The one constant in science is that science is never settled. Discovery brings new ideas, which translate to new understanding, shifting paradigms of thought, leading to innovation. This idea of an inheritable gut microbiome and gut metabolome is such a topic. The level of inheritance of the gut microbiome and gut metabolome is important to differentiate because the clarity of evidence differs between the two. Yet, the possibility of both breaks down the boundaries of possible.
The two inheritance terms to appropriately define, setting the stage for this discussion, are Intergenerational and transgenerational. Intergenerational is the seeding from parents to the infant. In the circle of genetics, language is more precise: F0 is the parental generation, and the infant is the F1 generation. It is the immediate and direct transmission of information and the transfer of this information is not only genomic. Intergenerational inheritance carries the transmission of genomics, one step, yet evidence shows Transgenerational inheritance goes even further.
Transgenerational inheritance involves the transmission from the parental generation (F0) beyond the F1 generation and F2 generation, but to the F3 generation and beyond. In epigenetics, this transgenerational transmission of stressor-induced DNA methylation and histone modification from parent to grandchild is called Epigenetic transgenerational inheritance of pathology. Remember, Epigenetics is that which is above the genome: RNA and Protein. It is the downstream effects of genomics: transcription and translation. It is what makes each of us unique and adaptable to our environments.
These impacts are not merely in the area of disease, but in behavior. Before we dive into the specifics of gut microbiome inheritance, let’s first look at the reality of epigenetic intergenerational and transgenerational inheritance of pathology from trauma.
Holocaust survivors help to connect trauma and intergenerational and transgenerational inheritance. Numerous studies have followed holocaust survivors to assess the impact and transfer of the stress and fear from the evil of the holocaust event from the founder generation (F0) to future generations, F1, F2, and beyond (intergenerational). Most studies have pointed to the development of distinct patterns of communication, behavior, and adaptation as the means of transgenerational and intergenerational inheritance.
In essence, it is nothing more than a learned or observed behavior passed down through the generations. It gives a whole new perspective to the legacy we pass on. However, recent studies point to the real possibility that transgenerational inheritance can induce epigenetic alterations, resulting in the transmission of inheritable pathological stress responses. The impact of this discovery changes everything in how we view stress, fear, and trauma.
Fear, stress, and trauma imprint a pathological stress response on the individual through alterations at the genotype level—methylation and histone modifications. But the response to the stress, fear, and trauma shows a translation to the physical expression level—called phenotype. All are included in epigenetic inheritance—legacy.
No longer can fear, stress, and trauma be viewed as an impact alone on the individual experiencing the fear, stress, and trauma, but the children, grandchildren, and even beyond may inherit the same pathological stress response, which sets the stage for an inheritance set for altered genetic expression, biochemical expression, physiologic expression, and even disease.
Can this same process of epigenetic intergenerational and transgenerational inheritance of pathology be applied to the gut microbiome and gut metabolome? It was once thought that epigenetic inheritance was not inheritable. Can health, or worse disease (e.g., cancer), be carried forward through the gut microbiome and metabolome intergenerationally, even transgenerationally?
Intergenerational
A 2025 meta-analysis of Bifidobacterium transmissibility looked at the intergenerational question. This meta-analysis of 810 mother-infant pairs found an estimated 30% vertical transmission of Bifidobacterium species from mother to child. The species shared included multiple Bifidobacterium strains, with B. longum strains persisting in the infant gut for up to six months. The transmission was highest in vaginal births compared to caesarean. You might say, “So what?” Yet, this study begins to cement the idea that, just as epigenetics is transmissible, the gut microbiome is transmissible—inheritable. It demonstrates that vertical intergenerational transmission of maternal Bifidobacterium strains from mother to infant is present and quantifiable.
A 2018 animal study took this concept much further. Maternal obesity and overnutrition, ultraprocessed and high-fat diets, alter the maternal gut microbiome. In this animal model, the altered maternal gut microbiome is vertically transferred to offspring, effectively reprogramming their gut microbiome and metabolome, increasing obesity risk. Moreover, this study expanded the window from pregnancy and birth to now, including breastfeeding. This animal study linked intergenerational transmission of the gut microbiome and gut metabolome to metabolic reprogramming in F1 offspring. This maternal overnutrition and obesity connection, which alters the maternal gut microbiome, is vertically transferred to F1 offspring, altering the gut microbiome and gut metabolome, and has been shown in human studies as well.
Additional studies have added systemic inflammation to the sequence:
- Maternal diet and obesity -> altered maternal gut microbiome -> altered maternal gut metabolome -> vertical transmission of altered gut microbiome to offspring -> vertical transmission of altered gut metabolome -> altered gut barrier and intestinal permeability (“leaky gut”) -> systemic inflammation.
Systemic inflammation was defined by periportal inflammation, macrophage accumulation, altered macrophage phenotype, endoplasmic reticulum stress, altered gut barrier function, and increased intestinal permeability.
Though the entire end-to-end sequence has not been shown yet in humans, the following has:
- Maternal diet and obesity -> altered maternal gut microbiome -> altered maternal gut metabolome -> vertical transmission of altered gut microbiome to offspring -> vertical transmission of altered gut metabolome
Though associations and links have been found, the last few steps, including altered immune priming, systemic inflammation, and cancer, have yet to be added, because the questions have yet to be asked.
The above proves the vertical transmission. Take the vertical transmission out, and the following has been shown in humans:
- Altered gut microbiome (dysbiosis) -> altered gut metabolome -> “leaky gut” -> altered/impaired immune priming -> systemic inflammation -> cancer
Now add the vertical transmission and connect the dots.
Transgenerational
Transgenerational transmission of the gut microbiome and gut metabolome is a little more difficult to tease out in the current scientific literature. I suspect because the gut microbiome paradigm is seemingly in its infancy, and its broad impact remains to be explored. Both the animal and human gut microbiome and gut metabolome are yet to be proven to be transgenerationally transmitted.
The accelerated overweight and obesity rates, changing cancer demographics, and age-adjusted mortality rates from obesity-associated cancers that have tripled in just two decades, soaring from 3.73 to 13.52 per million between 1999 and 2020, are the smoke that feeds the fire, but all the evidence is there.
Personally, I suspect only time and questions are the limiting factors in proving transgenerational transmission of the gut microbiome and gut metabolome. Currently, the pattern of transgenerational propagation exists, yet, without direct sequential human evidence, it is best labeled as intergenerational gut microbiome and gut metabolome transmission, plus epigenetic, developmental, immune, and metabolic reprogramming.
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