The fetus’s stool, called the “meconium,” is sterile but nevertheless causes inflammation of the abdominal cavity when it leaks out of the intestine after a perforation. Called “meconium peritonitis,” this is a life-threatening condition for the baby with a mortality rate of 10%-15% in humans, and neither a cause nor a treatment have been established.

The Kobe University pediatrician FUJIOKA Kazumichi and his team therefore decided to replicate the condition in mice. Since the intestinal development of mice and humans is different, the intestine of a newborn mouse pup is equivalent to that of a human fetus after the 12th week of pregnancy, but even so, the mouse pup is too small and fragile to induce the condition through an operation. The research team therefore created a slurry of meconium, which they took from human newborns, and injected it into the abdominal cavity of the pups. They then characterized the resulting condition and compared the pups’ mortality rates in response to different treatments.

Their results, published in the journal Pediatric Research, show that mortality was not influenced by antibiotic treatment, ruling out a bacterial cause. However, when they heat-treated the meconium slurry before injection, which disrupts the natural shapes of proteins, they found a significant reduction in mortality. This indicates that proteins contained in the meconium are responsible for the inflammation and in particular the researchers assume digestive enzymes that are abundant in the meconium to be the culprits.

The Kobe University development has more general implications, too. In a different set of experiments, Fujioka and his team characterized the condition of the mice pups after the meconium slurry administration by analyzing the mice’s biochemical and gene expression profiles. Comparing that to the results of a previously established mouse model, where the pups were injected an extract of intestinal contents of adult mice, they could show that their model results in different symptoms. Believing that their model is thus likely to be specific to meconium-caused inflammation, the researchers argue that it is an apt platform to conduct more research on the condition.

Fujioka and his team hope that their work will enable the search for an effective treatment of the condition, which occurs in about one out of every 35,000 live births. They conclude their paper saying, “As our mouse model is simple and highly reproducible, it can be used in research to elucidate the pathophysiology of meconium peritonitis.”

This research was funded by the Japan Society for the Promotion of Science (grants 18K15710 and 20K08229), the Morinaga Hoshi-kai Foundation, the Kawano Masanori Memorial Public Interest Incorporated Foundation for the Promotion of Pediatrics and the Japan Foundation for Pediatric Research.

“When your senses decline, you can’t experience the world as well,” said Jayant Pinto, MD, a physician and expert in olfactory dysfunction at UChicago Medicine. “You can’t hear colleagues or friends at the dinner table; you can’t discern what’s going on in your environment; you may have a hard time reading or making things out when you’re in your neighborhood. It makes all your cognitive burdens a little harder, and that probably wears you down over time and causes mental health problems.”

Along with Alexander Wang, a medical student at the UChicago Pritzker School of Medicine, Pinto recently led a study examining the prevalence and impact of sensory impairments among older adults. They found that people with sensory disabilities tend to have worse mental health, and that different types of sensory disability were associated with different aspects of mental health.

Revealing associations between perception and emotion

The UChicago researchers analyzed data on sensory function (vision, hearing and sense of smell) and self-reported mental health from nearly 4,000 older adults, collected over 10 years of follow-up as part of the National Social Life, Health & Aging Project. They found that people who had multiple senses impaired experienced more loneliness and had significantly worse self-reported mental health overall, and people with three sensory disabilities were more likely to experience frequent depressive episodes. In analyses that differentiated between the senses, vision impairment was most strongly associated with both loneliness and poor self-rated mental health.

Scientists are still exploring how changes in all five senses can impact people, but the UChicago researchers can already point to many ways sensory decline contributes directly to feelings of loneliness, sadness and boredom.

Older people with vision impairment may have trouble getting out of the house or seeing the faces of their friends and family, and hearing loss can make conversations stilted and frustrating. Even loss of smell can affect someone’s ability to find joy in familiar scents — like a favorite home-cooked meal or a loved one’s signature perfume — and perceive pheromones, which (though not registered consciously) contribute to social dynamics.

“We saw that hearing and vision disability tended to be associated with lower self-rated mental health and feelings of loneliness, but olfactory disability had a weaker association,” Wang said. “This stood out to me because hearing and vision disabilities tend to be much more stigmatized than olfactory disability. This made me reflect on the ways in which social stigma may be driving this worse mental health.”

Caring for one another in an aging society

In the face of that stigma, the researchers say their results highlight the importance of improving access to mental health services and increasing awareness of the connection between sensory loss and mental distress. In particular, understanding how different sensory disabilities impact the long-term mental health of older adults could help healthcare professionals — especially primary care providers, otolaryngologists and ophthalmologists — screen for mental health conditions when they identify sensory loss in their patients, providing opportunities for personalized and timely interventions.

In addition to proactively treating older adults’ mental health, the researchers pointed to steps that can be taken to directly lessen the day-to-day effects of sensory difficulties, which would in turn lessen their negative mental health implications.

“We have an aging society; everybody has a relative who’s getting older and having a harder time in life. It’s a burden for us all to share,” Pinto said. “Lessening the burdens of your aging relatives and friends can have a huge impact on people’s lives, their productivity and their quality of life.”

On a personal level, family members and friends can help by being patient and finding ways to communicate more effectively, such as speaking clearly or using written notes. On a societal level, public policies and community programs can ensure accessibility in public spaces and provide resources that improve quality of life.

Pinto also highlighted a wide range of technologies and medical interventions are available that can help compensate for sensory impairment. For hearing loss, there are cochlear implants, hearing aids and other hearing-assistive devices — which research has indicated could slow cognitive decline in addition to improving quality of life. For vision loss, there are glasses, contacts, cataract surgery and LASIK surgery, along with accommodations like text-to-speech computer programs. Even for the sense of smell, health experts can sometimes help by reducing sinus inflammation or conducting smell training exercises.

“In many cases, we can mitigate sensory difficulties in ways that might actually improve people’s lives, mental health and sense of loneliness — which is a huge epidemic,” Pinto said. “These are simple ways we can intervene to help people and potentially have a huge impact on society.”

Recognizing and destigmatizing sensory disability

The researchers said they intentionally used the word “disability” throughout the paper to underscore the significant impact of sensory impairments on individuals’ lives. This terminology also aligns with efforts to destigmatize these conditions and promote a more inclusive approach to healthcare.

“To some extent, our society already considers decreased sensory function to be a disability: think of the blind and d/Deaf communities,” Wang said. “Like many marginalized communities, the disabled community has historically had a very contentious relationship with the medical field, which can cause distress and limit access to mental health services. With better understanding and compassion, we can strive to improve the care we provide to older adults and disabled patients.”

He said that by framing the data this way, he hopes to encourage more healthcare providers to move away from thinking in terms of the Medical Model of Disability and move towards the Social Model of Disability.

“My understanding is that the Medical Model characterizes disability as something that is ‘deficient’ with a person, thus requiring some sort of ‘fixing’ of the individual,” he explained. “The Social Model characterizes disability as more of an identity, so limitations relating to disability stem from a society’s lack of accessibility and accommodation for disabled people.”

Recognizing sensory impairments as disabilities and acknowledging their impact on mental health are important steps toward more comprehensive and compassionate care. By addressing the medical, social and environmental barriers that exacerbate these impairments, clinicians — and society as a whole — can better support older adults in maintaining their independence.

It is a major risk factor for cirrhosis and liver cancer. And because treatment options are limited, MASH is the second leading cause for liver transplants in the United States after cirrhosis caused by chronic hepatitis C infection.

A better understanding of the pathological processes that drive MASH is critical to creating effective treatments. In a new paper published August 19, 2024 in PNAS, a team of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine and elsewhere, describe the complex interplay between diseased liver cells and macrophages — a type of white blood cell whose jobs include killing and removing harmful cells and pathogens and helping to spur normal healing.

Debanjan Dhar, PhD, associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, is senior author of the study. David Brenner, MD, president and CEO of Sanford Burnham Prebys, and Christopher Glass, MD, PhD, professor of cellular and molecular medicine at UC San Diego, are corresponding authors. Souradipta Ganguly, PhD, a postdoctoral research fellow at UC San Diego and Sanford Burnham Prebys, is first author.

The researchers found that the heterogeneous mix of macrophages involved with MASH was different, depending on whether the disease was progressing or regressing. More importantly, they identified specific macrophage subpopulations that are critical for resolving MASH and liver fibrosis in which accumulating scar tissue impairs the organ’s ability to function or repair itself. These fibrotic bands restrict blood flow, imperiling the entire organ.

“In MASH, Kupffer cells (a type of macrophage that resides in the liver) are lost and replaced by four distinct macrophage subpopulations. When the disease is in regression — that is, symptoms or severity are decreasing — two lipid associated macrophage subpopulations are dominant and express TREM2, a cell receptor that regulates cell survival, proliferation and anti-inflammatory responses,” said Brenner.

“MASH regression occurs in the presence if TREM2+ macrophages. They not only restrict the progression of MASH-fibrosis, but effectively slow it and reduce inflammation. The absence of TREM2+ macrophages allows the disease to progress.”

In early and moderate stages, MASH often produces no tell-tale symptoms, which is part of the why it has reached epidemic proportions in the U.S. The American Liver Foundation estimates 80 to 100 million Americans have fatty liver disease which, undiagnosed and untreated, progresses to nonalcoholic steatohepatitis, MASH, cirrhosis, liver cancer and death, often in combination with other conditions, such as obesity.

An estimated 1.5% to 6.5% of U.S. adults have MASH. afflicted by the condition, and roughly 24% of adults have metabolic dysfunction-associated steatotic fatty liver disease, the starting point for MASH, cirrhosis and worse.

“Our findings suggest that lipid associated macrophages that express TREM2 and TREM2 are required both for the emergence of more liquid associated macrophages and for their reparative functions,” said Dhar.

“Effective degradation of scar tissue as a protective mechanism is mediated by TREM2, and the absence of TREM2+ macrophages not only disrupts the liver’s ability to remove fibrotic tissue, but it also harms the entire immune response and healing process.”

Going forward, the scientists say a TREM2 agonist — a drug or substance that mimics the function of TREM2 — might be beneficial for MASH/fibrosis therapy and help spur MASH and fibrosis regression in patients also undergoing lifestyle modification, weight loss or bariatric surgery.

“There is only one approved treatment for MASH, and it was only approved earlier this year,” said Glass. “Any opportunities to expand clinical options that benefit patients need to be thoroughly pursued because liver disease in this country — and around the world — is only getting worse.”

Additional authors on the study include Sara Brin Rosenthal, Kei Ishizuka, Theresa V. Rohm, Naser Khader, Sebastiano Archilei, Jerrold M. Olefsky, Ariel E. Feldstein, Tatiana Kisseleva and Rohit Loomba, all at UC San Diego; Ty D. Troutman, UC San Diego and Cincinnati Children’s Hospital Medical Center, and German Aleman Muench, Yasuyo Sano and Pejman Soroosh, Janssen Research & Development, San Diego.

This study was supported by National Institutes of Health grants to D.D. (R01DK137061, R01DK133930), Altman Clinical and Translational Research Institute (ACTRI — KL2TR001444) and the San Diego Digestive Diseases Research Center (NIH DK120515). It was partially supported by the ACTRI (NIH UL1TR001442). T.K. was supported by NIH grants DK099205, AA028550, DK101737, AA011999, DK120515, AA029019, DK091183; C.K.G by NIH grants DK091183 and HL147835. T.D.T. was supported by NIH grants P30DK063491, T32DK007044, P30DK078392, the American Association for the Study of Liver Diseases (PNC23-216751) and the Center for Inflammation and Tolerance through the Cincinnati Children’s Research Foundation. R.L. received funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), the John C. Martin Foundation (RP124). J.M.O was supported by the Diabetes Research Center (P30DK063491) and Horton JPI MRA: Obesity and its metabolic complications (20175015). A.E.F was supported by the NIH grant R01DK113592. T.V.R was supported by grants from the Swiss National Science Foundation (P2BSP3_200177) and the Larry L. Hillblom Foundation (2023-D-012-FEL).

Dr Anne Hahn and Associate Professor Steven Zuryn from UQ’s Queensland Brain Institute said the findings could provide a promising therapeutic avenue to stop the onset of heritable and age-related diseases.

“Mitochondrial DNA is essential for cell function,” Dr Hahn said.

“But as we age it mutates, contributing to diseases like dementia, cancer and diabetes.

“Our team identified 2 enzymes that regulate a chemical modification — adenine methylation or 6mA — in mitochondrial DNA across various species, including humans.”

“Removing this modification leads to uncontrolled accumulation and inheritance of mutations in the DNA,” Dr Hahn said.

“Our study shows the 6mA modification controls these mutations, suggesting that enhancing levels of 6mA could slow disease progression.”

The concept of epigenetics is an evolving field of research that reveals how environmental factors such as childhood experiences, can influence gene expression.

This challenges the old belief that DNA mutations inevitably lead to disease.

Dr Hahn said the study bridges the gap between genetics and epigenetics.

“It shows how this epigenetic mark guards against disease-causing mutations and ensures the continuity of healthy cells,” she said.

Dr Zuryn said epigenetic modification was not only essential for individual health but also for safeguarding the genetic integrity of future generations.

“Our discovery was largely performed in the model organism C. elegans, and cells grown in a laboratory,” he said.

“The team is now exploring whether similar mechanisms exist in humans and how they might influence disease outcomes.

“This research has vast implications and offers a novel perspective on genetic and epigenetic factors in health and disease.”

Although the exact molecule they identified in the worms has not yet been studied in humans, the new work helps scientists better understand the complex crosstalk between the gut and the brain. It also may shed light on why fasting — not eating for set periods of time — has benefits that are independent from the number of calories a person eats. The new study was published in Nature Communicationson August 11, 2024.

“We’ve found for the first time that fasting is conveying information to the brain beyond just caloric withdrawal,” says Scripps Research Professor of Neuroscience Supriya Srinivasan, PhD, the senior author of the new study. “These findings make me wonder whether there are molecules made in the guts of other animals, including mammals, that explain some of the health outcomes associated with fasting.”

Researchers have long known that the brain controls the production and breakdown of fats in humans, other mammals and model organisms such as C. elegans. In 2017, Srinivasan’s group identified FLP-7, a brain hormone that triggers fat burning in the roundworm’s gut. However, C. elegans do not have sensory nerves in their intestines, so scientists have struggled to pin down the reverse communication pathway: How does the gut signal the brain?

“We knew that altering the metabolic state of the gut could change the properties of neurons in the brain, but it was very mysterious how this actually happened,” says Srinivasan.

In the new work, Srinivasan and her colleagues removed more than 100 signaling molecules from C. elegans intestines, one at a time, and measured their impact on the brain’s production of FLP-7. They found one molecule that had a large effect on FLP-7: a form of insulin known as INS-7. In humans, insulin is most known as the hormone produced by the pancreas that control blood sugar levels. But this insulin molecule was instead being made by gut cells and also impacting fat metabolism via the brain.

“When we first found that this was an insulin, we thought it was paradoxical,” recalls Srinivasan. “Insulin is so well studied in mammals, and there was no precedent for an insulin molecule having this role.”

However, when the group probed how INS-7 was impacting FLP-7-producing brain cells, they found that it was not activating insulin receptors — as all previously discovered insulin molecules do — but by blocking the insulin receptor. In turn, this blockade set off a cascade of other molecular events that eventually made the brain cells stop producing FLP-7.

“INS-7 is basically a signal coming from the intestines that tells the brain not to burn any more fat stores right now because there’s no food coming in,” explains Srinivasan.

Studies have previously shown that periods of fasting can influence the body in a variety of ways, but the mechanisms of those changes have been unclear. The new study points toward one way that an empty gut can signal the brain, which could potentially lead to a variety of health impacts beyond fat.

The new results, Srinivasan says, help explain how the brain and digestive system communicate in both directions to control metabolism based on the availability of food. More research is needed to uncover which specific pathways are involved in new gut-to-brain signals in mammals. Compounds that mimic gut hormones — such as semaglutide, commonly known under brand names such as Ozempic, Wegovy and Rybelus — have recently emerged as popular ways to control obesity and diabetes, so new gut peptides could add to this drug class. Srinivasan is also planning experiments to probe how C. elegans gut cells are triggered to produce INS-7 during fasting and which types of brain cells are affected by the molecule.

This work was supported by funding from the National Institutes of Health (R01 DK124706 and R01 AG056648).

Specifically, viperins and argonautes, two proteins that are known to play important roles in the immune systems of all complex life — from insects to plants to humans — came from the Asgard archaea. Versions of these defense proteins are also present in bacteria, but the versions in complex life forms are most closely related to those in Asgard archaea, according to the new scientific study published in the journal Nature Communications.

This research bolsters the idea that all complex life, called eukaryotes, arose from a symbiotic relationship between bacteria and Asgard archaea.

“It adds more support to the fact that the Asgards are our microbial ancestors,” said Brett Baker, associate professor of integrative biology and marine science and senior author. “It says that not only did eukaryotes get all these rich structural proteins that we’ve seen before in Asgards, now it’s saying that even some of the defense systems in eukaryotes came from Asgards.”

The researchers identified for the first time a large arsenal of defense systems in archaea that were previously known only in bacteria.

When viperins detect foreign DNA, which might indicate a dangerous virus, they edit the DNA so that the cell can no longer make copies of the DNA, which stops the virus from spreading. When argonautes detect foreign DNA, they chop it up, also halting the virus. Additionally, in more complex organisms, argonautes can block the virus from making proteins in a process called RNA silencing.

“Viral infections are one of the evolutionary pressures that we have had since life began, and it is critical to always have some sort of defense,” said Pedro Leão, now an assistant professor at Radboud University in the Netherlands and a recent postdoctoral researcher in Baker’s lab. “When bacteria and archaea discovered tools that worked, they were passed down and are still part of our first line of defense.”

The researchers compared proteins involved in immunity across the tree of life and found many closely related ones. Then they used an AI tool called ColabFold to predict whether ones that had similar amino acid sequences also had similar three-dimensional shapes (aka structures). (It’s the shape of a protein that determines how it functions.) This showed that variations of the viperin protein probably maintained the same structure and function across the tree of life. They then created a kind of family tree, or phylogeny, of these sister amino acid sequences and structures that showed evolutionary relationships.

Finally, the researchers took viperins from Asgard archaea genomes, cloned them into bacteria (so the bacteria would express the proteins), challenged the bacteria with viruses, and showed that Asgard viperins do in fact provide some protection to the modified bacteria. They survived better than bacteria without the immune proteins.

“This research highlights the integral role cellular defenses must have played from the beginning of both prokaryotic and eukaryotic life,” said Emily Aguilar-Pine, a former undergraduate researcher who contributed to the project. “It also inspires questions about how our modern understanding of eukaryotic immunity can benefit from unraveling some of its most ancient origins.”

“It’s undeniable at this point that Asgard archaea contributed a lot to the complexity that we see in eukaryotes today,” Leão said. “So why wouldn’t they also be involved in the origin of the immune system? We have strong evidence now that this is true.”

Other authors, all from UT, are Mary Little, Kathryn Appler, Daphne Sahaya, Kathryn Currie, Ilya Finkelstein and Valerie De Anda.

This work was supported by the Simons and Moore foundations (via the Moore-Simons Project on the Origin of the Eukaryotic Cell) and The Welch Foundation.