Can intestinal flora be inherited? New study: Poor development of offspring may be caused by the man's intestinal flora disorder

For modern workers, the intestines may be the most vulnerable organ for many people... The fast-paced life, irregular diet and rest, and all kinds of takeouts are constantly putting pressure on the intestines. Most gastrointestinal discomfort is actually caused by intestinal flora disorders. Perhaps in the eyes of many people, this is not a serious problem and can be dealt with by taking a few painkillers.

But what if this small microbiome can also affect the growth and development of the offspring? We all know that genes can be inherited, but it is unheard of that the intestinal flora can also affect the next generation through inheritance. Just recently, Jamie A. Hackett's team published a study in Nature that linked the growth and development of offspring with the intestinal flora of prospective fathers, and even established a gut-reproductive axis regulation mechanism, pointing to the fact that intestinal flora disorders are the culprit for the poor development of offspring .

The adverse development of offspring is persistent but also reversible

The researchers established an inducing model of intestinal microbiome imbalance in male mice by directly interfering with drugs using non-absorbable antibiotics (nABX). Six weeks of low-dose nABX administration to male mice led to a significant decrease in the diversity, abundance and richness of the intestinal microbiota in male mice, thus causing intestinal flora imbalance . However, it was found that this phenomenon was reversible and gradually recovered after 8 weeks of stopping nABX.

It should be noted that nABX cannot pass through gastrointestinal epithelial cells, so 16s ribosomal RNA sequencing can be used to show the direct response of intestinal microbiome imbalance to reproduction. The sequencing results showed that there was no significant effect on the weight, fertility and survival of male mice with intestinal flora imbalance after 6 weeks of nABX administration.

Next, the researchers mated male mice treated with nABX with female mice that had not been treated with nABX and analyzed the phenotype of the F1 offspring. The results showed that compared with the offspring of male mice in the control group, the offspring of nABX male mice were not only developmentally delayed, but also had a lower survival rate than the offspring of male mice in the control group.

In order to eliminate the interference of other potential antibiotics, the researchers cleaned the gastrointestinal tract of the male mouse model with an osmotic laxative (polyethylene glycol (PEG)), and found that the results were still the same. This once again shows that the disordered intestinal flora of the expectant father has an adverse effect on the development of his offspring.

Subsequently, the researchers conducted the following verification to see whether the developmental delay of offspring could be reversed after the intestinal flora returned to normal: the male mice stopped taking the medicine after 6 weeks, allowing their intestinal flora to recover on their own, and then mated with healthy female mice after a recovery period of 4 to 8 weeks.

The results showed that it took at least 8 weeks of recovery for the intestinal microbial flora of male mice to reach a balance, and the phenotype of the offspring also returned to normal. The above results show that the impact of intestinal flora disorder on the development of offspring by prospective fathers is reversible.

Testicular physiological function is directly related to intestinal flora disorders

The researchers found that the male mice treated with the drug had changes in testicular weight and seminiferous tubule structure. By comparing male mice treated with different drugs: 6 weeks of drug treatment, 6 weeks of drug treatment + 4 weeks of recovery treatment, it was found that there were significant differences between male mice with intestinal flora disturbance after drug interference and the control group, and this finding corresponds to the period of transmission of the F1 effect.

Furthermore, after 6 weeks of treatment + 8 weeks of recovery, the physiology of the treated male mice was consistent with that of the control group, suggesting that testicular physiology is affected by perturbations in the gut microbiota.

In addition, the researchers also conducted non-targeted metabolome and transcriptome tests on testicular samples and found that the content of leptin was significantly reduced in the testes and plasma of male mice with disturbed intestinal flora. Leptin is a hormone secreted by fat cells and plays a key role in energy metabolism and reproductive function. At the same time, the offspring of male mice lacking leptin showed transcriptome disorders.

The experimental results show that dysbiosis is a "hidden killer" that affects the testicular tissue structure and physiological functions such as lipid and fatty acid metabolism. Such experimental conclusions also confirm the existence of the gut-reproductive axis and that leptin is an important medium for regulating the gut-reproductive axis.

Expectant fathers with disordered intestinal flora may affect the placental function of their offspring

The researchers found that nabx-treated male embryos had no Degs compared to controls, and the embryonic transcriptomes were indistinguishable by PCA. Among the downregulated Degs, it was noteworthy that several factors important for placental development, such as Hand1 and Syna, were downregulated, suggesting that placental identity was impaired during development.

To further investigate this possibility, the researchers scored the ratio of placental mass to the embryo and found that F1 fetuses from nABX male mice had significantly reduced placental maze areas, significantly impaired vascularization, and increased placental infarction, suggesting that placental defects originated from expectant fathers with disturbed intestinal flora.

In summary, we can clearly know that the imbalance of the intestinal flora of prospective fathers is quite risky for the growth and development of their offspring. At the same time, the doubts at the beginning of the article have also been answered. There is an intestinal-reproductive axis between the intestines and the reproductive system, and the "pot" caused by intestinal disorders is indeed borne by the reproductive system, and this "pot" is well-founded. Therefore, prospective fathers should not only maintain healthy living habits, but also pay attention to the balance of intestinal flora, starting from the starting point, to comprehensively ensure the healthy growth of our offspring.

References:

[1] Argaw-Denboba A, Schmidt TSB, Di Giacomo M, Ranjan B, Devendran S, Mastrorilli E, Lloyd CT, Pugliese D, Paribeni V, Dabin J, Pisaniello A, Espinola S, Crevenna A, Ghosh S, Humphreys N, Boruc O, Sarkies P, Zimmermann M, Bork P, Hackett JA. Paternal microbiome perturbations impact offspring fitness. Nature. 2024 May;629(8012):652-659. doi: 10.1038/s41586-024-07336-w. Epub 2024 May 1. PMID: 38693261; PMCID: PMC11096121.