for empirical research – something whose components could be enumerated, sequenced, and experimentally manipulated.

Conceptual evolution: Through the 2010s, the term shifted from a descriptive label for specific symbiotic systems (corals, lichens) to a general framework claiming that all multicellular organisms are holobionts – that the host plus its microbiome is always the relevant biological unit. This generalization was driven largely by the explosion of metagenomic sequencing, which revealed that every plant and animal harbors complex microbial communities. The question shifted from “which organisms are holobionts?” to “what follows from the fact that all organisms are holobionts?”

2. Human Microbiome: Cell Counts and Functions

Revised Cell Count Estimates

The widely repeated claim that microbial cells outnumber human cells 10:1 originated from a rough estimate by Thomas Luckey (1972) and was propagated through decades of textbooks and popular science. It was never based on rigorous counting.

Sender, Fuchs, and Milo (2016) published a systematic reassessment in Cell (vol. 164, pp. 337-340): “Revised Estimates for the Number of Human and Bacteria Cells in the Body.” Their findings:

Human cells: approximately 3.0 x 10^13 (30 trillion), dominated by red blood cells (~70% of the total count, approximately 2.5 x 10^13).
Bacterial cells: approximately 3.8 x 10^13 (38 trillion), the vast majority residing in the colon.
Ratio: roughly 1.3:1 (bacteria to human cells), not 10:1. The ratio fluctuates around 1:1 and may temporarily favor human cells after a bowel movement.
By mass: bacteria contribute only about 0.2 kg (roughly 200 grams) of a 70 kg adult male’s body weight, because bacterial cells are much smaller than most human cells.

The 10:1 figure derived from overestimates of gut bacterial density and underestimates of human cell count. Sender et al. used updated measurements of bacterial concentration in the colon (~10^11 per gram of content) and modern estimates of total human cell number.

Microbial Diversity in the Human Gut

The human gut microbiome contains an estimated 500 to 1,000 species of bacteria, though some estimates range higher.
The total microbial gene catalog in the human gut is estimated at 3.3 million unique genes (Qin et al. 2010, Nature), roughly 150 times the ~22,000 protein-coding genes in the human genome.
The dominant phyla in the human gut are Bacillota (formerly Firmicutes) and Bacteroidota (formerly Bacteroidetes), which together typically comprise >90% of gut bacteria. Other significant phyla include Actinomycetota (formerly Actinobacteria), Pseudomonadota (formerly Proteobacteria), and Verrucomicrobiota.
Composition varies substantially between individuals, influenced by diet, geography, age, medication (especially antibiotics), and mode of birth (vaginal vs. cesarean).

Specific Functional Examples

Bacteroides thetaiotaomicron (B. theta):

A prominent member of Bacteroidota in the human gut, extensively studied by Jeffrey Gordon’s lab at Washington University in St. Louis.
Possesses an extraordinarily large repertoire of carbohydrate-active enzymes (CAZymes) – its genome encodes over 260 glycoside hydrolases and polysaccharide lyases, far more than the human genome’s ~17 carbohydrate-digesting enzymes.
Breaks down complex plant polysaccharides (xylans, pectins, starch) that human enzymes cannot digest, converting them into short-chain fatty acids (SCFAs) – primarily acetate, propionate, and butyrate – that the human host absorbs as an energy source.
SCFAs provide an estimated 5-10% of the caloric needs of the human host.
B. theta also induces angiogenesis in the gut mucosa and stimulates expression of host genes involved in nutrient absorption (Stappenbeck et al. 2002, PNAS).

Faecalibacterium prausnitzii:

One of the most abundant bacteria in the healthy human colon, typically comprising 5-15% of total fecal bacteria.
A major producer of butyrate, which is the preferred energy source for colonocytes (the epithelial cells lining the colon).
Exerts anti-inflammatory effects: produces a microbial anti-inflammatory molecule (MAM) that inhibits NF-kB activation in intestinal epithelial cells (Quevrain et al. 2016, Gut).
Reduced abundance of F. prausnitzii is consistently associated with Crohn’s disease and other inflammatory bowel diseases. Sokol et al. (2008, PNAS) demonstrated that F. prausnitzii supernatant reduced inflammation in a mouse model of colitis.
Cannot survive oxygen exposure (obligate anaerobe), which complicates its use as a probiotic.

Lactobacillus species (immune modulation):

Various Lactobacillus species (L. rhamnosus, L. acidophilus, L. plantarum, etc.) modulate the host immune system through several mechanisms:
- Stimulate production of secretory IgA, the primary antibody defending mucosal surfaces.
- Influence dendritic cell maturation and cytokine production, promoting a balanced Th1/Th2 response.
- Strengthen the intestinal epithelial barrier by upregulating tight junction proteins (claudins, occludin).
- Produce bacteriocins that directly inhibit pathogenic bacteria.
L. rhamnosus GG (LGG) is one of the most studied probiotic strains. Isolated by Sherwood Gorbach and Barry Goldin (1985), it adheres to intestinal mucosa and has demonstrated efficacy in preventing antibiotic-associated diarrhea and reducing rotavirus diarrhea duration in children (meta-analyses by Szajewska et al.).

3. Germ-Free Animal Studies

Germ-free (GF) or gnotobiotic animals are raised in sterile isolators from birth by cesarean delivery, so they develop without any microbial colonization. Comparing GF mice to conventionally raised (specific-pathogen-free, or SPF) mice reveals the microbiome’s constitutive role in host development.

Immune System Defects

IgA production:

GF mice have dramatically reduced secretory IgA levels in the gut. IgA is the most abundantly produced antibody in the body and is critical for mucosal defense.
Colonization of GF mice with a conventional microbiota restores IgA production within weeks (Macpherson and Uhr 2004, Science).

T-cell maturation:

GF mice have fewer and less mature CD4+ T cells in the gut-associated lymphoid tissue (GALT).
Specific bacterial species drive specific T-cell populations. Bacteroides fragilis (through its polysaccharide A, PSA) promotes regulatory T-cell (Treg) differentiation and IL-10 production, an anti-inflammatory cytokine (Mazmanian, Round, and Kasper 2008, Nature).
Segmented filamentous bacteria (SFB) drive the differentiation of Th17 cells in the small intestine (Ivanov et al. 2009, Cell). GF mice essentially lack Th17 cells; monocolonization with SFB restores them.

Peyer’s patches and lymphoid structures:

GF mice have smaller Peyer’s patches (organized lymphoid tissue in the small intestine), fewer isolated lymphoid follicles, and a thinner lamina propria with fewer immune cells overall.

Gut Morphology

Cecum enlargement: GF mice have a massively enlarged cecum (4-6 times normal size) filled with undigested mucus, because bacteria that normally break down mucus and ferment fiber are absent.
Villus structure: GF mice show altered villus-to-crypt ratios. Villi tend to be longer and thinner, while crypts are shallower. The epithelial cell turnover rate is slower (normally, gut epithelial cells are completely replaced every 3-5 days; in GF mice this is prolonged).
Mucus layer: The two-layered mucus system (a firm inner layer and a loose outer layer in the colon) is altered in GF mice. The inner layer is thinner; the outer layer, normally colonized by commensal bacteria, is essentially empty.

Brain and Behavior

Anxiety-like behavior:

Sudo et al. (2004, Journal of Physiology) first demonstrated that GF mice show an exaggerated hypothalamic-pituitary-adrenal (HPA) axis response to stress (elevated corticosterone). This could be partially reversed by colonization with Bifidobacterium infantis, but only if colonization occurred early in life – suggesting a critical developmental window.
GF mice on a BALB/c background (normally anxious) show increased exploratory behavior and reduced anxiety-like behavior in the elevated plus maze, paradoxically suggesting the microbiome contributes to normal anxiety responses (Diaz Heijtz et al. 2011, PNAS). This was reversed by colonization during early postnatal life but not in adulthood.
The direction of the behavioral effect depends on the mouse strain, complicating interpretation. GF Swiss Webster mice show reduced anxiety; GF BALB/c mice also show reduced anxiety. The consistent finding is that the behavioral phenotype is different, not that it is always shifted in one direction.

BDNF (Brain-Derived Neurotrophic Factor):

GF mice have altered BDNF expression in multiple brain regions. Diaz Heijtz et al. (2011) found reduced BDNF mRNA in the hippocampus and increased BDNF in the amygdala of GF mice compared to SPF controls.
BDNF is critical for synaptic plasticity, learning, and memory. Altered BDNF levels in GF mice suggest that the microbiome influences fundamental aspects of neural development and function.

Serotonin:

Approximately 90% of the body’s serotonin (5-HT) is produced in the gut, primarily by enterochromaffin cells.
Yano et al. (2015, Cell) showed that GF mice have approximately 60% less serotonin in the colon and in circulating blood compared to conventionally colonized mice.
Specific spore-forming bacteria (primarily Clostridia) promote serotonin biosynthesis by enterochromaffin cells. The mechanism involves bacterial metabolites (short-chain fatty acids, secondary bile acids) stimulating tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in gut serotonin synthesis.
Colonization of GF mice with spore-forming bacteria restored colonic and blood serotonin to near-normal levels.

Myelination:

Hoban et al. (2016, Translational Psychiatry) found that GF mice have hypermyelination of neurons in the prefrontal cortex – increased expression of myelin-related genes and thicker myelin sheaths. This was normalized by post-weaning colonization.

4. Coral Holobionts

Components

The coral holobiont comprises:

The coral animal – a cnidarian, typically colonial, with polyps that secrete a calcium carbonate skeleton.
Symbiodiniaceae (formerly classified as a single genus Symbiodinium, now split into multiple genera including Cladocopium, Durusdinium, Breviolum, and Symbiodinium sensu stricto). These are dinoflagellate algae that live within the coral gastrodermal cells (endosymbiosis). They photosynthesize and transfer up to 90% of their photosynthetic products (glycerol, glucose, amino acids) to the coral host, providing the major energy source for reef-building corals. In return, the coral provides a protected environment with access to light and inorganic nutrients (ammonium, phosphate, CO2).
Bacteria and archaea – the coral surface mucus layer and tissues host diverse bacterial communities. Dominant groups include Gammaproteobacteria, Alphaproteobacteria, and Bacteroidetes. Functions include nitrogen fixation (diazotrophic bacteria fix atmospheric N2, supplementing the nitrogen-poor reef environment), sulfur cycling, antimicrobial compound production (protecting the coral from pathogens), and chitin degradation.
Viruses – coral-associated viromes are enormously diverse. Phages (viruses that infect bacteria) may play a role in regulating the bacterial community (the “phage defense” hypothesis, proposed by Barr et al. 2013, PNAS: phages concentrated in the coral mucus layer preferentially lyse potential bacterial pathogens, acting as an innate immune analog).
Fungi and other eukaryotic microorganisms – endolithic fungi bore into the coral skeleton; protists and other microeukaryotes also inhabit coral tissues.

Coral Bleaching: Mechanism

Coral bleaching is the expulsion or degradation of Symbiodiniaceae from coral tissues. The mechanistic pathway:

Thermal stress (typically 1-2 degrees C above the normal summer maximum, sustained for weeks) or other stressors (UV radiation, pollution, low salinity) damage the photosynthetic apparatus of Symbiodiniaceae.
Photoinhibition occurs: excess excitation energy in photosystem II (PSII) cannot be dissipated through normal photochemistry. The D1 protein of the PSII reaction center is damaged faster than it can be repaired.
Reactive oxygen species (ROS) production spikes. Damaged photosystems leak electrons to molecular oxygen, producing superoxide (O2-), hydrogen peroxide (H2O2), and hydroxyl radicals. These ROS overwhelm the antioxidant defenses (superoxide dismutase, ascorbate peroxidase, catalase) of both the Symbiodiniaceae and the coral host cells.
The coral host expels the symbiont through a combination of mechanisms: exocytosis (ejecting the symbiont-containing vacuole), apoptosis and autophagy of host gastrodermal cells containing symbionts, and in situ degradation of symbiont cells within the host. The exact signaling cascade triggering expulsion involves nitric oxide (NO), ROS, and innate immune pathways (NF-kB, complement-like systems).
The coral loses its color (the brown/green color of healthy coral comes from symbiont pigments, primarily chlorophyll and peridinin) and becomes white – “bleached.”
If the stress is short-lived, the coral may recover by re-establishing symbiosis with Symbiodiniaceae (either residual populations that survived or new uptake from the water column). If the stress persists, the coral starves (having lost its primary photosynthetic energy source) and dies.

Different Symbiodiniaceae genera/species have different thermal tolerances. Durusdinium trenchii (formerly Symbiodinium clade D) is more thermally tolerant than Cladocopium species, leading to interest in “symbiont shuffling” as a coral adaptation mechanism – stressed corals may shift their symbiont community composition toward more heat-tolerant species.

Rohwer Lab and the Hologenome Connection

Forest Rohwer’s lab at San Diego State University has been central to coral holobiont research. Key contributions:

Establishing the concept of the coral holobiont as a unit for study (Rohwer et al. 2002).
Characterizing coral-associated viromes using metagenomics.
The “Coral Probiotic Hypothesis” (Reshef et al. 2006, Environmental Microbiology): the idea that the coral holobiont can adapt to changing conditions by shifting its microbial community composition, a faster mechanism than genetic adaptation of the coral host alone.
This idea fed directly into the hologenome theory of evolution (see below).

5. Hologenome Theory of Evolution

The Proposal

Ilana Zilber-Rosenberg and Eugene Rosenberg (2008, FEMS Microbiology Reviews) formally proposed the “hologenome theory of evolution,” arguing that:

All animals and plants are holobionts – hosts plus their associated microorganisms.
The “hologenome” is the sum of the genetic information of the host and all its symbiotic microorganisms.
Natural selection acts on the holobiont as a unit, not just on the host genome.
Variation in the hologenome can arise not only through mutation and recombination in host and microbial genomes, but also through changes in microbial community composition (acquisition of new microbial species, loss of existing ones, changes in relative abundance). This provides a mechanism for heritable variation that is faster than mutation in the host genome.

The Rosenbergs drew on Eugene Rosenberg’s earlier work on coral bleaching (the “Coral Probiotic Hypothesis”) and on evidence that:

Microbial communities are often faithfully transmitted between host generations (vertical transmission through eggs, birth canal, breast milk, or close contact).
Changes in the microbiome can produce heritable phenotypic changes in the host.
The holobiont can adapt to environmental change through microbial community shifts within a single host generation (a Lamarckian-like mechanism operating alongside Darwinian selection on the host genome).

Scientific Debate

The hologenome theory has been influential but contested. The debate centers on several issues:

In favor:

There is strong evidence that microbial communities are transmitted vertically in many systems (insects, plants, mammals). Obligate endosymbionts (e.g., Buchnera in aphids) are clearly co-inherited.
Microbial community changes can produce rapid adaptive responses (e.g., Kohl et al. 2014 demonstrated that woodrats detoxify creosote plant toxins via their gut microbiome, and this ability is transferable through fecal transplant).
Selection on host traits that are microbiome-dependent (e.g., diet, immune function) is effectively selection on the holobiont.

Against / skeptical:

Douglas and Werren (2016, Nature Microbiology) argued that the hologenome concept conflates several distinct phenomena under one umbrella. They note that for the holobiont to be a unit of selection, the host-microbiome association must be faithfully transmitted across generations with sufficient fidelity – but many components of the microbiome are environmentally acquired each generation, not vertically transmitted.
Moran and Sloan (2015, Cell) pointed out that many microbial associates are acquired horizontally (from the environment), their interests may conflict with the host’s, and the conditions for the holobiont to function as a genuine unit of selection (aligned fitness interests, faithful co-transmission) are met only for a subset of host-microbe associations (primarily obligate endosymbionts).
The multilevel selection debate: for the holobiont to be a unit of selection, selection at the holobiont level must override selection at the level of individual microbial lineages. But microbes within a holobiont are also subject to their own selection pressures, and microbial “cheaters” that benefit themselves at the expense of the holobiont can invade the community.
Bordenstein and Theis (2015, PLOS Biology) attempted a synthesis, arguing that the hologenome concept is valid but needs a more rigorous framework distinguishing between different levels of host-microbe association (obligate vs. facultative, vertical vs. horizontal transmission).

Current consensus (as of mid-2020s): The holobiont is widely accepted as a useful descriptive framework – it is now standard in microbiome research to consider the host plus its microbiome as a functional unit. However, the stronger claim that the holobiont is a unit of natural selection (analogous to the individual organism in classical evolutionary theory) remains debated. Most evolutionary biologists accept that the hologenome concept captures something real about host-microbe coevolution but resist elevating the holobiont to the primary level of selection, preferring a multilevel selection framework where selection acts at multiple levels (gene, organism, holobiont, group) depending on the system and the degree of partner fidelity.

6. Recent Research (2020-2026)

Human Microbiome Project (HMP) Results

The NIH Human Microbiome Project ran in two phases:

HMP1 (2008-2013): Characterized the microbial communities at 18 body sites in 242 healthy adults. Key finding: there is enormous interpersonal variation in microbial community composition, but the functional gene profile (what the microbiome can do) is more conserved than the taxonomic profile (which species are present). Published as a consortium in Nature (2012).
HMP2 / iHMP (Integrative HMP, 2014-2019, published 2019): Focused on three conditions – inflammatory bowel disease (IBD), pre-term birth, and type 2 diabetes (onset). Used multi-omic approaches (metagenomics, metatranscriptomics, metabolomics, proteomics) to track how the microbiome changes during disease. Key finding for IBD: patients show “dysbiosis” – disrupted microbial communities – but the disruption is episodic and individualized, making it difficult to define a single “IBD microbiome.”

Fecal Microbiota Transplantation (FMT) for Clostridioides difficile

C. difficile infection (CDI) is a leading cause of healthcare-associated diarrhea, often occurring after antibiotic treatment disrupts the normal gut microbiome, allowing C. difficile to proliferate and produce toxins (TcdA and TcdB).

FMT involves transferring fecal material from a healthy donor into the patient’s gastrointestinal tract. The goal is to restore a diverse microbial community that suppresses C. difficile.
van Nood et al. (2013, New England Journal of Medicine) published a landmark randomized trial showing FMT cured 81% of recurrent CDI patients (15/16 after up to 2 infusions) vs. 31% for vancomycin alone. The trial was stopped early because FMT was so clearly superior.
Rebyota (fecal microbiota, live-jslm) was approved by the FDA in November 2022 as the first FDA-approved fecal microbiota product for prevention of recurrence of CDI in adults following antibiotic treatment. Manufactured by Ferring Pharmaceuticals (from Rebiotix).
Vowst (fecal microbiota spores, live-brpk) was approved by the FDA in April 2023 as the first orally administered fecal microbiota product for CDI recurrence prevention. Manufactured by Seres Therapeutics. This is a capsule containing purified Firmicutes spores rather than whole stool.
FMT cure rates for recurrent CDI are consistently reported at 85-90% across multiple trials and meta-analyses.

Gut-Brain Axis Research (2020-2026)

The gut-brain axis refers to bidirectional communication between the gastrointestinal tract (and its microbiome) and the central nervous system, mediated by the vagus nerve, the immune system, microbial metabolites (SCFAs, tryptophan metabolites, bile acids), and the enteric nervous system.

Key developments:

Psychobiotics: The concept of “psychobiotics” (live organisms that produce health benefits in patients with psychiatric illness) was coined by Dinan, Stanton, and Cryan (2013). Clinical trials of specific probiotic strains (e.g., Lactobacillus helveticus R0052, Bifidobacterium longum R0175) have shown modest but statistically significant reductions in self-reported stress, anxiety, and depression scores in healthy volunteers and some clinical populations.
Autism spectrum disorder (ASD): Multiple studies have reported altered gut microbiome composition in children with ASD, with reduced Prevotella, Coprococcus, and Veillonella (Kang et al. 2013, PLOS One). Kang et al. (2017, Microbiome) conducted an open-label trial of microbiota transfer therapy in 18 children with ASD, reporting improvements in GI symptoms and behavioral symptoms that persisted at 8-week follow-up. A follow-up study (Kang et al. 2019, Scientific Reports) found behavioral improvements persisted at 2 years, with gut microbiome changes becoming more “typical.” These results are suggestive but based on small, unblinded studies.
Parkinson’s disease: Gut microbiome alterations (reduced Prevotella, increased Enterobacteriaceae) have been consistently reported in PD patients. The hypothesis that PD pathology begins in the gut (alpha-synuclein aggregation starting in the enteric nervous system and spreading to the brain via the vagus nerve) has gained traction. Kim et al. (2019, Cell) showed that gut microbiota from PD patients worsened motor deficits in a mouse model of PD. Vagotomy (cutting the vagus nerve) has been associated with reduced PD risk in epidemiological studies (Svensson et al. 2015, Annals of Neurology).
Depression and metabolites: Valles-Colomer et al. (2019, Nature Microbiology) analyzed gut metagenomes from 1,054 individuals enrolled in the Flemish Gut Flora Project. They found that Coprococcus and Dialister were consistently depleted in individuals with depression, and that bacterial production of DOPAC (a dopamine metabolite) correlated with mental quality of life. This was one of the first large population-level studies linking specific microbial taxa to mental health outcomes.

Other Notable Advances (2020-2026)

Microbiome and immunotherapy response: Routy et al. (2018, Science) and Gopalakrishnan et al. (2018, Science) showed that gut microbiome composition predicts response to checkpoint immunotherapy (anti-PD-1) in cancer patients. Patients with higher abundance of Akkermansia muciniphila or Faecalibacterium responded better. FMT from responders to non-responders improved immunotherapy response in mouse models and in early human trials.
Engineered probiotics: Synthetic biology approaches to engineering bacteria for therapeutic purposes are advancing. Isabella et al. (2018, Nature Biotechnology) engineered an E. coli Nissle strain (SYNB1618) to consume phenylalanine in the gut as a treatment for phenylketonuria (PKU). Phase 2 clinical trial results published 2023.
Phage therapy for microbiome modulation: Rather than using broad-spectrum antibiotics, targeted bacteriophages can selectively eliminate specific problematic bacteria from the microbiome (e.g., targeting Klebsiella pneumoniae in the gut without disrupting the broader community). This area is in early clinical development.
Vertical transmission at birth: Bogaert, van Beveren et al. (2023, Cell) published detailed work on microbial transmission from mother to infant, confirming extensive vertical transfer of microbial strains during vaginal delivery, with cesarean-born infants receiving different (more skin-associated, hospital-environment) strains. The clinical significance of these differences remains debated.

Key Cited Works

Sender R, Fuchs S, Milo R (2016). “Revised Estimates for the Number of Human and Bacteria Cells in the Body.” Cell 164: 337-340.
Qin J et al. (2010). “A human gut microbial gene catalogue established by metagenomic sequencing.” Nature 464: 59-65.
Rohwer F, Seguritan V, Azam F, Knowlton N (2002). “Diversity and distribution of coral-associated bacteria.” FEMS Microbiology Ecology.
Zilber-Rosenberg I, Rosenberg E (2008). “Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution.” FEMS Microbiology Reviews 32: 723-735.
Douglas AE, Werren JH (2016). “Holes in the hologenome.” Nature Microbiology 1: 15024.
Moran NA, Sloan DB (2015). “The hologenome concept: helpful or hollow?” PLOS Biology 13: e1002311.
Bordenstein SR, Theis KR (2015). “Host Biology in Light of the Microbiome.” PLOS Biology 13: e1002226.
Diaz Heijtz R et al. (2011). “Normal gut microbiota modulates brain development and behavior.” PNAS 108: 3047-3052.
Yano JM et al. (2015). “Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.” Cell 161: 264-276.
van Nood E et al. (2013). “Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile.” NEJM 368: 407-415.
Sudo N et al. (2004). “Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.” Journal of Physiology 558: 263-275.
Ivanov II et al. (2009). “Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria.” Cell 139: 485-498.
Barr JJ et al. (2013). “Bacteriophage adhering to mucus provide a non-host-derived immunity.” PNAS 110: 10771-10776.

Holobiont – conceptual/relational treatment
Niche Construction – holobionts as niche constructors