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Dad’s gut microbes matter for pregnancy health and baby’s growth

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THE PAPER IN BRIEF

• Gut bacteria can affect biological processes at body sites far from the gut.

• The extent to which gut bacteria can affect reproductive tissues is not fully understood.

Argaw-Denboba et al.1 report that altering the community of gut bacteria in male mice had negative consequences for the health and lifespan of offspring.

• Abnormalities in sperm RNA and the placenta were some of the changes associated with changes to male gut microbes.

• More work will be needed to uncover all the mechanisms underlying this phenomenon.

LIISA VEERUS & MARTIN J. BLASER: The power of paternal bacteria

The microbial communities living in and on animal hosts have become a notable focus of scientific research in recent decades. Studies have explored the many interactions that these microbiomes have with their hosts, and the consequent implications for health and disease. Argaw-Denboba and colleagues now present work that contributes to the emerging field of cross-generational microbiome effects. They investigated how the gut microbiome of male mice might affect the health of the animals’ offspring through changes in the paternal germline tissue, which contains the cells that form sperm. The authors’ observations pointing to a gut–germline axis could, if confirmed, shift the focus of microbiome research from the current mother–newborn model2 towards a new mother–father–newborn interactive system.

After changing the community of gut microbes in prospective fathers by administering either gut-specific (primarily non-absorbable) antibiotics or laxatives, the authors showed that the sperm from a father with a perturbed gut microbiome triggered changes in the placenta (which forms from cells of the embryo) that developed in its mating partner. Some of the resulting offspring had a lower birth weight and a higher chance of premature death (Fig. 1) than did offspring of fathers with a normal microbiome.

Figure 1

Figure 1 | The effect of male gut microbes on offspring health. Argaw-Denboba et al.1 report that using antibiotics to alter the community of gut microbes in male mice affected the production of healthy sperm in a way that had negative consequences for the development of embryonic cells into the placenta and for offspring weight and lifespan. The molecular pathways underlying this phenomenon are not yet fully understood. The effect was reversed after recovery from antibiotic treatment.

By using a variety of methods, such as microbiome transplantation, in vitro fertilization and analysis of gene expression, Argaw-Denboba et al. go beyond correlation to pinpoint that the disadvantageous effect in the offspring is transferred through sperm cells, not through the paternal microbiome. And they demonstrate that the effect is not inherited genetically, but through epigenetic modifications (alterations that do not change the DNA sequence) in the male reproductive system, with differences in sperm RNA reported. The authors also show that the paternal microbiome was restored naturally within eight weeks of the perturbation, and that this restoration was associated with a return to producing healthy offspring, indicating that the microbiome alteration effect was short-lived.

One limitation of the study is that it does not define the molecular pathway through which the perturbed gut microbiome affects the male germline. Doing so could be a goal of future research. The authors note that the disadvantageous aspects of offspring development, including severe growth restriction, did not arise in all offspring, suggesting that further investigation will be required to understand the proposed gut–germline axis and its effect on offspring health.

Whether these findings in mice are also relevant to humans remains to be determined. Another interesting question is how long the gut microbiome takes to recover in people who receive a course of antibiotics. The authors’ finding that the negative effect is reversible might prove useful in providing advice on the optimal timing for fertilization, to avoid costs to the offspring.

Argaw-Denboba and colleagues’ carefully planned research demonstrates how little we still know about antibiotics’ potential effects and underlying mechanisms in relation to crucial concerns such as healthy fertilization and offspring. Exploring the modulation of the gut microbiome and the consequent effects across organ systems is a scientific frontier. Although the health implications of antibiotic use in mothers and newborns have garnered interest in previous publications3,4, the role of fathers has been mostly ignored. This study shows that the preconception microbiome has a role, and that fathers are not just gene donors, but can also, through their microbiomes, affect their offspring’s health5.

YOEL SADOVSKY & ELDIN JAŠAREVIĆ: A father’s microbes and pregnancy outcomes

In mammalian species that form placentas, embryonic development and subsequent fetal growth depend on the genetic contributions and related signals carried in the egg and the sperm, with roles for the placenta, the maternal host tissues and the external environment. These influences are mediated by the exchange of gases, nutrients and metabolic waste, and are modulated by hormones. They are also affected by exposure to microbial or viral disease-causing agents and to inflammation, toxic compounds and social and behavioural stressors. The integration of these signals determines the outcome of pregnancy, and adverse influences can compromise fetal and maternal health and lifespan.

A key challenge in studying pregnancy relates to the dynamic and complex signals arising from factors that the parent encounters during their lifetime (described as lifetime exposures), and to how these signals affect fetal and placental development. A mother might generate or modulate health-related signals in many ways during pregnancy. By contrast, the father’s influences are limited mostly to sperm-dependent genetic (DNA) contributions, and to effects resulting from epigenetic modifications of DNA and its associated proteins, which are commonly induced by stress and dietary changes6,7. Paternal effects on offspring health, such as those mediated by stress, exposure to inhaled or ingested chemicals, or male help in providing maternal nutrition, are thought to be indirect when compared with the more direct maternal effects on the offspring.

A growing body of work demonstrates that gut bacteria and the metabolite molecules that they produce are key intermediaries between maternal lifetime exposures, pregnancy outcomes and lasting outcomes for offspring810. In their related findings, Argaw-Denboba and colleagues add an unexpected dimension to parental gut microbiome influences on gestational biology — namely, the effect of antibiotic-mediated disruption of the paternal microbiota on a male germline. Using mice, the authors established a strong association between a perturbed paternal gut microbiome and sex-independent restriction of fetal growth; the resultant low birth weight lingered into early adulthood and was associated with reduced survival times compared with the offspring of males who had unperturbed gut microbes.

Crucially, the effect was reversed when the paternal gut microbiome was restored to normal by ceasing antibiotic exposure, and was recapitulated through in vitro fertilization using sperm from males harbouring the perturbed gut microbiome. Furthermore, the altered paternal microbiome was associated with changes in male reproductive tissue (smaller testes and seminiferous tubules with a swollen (vacuolated) appearance and thinner than normal layers of epithelial cells). The authors observed intact genomic parental-specific expression of genes (imprints) but altered transcriptome, metabolome and methylome profiles (relating, respectively, to gene expression, production of metabolite molecules and the attachment of methyl groups to DNA); these profiles were of unknown relevance to the observed outcome.

Do any of these changes causally explain the prenatal and postnatal effects on the offspring? Examining samples of fetal and placental tissue, Argaw-Denboba et al. listed a series of changes in the fetal gene-expression profiles, highlighting differentially expressed genes related to lipid and metabolic processes. These changes were associated mainly with the fetal brain and brown adipose tissue. Placental analysis at embryonic days 13.5 and 18.5 revealed a smaller labyrinth (the mouse placental region that governs gas and nutrient exchange between the mother and the fetus) and impaired formation of blood vessels.

Gene-expression analysis highlighted altered expression of genes related to a metabolic process called glycolysis, to the metabolism of molecules called prolactin and steroids and to several regulators of placental development (such as the genes Hand1 and Syna). Intriguingly, some of the transcriptional changes can cause placental dysfunction. Certainly, further characterization will be crucial to determine whether effects similar to those observed in the placenta-associated condition pre-eclampsia (which involves maternal hypertension and target-organ injury and can lead to fetal or maternal illness or death) are an underlying cause of disease in this context.

These exciting observations establish a link between the paternal gut microbiota, sperm RNA content and pregnancy outcome. Although the mechanisms linking altered sperm biology with changes in the offspring and placenta and with altered gene expression remain to be unravelled, this line of investigation highlights antibiotic-mediated disruption of the paternal gut microbiota as a previously unknown mode of a sperm-mediated effect on fetal development and offspring health. Furthermore, if validated in humans, the work might indicate a potentially modifiable preconceptional contribution by the father’s microbiome to pregnancy health, which would be a pioneering concept in the biology of human pregnancy.

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Pregnancy advances your ‘biological’ age’

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An image of the front of the Large Aperture Telescope Receiver (LATR) just before the final closing.

The front of the Simons Observatory’s Large Aperture Telescope Receiver, the largest receiver for observing the cosmic microwave background built so far.Credit: Mark Devlin/University of Pennsylvania

In a few weeks, a new observatory high in northern Chile’s Atacama Desert will be ready to map the cosmic microwave background (CMB) with unprecedented sensitivity. One of the goals of the Simons Observatory is to find fingerprints left in the CMB by gravitational waves that originated from the Big Bang itself. These would provide incontrovertible evidence for cosmic inflation, a brief moment when the expansion of the early universe is thought to have accelerated hugely. There is no guarantee that the inflation signature, if it exists, is strong enough for the Simons Observatory to detect, says cosmologist Suzanne Staggs, who is the observatory’s co-director. “But oh my gosh — if they were right there, it would be amazing.”

Nature | 7 min read

A 62-year-old man with end-stage renal failure has become the first living person to receive a pig kidney transplant. The kidney was taken from a miniature pig carrying a record 69 genomic edits, which were aimed at preventing rejection of the donated organ and reducing the risk that a virus lurking in the organ could infect the recipient. So far, the patient is recovering well and the pig kidney is producing urine and showing other signs of a working organ. This early success has raised researchers’ hopes for larger clinical trials involving pig organs. It follows from news last week that surgeons say they have transplanted a genetically modified pig liver into a person for the first time.

Nature | 6 min read

Studies in mice and humans suggest that being pregnant can increase a person’s ‘biological age’ by a couple of years — but giving birth reverses these changes. Biological age can be estimated from patterns of DNA methylation, which occurs when chemical methyl groups are added to DNA. The patterns reflect the stresses that a body accrues over time. The work supports the idea that “biological age is quite flexible; it’s a fluid parameter. It can go up and down”, says biomedical scientist Vadim Gladyshev.

Nature | 5 min read

Reference: Cell Metabolism paper

China has launched a spacecraft to the Moon that will act as a communications link between Earth and the lunar far side.Queqiao-2, named after a folktale in which magpies form a bridge across the sky, will support China’s Chang’e-6 mission, set to launch in May. Chang’e-6 aims to become the first mission to collect samples from the far side of the Moon, which is permanently hidden from Earth. Queqiao-2 will also support future Chinese missions to the lunar south pole and will take over from its predecessor, Queqiao-1.

SpaceNews | 3 min read

Read more on Queqiao-1: Chinese satellite launch kicks off ambitious mission to Moon’s far side (Nature | 4 min read, Nature paywall)

Features & opinion

There is a type of test for infections such as COVID-19 that is almost as accurate as a polymerase chain reaction (PCR) test — which has to be done by a laboratory — and as easy and quick as the rapid antigen tests many of us have used at home. They are ‘isothermal tests’ — so-called because they operate at a consistent temperature, eliminating the need for the repetitive heating and cooling cycles of PCR. They’re comparatively expensive and have stumbled over bureaucratic hurdles. Still, developers are pushing forward, targeting applications such as at-home testing for sexually transmitted infections.

Nature | 10 min read

This article is part of the editorially independent supplement Nature Outlook: Medical diagnostics, produced with financial support from Seegene.

A study that looked at home-grown food and community gardens in the United States and Europe unveiled a surprising conclusion: the carbon footprint of food from urban agriculture is six times greater than the conventional, commercial version. Allotmenteers recoiled from the result, but the authors — keen home-growers themselves — emphasize that their findings can help make urban efforts (which have worthwhile social benefits) more carbon-efficient. Upcycling refuse as infrastructure such as raised beds, using equipment for a long time, collecting rainwater for irrigation and practising optimal composting can all help. And for some carbon-intensive commercial products, such as tomatoes, growing locally is already on par with big farms.

BBC Future | 7 min read

Reference: Nature Cities paper

Peggy Oti-Boateng, a Ghanaian biochemist, and Lise Korsten, a South African food-security researcher, are at the helm of the African Academy of Sciences at a critical time. They have a new strategic plan, with five areas of focus, and a desire to recruit scientists in the African diaspora as members. “We have lost a group of young academics who should have now been leaders on the continent, the professors of the future — and maybe we can partially bring them back,” says Korsten, the academy’s first female president.

Nature | 5 min read

Where I work

Antonia Bornas stands wth sea and a volcano in the background

Mariton Antonia Bornas is chief of the Volcano Monitoring and Eruption Prediction Division of PHIVOLCS in Quezon City.Credit: Dave Tacon for Nature

“We have a lot of natural disasters in the Philippines,” says Mariton Antonia Bornas, pictured here standing next to a monitoring station overlooking Taal volcano, which erupted in January 2020. As chief of the Volcano Monitoring and Eruption Prediction Division, her job is to provide early warning of potential eruptions and to monitor levels of harmful emissions. The hardest part of the job is “dealing with the non-science,” she says. “Responding to people online — even to psychics predicting an eruption — is part of my job and it doubles my work. I have to be a communicator, not just a scientist.” (Nature | 2 min read)

Quote of the day

Engineer Caleb Chung, who invented Furby — a big-eyed toy that gave the impression of being a sort of proto-chatbot — chimes in on people’s tendency to ascribe personalities to AI systems such as ChatGPT. (The New Yorker | 14 min read)

Last week in our penguin-search puzzle, Leif Penguinson was enjoying the river landscape of Oulanka National Park in Finland. Did you find the penguin? When you are ready, here’s the answer.

Thanks for reading,

Flora Graham, senior editor, Nature Briefing

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Pregnancy advances your ‘biological’ age — but giving birth turns it back

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A young woman holds her newborn baby in a hospital bed at at the University of Chicago Medical Center.

Giving birth shifts a person’s DNA markings back toward a more youthful state, but this trend is less noticeable in new birth parents with obesity.Credit: Chicago Tribune/Getty

Aches and pains aren’t all that pregnancy shares with ageing. Brewing a baby leads to changes in the distribution of certain chemical markers on a pregnant person’s DNA — changes similar to those that are a hallmark of getting older. But new research shows that, several months after a person gives birth, the chemical patterns revert to an earlier state1. The results strengthen previous work in mice and preliminary results in humans2.

It’s not surprising that pregnancy takes a toll, but the reversal was “somewhat unexpected”, says perinatal-health specialist Kieran O’Donnell at Yale University in New Haven, Connecticut, a co-author of the study. It was published 22 March in Cell Metabolism.

Aged DNA

The chemical tags analysed in the study are called methyl groups, and they are added to DNA in a process called methylation. They are one example of the ‘epigenome’, features of DNA that change gene activity without altering the genetic code.

DNA-methylation patterns can be used to estimate a person’s ‘biological age’, which reflects the physiological stresses that a person’s body has accrued over time. Some research has found that biological age is a better predictor of health problems such as cardiovascular disease3 and dementia4 than a person’s chronological age.

But unlike chronological age, “biological age is quite flexible; it’s a fluid parameter. It can go up and down”, says biomedical scientist Vadim Gladyshev at Harvard Medical School in Boston, Massachusetts. Last year, his team published a study in Cell Metabolism2 that noted a decrease in biological age after pregnancy in mice and suggested that there could be a similar effect in humans. Cessation of several other stressful conditions also reversed biological age.

Obesity’s effect

The new study confirmed Gladyshev and colleagues’ results in humans and also showed that not everyone bounces back from pregnancy to the same degree. People who were at the cusp of obesity before pregnancy shed fewer years of biological age in the three months after birth than did people who had a body weight classified as “normal,” O’Donnell and his colleagues found. Meanwhile, people who breastfed exclusively experienced a greater reduction in biological age than did those who used formula or a mix of formula and breast milk.

Some participants’ biological ages were a few years younger postpartum than in early pregnancy. That’s “one thing that caught my eye”, says ageing-biologist Yousin Suh at Columbia University in New York City, who was not involved in the work.

The researchers didn’t measure the biological age of participants before pregnancy, so “we can’t claim that this is a rejuvenation effect”, O’Donnell says. But the data are suggestive, and he’d like to follow up with the participants in the future.

Not to worry

Interpreting Gladyshev and O’Donnell’s findings is tricky, some researchers say. Methylation clearly changes during pregnancy, but “we would be wrong to assume pregnancy is a state of accelerated ageing”, says Dena Dubal, a physician-scientist and specialist in ageing at the University of California, San Francisco. Dubal thinks that methylation might not be a hallmark of ageing but could instead underlie some of the sweeping changes that the body must undergo to support a growing fetus, such as altered gene expression.

Suh isn’t so sure. “Methylation is, thus far, one of the most robust markers of biological age,” she says.

Whether a reversible state can truly be called “age” is “a really important point”, O’Donnell says. “Perhaps as we begin to focus on pregnancy as a new area for ageing research, maybe there’s new terms and terminology that will need to be developed.”

In the end, people shouldn’t worry about any pregnancy-related increase in their biological age, scientists say. “We are talking about, you know, changes of about two, three years,” Gladyshev says.

And Dubal points out that pregnancy should not be conceptualized as a biological problem, even for people who don’t maximize recovery by breastfeeding. “While the benefits of breast feeding are many, its absence is not a dangerous predicament,” she says.

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Hailey Bieber Pregnancy Rumors: Hailey Resolves It

Justin Bieber and Hailey Bieber fueled pregnancy rumors in September 2021 after the pop star was pictured on the Met Gala red carpet clutching his wife’s stomach. That rumor was immediately debunked, but curiosity about when the longstanding couple might start trying has not stopped.

Justine Bieber and his wife, Hailey Bieber

We were led to believe that it could happen as soon as 2022, after the release of the Justin Bieber: Our World documentary. However, according to an interview in February 2022, the model needed to be ready.

Before starting her beauty line, Hailey told the Wall Street Journal, “I think I had it ingrained in my head that I was going to want to have kids right away, and I was going to want to have kids super, super young.” Then I hit 25 and realized I was still very young.”

Despite this, she said they will begin attempting it in the “next couple of years.” In September 2019, Justine and Hailey exchanged marriage vows. Despite the intense attention, the Biebers have always been upfront about their relationship. This could all end soon, as the 26-year-old told the tabloid she would no longer disclose her personal life.

Wedding photo of Justine Bieber and Hailey Bieber

She asserted that “the media has always been a disgusting thing,” adding that “the media loves to take a tiny little blurb of something for clickbait.”

hailey bieber sparks-pregnancy rumors

Behind closed doors, we’re two incredibly ordinary people who simply happen to lead not-normal lives and occupations, the model continued. Justin is an average person, which is unusual, in my opinion, considering the significance of his work.