WOMENS HEALTH
Mothers massively change their intestines during pregnancy and nursing
Scientists discover the molecular and structural principles of intestinal changes in pregnancy, critical for nutrient uptake and the health of babies
Medical University of Vienna
When women are pregnant and nurse their babies, their bodies change and various organs, such as the breasts or the immune system, are adapted to ensure the health of both mother and child. This happens throughout evolution in all mammals. An international research team led by Josef Penninger and Masahiro Onji, Medical University of Vienna, now reports the surprising finding that the intestine also changes completely in pregnant and nursing females, resulting in a doubling of the intestinal surface area and a striking structural reorganisation. The researchers also provide the first genetic and mechanistic evidence of how this intestinal epithelial expansion occurs in mothers, with direct implications for the transgenerational health of the babies. The study is being published in "Nature".
A multinational team led by Josef Penninger (MedUni Vienna, IMBA - Institute of Molecular Biotechnology, Vienna, University of British Columbia, Canada, Helmholtz Centre for Infection Research, Germany) observed that the intestinal villi reorganise during pregnancy and breastfeeding and significantly enlarge, doubling their surface area. The studies were carried out in genetically modified mice and intestinal organoids from mice and humans - self-organised three-dimensional tissues derived from stem cells in the intestine. Mechanistically, the researchers identified the RANK receptor/RANK ligand (RANK/RANKL) system as the key to the villous enlargement of the small intestine during reproduction, which is regulated by sex and lactation hormones. When mice were engineered to lack the RANK/RANKL system in the intestine, the villous expansion during pregnancy and breastfeeding was significantly impaired.
Fundamental importance for evolution
For decades, researchers have studied the RANK/RANKL system as a key facilitator of essential, evolutionarily conserved processes. The Penninger group has already identified key functions of the RANK/RANKL system in bone turnover, in the biology of the mammary gland, in breast cancer, and in immune tolerance in pregnancy, contributing to the development of drugs against bone loss used by millions of people and clinical trials for breast cancer prevention and cancer immunotherapies are underway. The researchers now discovered that these intestinal changes, which appear to be completely reversible when nursing is stopped, are important for proper feeding and nourishment of the babies. "Our study shows that the impairment of this intestinal expansion by the lack of the RANK/RANKL system during pregnancy changes the milk of the nursing mothers. This results in lower weights of the babies and transgenerational long-term metabolic consequences," states the lead author Masahiro Onji. "Mothers need to eat for themselves and their babies. These new studies provide for the first time a molecular and structural explanation of how and why the intestine changes to adapt to enhanced nutrient demand of mothers, which is probably the case in all pregnant and nursing mammals," adds study leader Josef Penninger.
How mothers adapt to the demands of pregnancy and breastfeeding remains a central question of evolution and human health. During this phase, female hormones influence multiple organs to control and change their structure and functions, which is crucial for the health of the mother and the development of the offspring. It was known that pregnant women have enhanced nutrient demands. However, this fundamental aspect has not been well studied until now: "By identifying the RANK/RANKL system as the driving force behind intestinal adaptation during pregnancy and lactation, our study contributes to a deeper understanding of biological processes that are of fundamental importance for evolution and human health", says Josef Penninger, summarising the impact of the findings.
This massive expansion is controlled by sex and pregnancy hormones, which change the stem cells in the gut via the RANK/RANKL system and then give the intestinal cell a survival signal to grow much larger. This growth then leads to a near doubling of the intestinal surface area, which also increases the molecular machinery for the uptake of sugar, protein, and fat, and even leads to a profound architectural change in the intestinal villi, which probably slows down the flow of food, again maximising the uptake of nutrients. Josef Penninger: "Our team has discovered an amazing new way how mother’s bodies change to keep babies healthy. Hardly anybody knew about this, apart from a few old studies that have largely been forgotten. We have also found that this system, via stem cells, can directly affect tumours in the intestine; maybe we can learn from pregnant and nursing mothers to reversibly rewire this system to develop new treatments and a better understanding of intestinal cancer or gut regeneration."
The study was a close collaboration between the Medical University of Vienna, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, the Life Sciences Institute in Vancouver, the Helmholtz Centre for Infection Research, Braunschweig, the Hubrecht Institute, Utrecht, and the Kiel University. Researchers from the University of Tokyo and the University of Cambridge also participated.
Journal
Nature
Article Title
RANK drives structured intestinal epithelial expansion during pregnancy
Article Publication Date
4-Dec-2024
New study finds neurobiological evidence of peripartum depression in women, distinguishing it from major depressive disorder
Novel research in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging provides insights into the biological underpinnings of peripartum depression that can help destigmatize this condition and contribute to better care for mother and child
Elsevier
image:
A) Glass brain rendering of significant right basal ganglia cluster. B) Slices of the brain showing significant right brain cluster. C) Model of the moderation analysis with peripartum depression (PPD) moderating the association between estradiol polygenic risk scores (PRSs) and grey matter volumes. D) Partial least squares regression results with the 11 PRSs for estradiol entered as predictors for extracted significant right basal ganglia cluster. Three PRSs were selected as significant in contributing to explain variance in cluster volumes. E) Graph showing individual effects of the estradiol PRSs on cluster volumes in the PPD group and no PPD group.
view moreCredit: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Philadelphia, December 5, 2024 – Researchers have identified structural grey matter differences in the brains of women with a history of peripartum depression and those without within a group of major depressive disorder patients. The women who had experienced peripartum depression were also found to be more sensitive to hormone fluctuations during the peripartum period. The novel study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, recognizing the biological underpinnings of peripartum depression and disentangling them from major depressive disorder, contributes to improving maternal and child health.
Peripartum depression is a common complication of pregnancy and childbirth and could have potential consequences for the mother’s wellbeing and the infant’s development. Whether peripartum depression should be considered a separate clinical entity from major depressive disorder is currently being debated. In this study a whole brain approach was used for the first time to help determine the answer to this question. Researchers examined 64 female patients with major depressive disorder using voxel-based morphometry analysis, a whole brain approach without a priori hypothesis, to identify potential grey matter structural differences between women who had a history of peripartum depression and those who did not.
Yasmin A. Harrington, PhD candidate at the Vita-Salute San Raffaele University, Milan, Italy, and first author of the study, says, "We found bilateral grey matter clusters within the basal ganglia, an area crucial for motivation, decision-making, and emotional processing, to be larger in women with a history of peripartum depression compared to women who have only experienced depressive episodes outside of this time period."
A biological mechanism often thought to separate major depressive disorder from peripartum depression is the involvement of sex hormones. During pregnancy, hormonal levels, specifically estradiol and progesterone, physiologically soar to high levels and drop sharply shortly before birth. Previous research has hypothesized that women who suffer from peripartum depression have a particular sensitivity to these fluctuations in hormones. Previous studies have shown the significant effects sex hormones have on the brain including altering brain structure and function, providing neuroprotection, and influencing behavioral outcomes.
Lead investigator Francesco Benedetti, MD, Head of the Psychiatry & Clinical Psychobiology Unit at the IRCCS Scientific Institute Ospedale San Raffaele, and Professor of Psychiatry at Vita-Salute San Raffaele University, explains, "We calculated genetic risk scores for estradiol levels and assessed their association with the identified grey matter cluster from the voxel-based morphometry analysis to see if the effect of the genetic scores on the brain was different based on history of peripartum depression. Our findings show that estradiol genetic scores had a positive effect on basal ganglia volumes in women with peripartum depression and a negative effect in women without peripartum depression, suggesting a differential effect of the genetic load from estradiol on brain structure based on history of peripartum depression."
Yasmin A. Harrington says, "We were surprised that the effect of peripartum depression could be seen years after the episode, suggesting that these differences are related to the neurobiology of the disorder rather than to the specific episode. Further corroborating this finding, the genetic load for estradiol showed an impact years after the peripartum episode, suggesting a lifetime neurobiological sensitivity to estradiol in peripartum depression and giving further support for the reproductive hormone theory of the disorder."
Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine, comments, "This study not only advances our understanding of major depressive disorder's heterogeneity, but also holds implications for refining clinical strategies to improve outcomes for individuals experiencing depressive episodes both within and beyond the perinatal period."
The researchers of this study hope that their findings can contribute to the destigmatization of peripartum depression.
Dr. Benedetti notes, "Many women still perceive the terrible burden of peripartum depression as their fault, feeling guilty because they cannot meet expectations regarding their role as mothers. We showed that genetic factors that physiologically affect steroid hormones do impact brain structures at a very basic level, possibly predisposing women to develop depressive psychopathology when hormones markedly oscillate, as they do in the peripartum period. We think that refining knowledge on these mechanisms will eventually lead to more precise and personalized strategies for prevention and treatment of this condition."
Journal
Biological Psychiatry Cognitive Neuroscience and Neuroimaging
Method of Research
Imaging analysis
Subject of Research
People
Article Title
History of Peripartum Depression Moderates the Association Between Estradiol Polygenic Risk Scores and Basal Ganglia Volumes in Major Depressive Disorder
COI Statement
The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article. Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California, Irvine School of Medicine. His disclosures of financial and conflicts of interests are available at https://www.biologicalpsychiatrycnni.org/bpsc-editorial-disclosures.
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Women pay for AI to boost mammogram findings
Radiological Society of North America
image:
AI enhanced screening mammography.
view moreCredit: Radiological Society of North America (RSNA) and DeepHealth
CHICAGO – More than a third of women across 10 health care practices chose to enroll in a self-pay, artificial intelligence (AI)-enhanced breast cancer screening program, and the women who enrolled were 21% more likely to have cancer detected, according to research being presented today at the annual meeting of the Radiological Society of North America (RSNA).
AI has shown great promise in mammography as a “second set of eyes” for radiologists providing decision support, risk prediction and other benefits. Despite its promise, AI is not yet reimbursed by insurance, which likely is slowing its adoption in the clinic. Some practices have elected to offer enhanced workflows enabled by AI at additional cost, much like what was done when digital breast tomosynthesis was originally deployed.
For the study, researchers investigated the impact of AI—including a safeguard review—as a self-pay option in screening mammography. A self-pay, AI-powered screening mammography program was offered to patients across 10 clinical practices, ranging from a few sites up to 64 sites at the largest practice. Women who enrolled had U.S. Food and Drug Administration-compliant AI software applied to their mammograms. An expert breast radiologist provided a third, safeguard review in cases where there was discordance between the first reviewer and the AI.
Out of the 747,604 women who underwent screening mammography over an initial 12-month period, the overall cancer detection rate was on average 43% higher for enrolled women than for unenrolled women. The pattern of a substantially higher cancer detection rate in enrolled women was observed at all 10 practices.
Further analysis attributed 21% of the increase in cancer detection to the AI program. The researchers credited the remaining 22% increase in detection to the fact that higher-risk patients chose to enroll more frequently.
“These data indicate that many women are eager to utilize AI to enhance their screening mammogram, and when AI is coupled with a safeguard review, more cancers are found,” said study senior author Gregory Sorensen, M.D., from DeepHealth Inc. in Somerville, Massachusetts.
The recall rate—the rate at which women were called back for additional imaging—was 21% higher for enrolled versus unenrolled women. Relatedly, the positive predictive value for cancer was 15% higher for the enrolled women, indicating that each recall resulted in more cancer diagnoses in the enrolled population.
“This is the first report on results from a program that provides an AI-powered enhanced review that patients can elect to enroll in,” said study lead author Bryan Haslam, Ph.D., from DeepHealth. “The AI-driven enhanced review program leverages AI in a novel workflow to ensure women with suspicious findings get expert level care that could help detect many more breast cancers early. The number of women electing for this program is now at 36% and growing, and the rate of cancer detection continues to be substantially higher for those women.”
In the future, the researchers hope to better quantify the benefit of the AI-driven safeguard review with prospective randomized controlled trials that would eliminate the self-selection bias and provide the highest level of evidence.
Co-authors are Leeann Louis, Ph.D., Jacqueline S. Holt, M.D., and Janet M. Storella, M.D.
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Note: Copies of RSNA 2024 news releases and electronic images will be available online at RSNA.org/press24.
RSNA is an association of radiologists, radiation oncologists, medical physicists and related scientists promoting excellence in patient care and health care delivery through education, research and technologic innovation. The Society is based in Oak Brook, Illinois. (RSNA.org)
For patient-friendly information on breast cancer screening, visit RadiologyInfo.org.
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