on October 07, 2026
The human being as a biological ecosystem
For a long time, the human body was considered primarily as a collection of cells governed by their own genetic heritage. Modern microbiome research has progressively expanded this perspective, showing that the organism lives in constant interaction with an extraordinary community of microorganisms that colonize the intestine, skin, oral cavity, and other anatomical niches.
This new vision gives rise to the concept of the holobiont: a biological system in which the host organism and the associated microbial communities interact dynamically. Functionally, the microbiome can be considered a kind of expansion of the host's genetic heritage, because microorganisms possess a vast number of genes capable of producing enzymes and metabolites that participate in the physiology of the human organism.
This does not mean that human and microbial DNA become a single genome. Rather, it means that different genomes participate in a common biological network, in which environment, diet, metabolism, and immune response mutually influence each other.
The concept of the holobiont is now used precisely to describe this dynamic relationship between host and microbiota. Diet represents one of the main environmental factors capable of modifying this interaction.
Three genetic heritages in dialogue
Three functionally interconnected genetic levels can be distinguished in the human biological system:
- the nuclear DNA, contained in the cells of the organism;
- the mitochondrial DNA, housed in the mitochondria;
- the genetic heritage of the microbiome, consisting of the set of genes from the microorganisms associated with the organism.
The microbiome is often defined as a “second genome” because its genes encode a vast array of metabolic functions that the human organism does not possess to the same extent on its own.
Intestinal bacteria can, in fact, transform food components that are indigestible by human enzymes, producing bioactive molecules that interact with the host's cells.
It is precisely this step — from diet to microbial metabolism, from microbial metabolism to cellular signaling — that is becoming one of the main objects of contemporary nutritional research.
Mitochondria and microbiota: a relationship rooted in evolution
The connection between microbiota and mitochondria is not merely metabolic. It also has a profound evolutionary dimension.
The endosymbiotic theory, now widely accepted, holds that mitochondria derive from ancient bacteria, probably belonging to the α-proteobacteria lineage, which over the course of evolution established a stable symbiotic relationship with ancestral eukaryotic cells.
Mitochondria still retain characteristics that recall this bacterial origin, including their own genome.
This common origin helps explain why mitochondria and microbiota can be considered two distinct but deeply interconnected biological systems.
Contemporary research increasingly speaks of mitochondria–microbiome crosstalk, that is, a bidirectional dialogue in which the microbiota can modify mitochondrial function through metabolites and molecular signals, while the host's mitochondrial function can, in turn, influence the environment in which the microorganisms live.
The microbiota–mitochondria dialogue is bidirectional
The relationship cannot be interpreted simply as “bacteria influencing cells.”
The intestinal microbiota produces metabolites capable of reaching the host's cells and modulating processes such as:
- energy metabolism;
- immune response;
- cellular signaling;
- redox balance;
- intestinal barrier integrity;
- lipid and carbohydrate metabolism;
- mitochondrial activity.
In parallel, mitochondria contribute to cellular homeostasis through energy production, the regulation of reactive oxygen species, metabolic signaling, and numerous cellular adaptation processes.
Reactive oxygen species represent one of the possible points of convergence between these two systems. Under physiological conditions, they participate in cellular signaling; when their production exceeds antioxidant control capacity, they can instead contribute to oxidative stress. The literature therefore describes a reciprocal relationship between mitochondrial status, ROS, microbiota, and intestinal homeostasis.
The most recent research further expands this model, indicating that short-chain fatty acids, secondary bile acids, and microbial components capable of influencing mitochondrial bioenergetics, redox balance, and inflammation are also mediators of the dialogue.
Fiber is not just fiber: the concept of MAC
One of the most interesting aspects of this new vision concerns the biological significance of dietary fiber.
Not all fibers are equal, and not all are used by the microbiota in the same way.
To describe the carbohydrates actually accessible to the metabolism of intestinal microorganisms, the concept of Microbiota-Accessible Carbohydrates (MACs) has been introduced.
MACs include carbohydrates that resist digestion and absorption by the host and can therefore reach the microbiota, where they are used as metabolic substrates.
Their biological significance depends not only on the ingested molecule, but also on the composition of the individual's microbiota. The same substrate can, in fact, be metabolized differently by individuals with different microbial communities.
This leads to moving beyond a purely quantitative conception of fiber.
It is not only a matter of how many grams of fiber are introduced, but also which carbohydrates reach the microbiota, which microorganisms use them, and which metabolites are produced.
From MACs to SCFAs: fiber becomes a biological signal
One of the main results of the microbial fermentation of carbohydrates accessible to the microbiota is represented by short-chain fatty acids, or SCFAs (Short-Chain Fatty Acids).
The main ones include:
- acetate;
- propionate;
- butyrate.
These are accompanied by other metabolites derived from the microbial metabolism of amino acids and different fermentative pathways.
SCFAs should not be considered simply as waste products of digestion. They are bioactive molecules that participate in communication between the microbiota and the host organism.
They can contribute to the regulation of the intestinal epithelium, immune response, energy metabolism, and cellular signaling. Butyrate, in particular, represents an important energy substrate for the cells of the colon epithelium.
The literature on MACs also indicates that the availability of carbohydrates accessible to the microbiota can modify both the composition of the microbial community and its metabolic functionality.
When the diet impoverishes the microbiota
A chronically low-substrate diet accessible to the microbiota can profoundly alter the intestinal ecosystem.
Experimental studies on MACs have shown that insufficient availability of these substrates can reduce the production of beneficial microbial metabolites and promote a progressive alteration of the intestinal ecosystem.
One particularly interesting aspect concerns the relationship between microbiota and intestinal mucus.
When sufficient dietary substrates are lacking, some bacterial populations may increase their use of mucus-derived components as an energy source. In the experimental model, this phenomenon can contribute to the thinning of the mucus layer and the loss of some barrier functions.
The intestinal barrier is not, in fact, a simple physical wall. It is a dynamic biological system in which mucus, epithelial cells, cellular junctions, the immune system, and microbiota interact.
When this balance is altered, permeability may increase and the dialogue between microbiota and the immune system may change.
Microbiota, intestinal barrier, and inflammation
The intestine represents one of the main points of contact between the external environment and the organism.
Every day, enormous quantities of molecules, antigens, and microorganisms are introduced through food. The intestinal immune system must therefore maintain an extremely sophisticated balance: tolerating what is harmless and reacting appropriately to what represents a threat.
The microbiota participates in this regulation.
Its composition and metabolites contribute to the maintenance of immune homeostasis and the intestinal barrier. A persistent alteration of the microbial ecosystem can, instead, alter the microbiota–immunity dialogue.
The Western diet, generally characterized by a higher consumption of ultra-processed foods and a reduced presence of fiber-rich plant foods, has been associated in numerous reviews with alterations in the microbiota and the microbiota–immune system interaction. Conversely, the Mediterranean model, rich in plant-based foods, fiber, and bioactive compounds, presents nutritional characteristics favorable to a more balanced interaction between diet, microbiota, and immune system.
Clinical evidence for whole grains
The relationship between fiber, microbiota, and inflammation is not limited to experimental research.
A randomized controlled trial studied 80 healthy overweight or obese adults characterized by a diet low in fruit and vegetables and a sedentary lifestyle. The intervention with whole wheat produced favorable changes in some markers related to inflammation compared to the control. The study also examined the role of polyphenols associated with the fiber of cereals.
This result is particularly interesting because it shows how the biological effect of a food cannot be reduced to the mere quantity of macronutrients.
The food matrix contains, in fact, fibers, polyphenols, minerals, phenolic compounds linked to the plant wall, and other molecules that can interact with the microbiota.
Fiber can therefore become not only a fermentable substrate, but also a vehicle for bioactive compounds.
Fiber as a biological matrix
The concept of fiber as a simple indigestible material is progressively being superseded.
Some phenolic compounds present in plant foods can be associated with the fibrous matrix and reach the colon, where microbial metabolism can contribute to their transformation into more readily available molecules or those with different biological activities.
This creates a sequence:
food → fiber/MAC → microbiota → metabolites → host cells → metabolic and immune response.
It is a true chain of biological communication.
This model also helps us understand why the overall quality of diet can have effects that go far beyond a simple calorie balance.
From the microbiota to the mitochondria
The next step in research is particularly fascinating: understanding how metabolites produced by the microbiota can reach and modulate the mitochondria.
Available evidence indicates that the microbiota–mitochondria dialogue can involve different metabolic and signaling pathways.
SCFAs are among the most studied candidates. They can influence cellular metabolism and contribute to the regulation of energy and immune balance.
Other microbial metabolites, including bile acid derivatives and those from amino acid metabolism, can intervene in communication between the gut, immune system, and peripheral tissues.
2024 research on microbiota–mitochondria crosstalk highlights precisely the central role of metabolites as mediators of bidirectional communication and the potential role of diet in simultaneously altering the microbiota and mitochondrial function.
In 2026, a new review further expanded this model, describing the microbiota–mitochondria axis as a molecular communication system capable of involving energy metabolism, immunity, inflammatory signaling, and redox balance.
It is important to emphasize, however, that many of these relationships are still being studied and that the demonstration of a biological mechanism does not automatically equate to the demonstration of a clinical effect.
The microbiota–mitochondria axis as the new frontier of nutrition
The relationship between diet, microbiota, and mitochondria suggests a model in which diet acts simultaneously on multiple levels.
A rich and diverse diet of plant foods can provide:
substrates for the microbiota, through fibers and MACs;
polyphenols and other bioactive compounds, which can be transformed by microbial metabolism;
micronutrients, essential for numerous cellular reactions;
molecules capable of influencing energy metabolism and the immune response.
The microbiota therefore transforms part of what we eat into a kind of “metabolic language” that the organism can interpret.
This perspective helps explain why two diets with a similar calorie intake can have different biological consequences.
Food is not just energy.
It is also metabolic information.
From the chemical view to the clinical view of fiber
Modern nutrition is therefore moving from a quantitative conception of fiber to a more complex view.
It is no longer enough to ask:
“How many grams of fiber does this food contain?”
It is also necessary to ask:
“Which components are accessible to the microbiota?”
“Which microorganisms can use them?”
“Which metabolites are produced?”
“How do the intestinal barrier, the immune system, and the host’s metabolism react?”
These questions pave the way for precision nutrition, in which the individual response to a food also depends on the composition and functionality of the microbiota.
Research on the microbiota has indeed shown that the effect of a given carbohydrate is not necessarily identical in all individuals: the ability to use it also depends on the genetic and metabolic makeup of the microbial community present in the gut.
One Health: an ecosystem that transcends the boundaries of the organism
The holobiont perspective naturally fits into a broader view of One Health, in which human health, the environment, diet, and microbial communities are considered parts of an interconnected system.
The microbiota is not static.
It is influenced by diet, lifestyle, the environment, medications, and numerous other factors.
At the same time, through its metabolites, it helps alter the functioning of the host organism.
Diet therefore becomes one of the main tools through which the environment interacts with our biological heritage.
In this perspective, dietary fiber takes on a new meaning: it is not just a food component useful for intestinal function, but can represent a substrate through which the organism communicates with its own microbial ecosystem.
A new way of thinking about health
The discovery of the dialogue between the microbiota, mitochondria, and human cells does not mean that every disease can be attributed to dysbiosis or mitochondrial dysfunction.
The system is much more complex.
Genetics, age, physical activity, sleep, stress, medications, the environment, and diet continuously interact. The microbiota is also extremely individual and dynamic.
Research is, however, outlining a model in which the human genome, the mitochondrial genome, and the microbiome can no longer always be studied as independent biological compartments.
The meeting point is metabolism.
And at the center of metabolism we also find what we introduce daily through food.
For this reason, fiber, and in particular the fraction actually accessible to the microbiota, can be considered one of the most interesting tools through which nutrition interacts with the biology of the organism.
The holobiont perspective thus leads to a fundamental consideration: health is not only the result of the functioning of our cells, but also of the quality of the biological relationships those cells maintain with the microbial ecosystem that lives with us.
Bibliographic references
- Vitaglione P, et al. Whole-grain wheat consumption reduces inflammation in a randomized controlled trial on overweight and obese subjects with unhealthy dietary and lifestyle behaviors: role of polyphenols bound to cereal dietary fiber. American Journal of Clinical Nutrition. 2015;101(2):251-261. doi:10.3945/ajcn.114.088120.
- Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metabolism. 2014;20(5):779-786. doi:10.1016/j.cmet.2014.07.003.
- Cronin P, Joyce SA, O’Toole PW, O’Connor EM. Dietary Fibre Modulates the Gut Microbiota. Nutrients. 2021;13(5):1655. doi:10.3390/nu13051655.
- García-Montero C, et al. Nutritional Components in Western Diet Versus Mediterranean Diet at the Gut Microbiota-Immune System Interplay. Implications for Health and Disease. Nutrients. 2021;13(2):699. doi:10.3390/nu13020699.
- Ballard JWO, Towarnicki SG. Mitochondria, the gut microbiome and ROS. Cellular Signalling. 2020;75:109737. doi:10.1016/j.cellsig.2020.109737.
- Zachos NC, et al. The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease. Frontiers in Pharmacology. 2024. doi:10.3389/fphar.2024.1428242.
- Lange O, Proczko-Stepaniak M, Mika A. Short-Chain Fatty Acids—A Product of the Microbiome and Its Participation in Two-Way Communication on the Microbiome-Host Mammal Line. Current Obesity Reports. 2023;12:108-126.
- Koynova-Tenchov R. Molecular Dialogues in the Mitochondria–Microbiome Crosstalk: Metabolites, Signaling, and Immunity. Comprehensive Physiology. 2026;16(3). doi:10.1002/cph4.70164.
