Gut microbiota has been shown to be crucial for liver repair

A new study shows that a lack of specific bacteria in the gut stalls liver regeneration – a life-saving process in the body. Our tummy is home to a menagerie of tiny microbes, such as viruses, fungi, and bacteria, which form our microbiome, a symbiotic entity that plays many roles in our body, including the regulation of our digestive system and immune responses. Now, a recent study by Technical University Munich (TUM) researchers suggests this omnipotent colony may also assist in liver regeneration following significant tissue loss. Their work, involving live mice and human liver tissue, found that a lack of the bacterial species responsible for producing fatty acids in the gut stalled the rate of hepatic regeneration after part of the organ was surgically removed (resected). These findings were observed in mice who had received a course of antibiotics that caused an imbalance of microbiotic species in the gut-a state known as dysbiosis-whereupon an uncommon species took over that couldn’t produce the lipids needed to rebuild the animal’s livers. An essential reason for this study revolves around the dichotomy of the liver’s remarkable capacity to recover from injury or a partial loss of tissue coupled with high rates of liver disease, which is still a major killer worldwide. And as experts consider inhibited hepatic regeneration the main culprit, the mechanisms responsible for this process continue to be the target of intense research, with the hope that the knowledge gained will one day lead to novel strategies to improve the outcomes of many liver diseases.  So far, metabolites produced by gut microbiota have been associated with liver disease and progression, hinting at a limited or expedited healing process. However, the effects of these microbial products on hepatic regeneration after an injury or surgery are still not fully understood. Up until now. The new study makes a significant discovery in the field by identifying the species of gut bacteria responsible for this process. Specifically, it shows that liver regeneration comes to a standstill when there is a decrease in the Firmicutes and Bacteroidetes microbiota in the gut. These bacteria-the dominant taxa in the gut microbiome-produce an essential enzyme and the lipids needed to rebuild the liver after an injury or tissue loss. The team says these new findings could proffer a way for doctors to check that host conditions are optimal for the liver to reconstruct itself before surgery has even taken place. “Liver cells need these fatty acids to grow and divide,” explains study leader Prof. Klaus-Peter Janssen from TUM’s School of Medicine. “We have now succeeded in showing for the first time that gut bacteria influence the lipid metabolism in liver cells, and therefore their ability to regenerate.” Mapping antibiotic damage Partial resection of the liver remains a mainstay for treating hepatic diseases. However, ‘insults’ to the gut microbiota, like antibiotics that cause dysbiosis, can stall the regeneration of the liver. In the past, scientists had assumed that antibiotics alone were affecting this reconstruction, but the TUM researchers hypothesized that if the antimicrobials were affecting the gut microbiota, then this native entity must also have the capacity to impair hepatic synthesis. It was now up to them to find out just how this microcosm does this. The first step was to induce dysbiosis in mice using antimicrobials. The animals, known as the antibiotics group, were compared to germfree mice bred without a gut microbiota and a control group raised under normal conditions. All three murine groups had their livers resected to stimulate the proliferation of specialized cells called hepatocytes, which make up most of the liver. The scientists determined the number of cells produced using blood tests and weighing the animals at various time stamps after surgery to establish how much the liver had grown. As these cells depend on lipids for growth and proliferation, the team was also able to firmly posit that fat cells play a large part in liver regeneration. After three days of antibiotics, this group exhibited delayed regeneration, which recovered with the animals’ microbiomes within a few weeks. However, they didn’t produce as many hepatocytes as mice in the control group, who also propagated larger-sized cells. Startingly, in mice lacking gut bacteria, no regeneration occurred, but the researchers say they were able to kickstart the process by performing a microbiome transplant on the animals. Essential bacteria depleted Using cultures of fecal pellets and intestinal or cecal content, the researchers say they identified the bacterial communities or taxa present. Results show that the antibiotic treatment led to a massive increase in Proteobacteria, accompanied by decreased levels of fatty acids. In contrast, the abundance of Bacteroidetes and Firmicutes bacteria remained relatively stable in controls, while the amount of Proteobacteria remained very low. In their white paper, the scientists explain that the Proteobacteria taxa only constitute around one percent of the healthy microbiota, with the Firmicutes and Bacteroidetes species comprising the other 90 percent. These two dominant phyla are also responsible for producing fatty acids by fermenting dietary fiber in the gut – a functionality Proteobacteria does not possess – explaining the low levels of lipids accompanying the decimation of this dominant species in the antibiotics group. How does fat build the liver? Using mini liver organoids made up of mouse cells in a Petri dish, the researchers demonstrated how fatty acids provide essential building blocks for the liver’s cell membranes. Their experiments showed that if there aren’t enough lipids present, the cells won’t be able to grow and reproduce. In comparison, as long as the microbiota is healthy, they can produce a fatty acid called acetate, which reaches the liver via the portal vein. Once there, it’s modified in hepatocytes by the enzyme SCD1 to produce monounsaturated fatty acids and incorporated into the liver’s cellular membranes as phospholipids – fat cells organized into bilayers. It’s important to mention that the team found out that the SCD1 enzyme plays a vital part in liver regeneration, and its activity depends entirely on the microbiome’s state. They confirmed this by studying human tissue and observing that the enzyme’s expression increased significantly after resection, upon which antibiotics

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Researchers have just uncovered a whole new part of the brain

A new study has discovered a previously unknown structure, a few cells thick, that surrounds the brain. A newfound anatomical structure has been discovered in the brain, which appears to play an essential role in the brain’s waste disposal and immune systems, acting as a protective barrier and harboring immune cells that watch for toxic proteins. Playing a multi-faceted role in the brain’s immunity, the team posits that when this layer of tissue, dubbed the subarachnoid lymphatic-like membrane (SLYM), goes awry, it likely causes many brain disorders such as multiple sclerosis and Alzheimer’s disease. A vast system of interconnected cells and pathways, due to technological advances, the brain is still throwing up amazing discoveries from its fathomless depths – with this latest find taking us on a wondrous journey in and around its entirety. As the realm of the central nervous system (CNS) increases with each new study, a team led by the University of Copenhagen adds to this body of work by discovering a previously unknown protective barrier called the SLYM. The group says the distinct layer, found in both mouse and human brains using two-photon microscopy and dissections, acts as a platform for immune cells such as myeloid cells and macrophages – to monitor the brain for any harmful events that may cause inflammation. Their research, detailed in the journal Science, focuses on the membranes encasing the brain comprising individual layers called the dura, arachnoid, and pia matter. These shields, known collectively as the meninges, keep the brain bathed in the cerebral spinal fluid (CSF), protecting it from the rest of the body and the inflammatory white blood cells held within its bone marrow, blood, and lymph tissue: providing privileged immunity. As part of this exemption, the SLYM dissects the chamber below the arachnoid layer, the subarachnoid space, dividing it into two compartments where it appears to separate freshly made CSF from ‘tainted’ CSF containing waste products and antigens. Therefore, the group state that it is likely involved in the glymphatic system – a network responsible for waste removal in the brain. In their whitepaper, the team state: “SLYM is the host for a large population of myeloid cells, the number of which increases in response to inflammation and aging, so this layer represents an innate immune niche ideally positioned to surveil the cerebrospinal fluid.” Structural immunity The CNS’ privileged immunity also means it does not contain a lymphatic drainage system to flush away antigens and other foreign bodies, so it relies heavily on CSF to carry these unwanted substances to the lymphatic system in the peripheral nervous system. Transported through an extensive network of tubes and compartments all over the brain, CSF acts as a shock absorber for its percipient host while delivering nutrients and carrying away unwanted products. And this is where the SLYM plays a vital role. Sitting in its CSF-filled chamber housing blood vessels and connective tissue joining the arachnoid and pia mater layers, the team state that the new anatomical structure helps control the flow of CSF around the brain, providing us with a “greater appreciation of the sophisticated role that CSF plays not only in transporting and removing waste from the brain, but also in supporting its immune defenses,” said Maiken Nedergaard, co-director of the Center for Translational Neuromedicine in Live Science.  The SLYM itself is only a few cells thick and shares molecular markers with mesothelium, a type of membrane covering other organs in the body, such as the lungs and heart. Mesothelium also plays the role of lubricant between organs that slide against each other. For this reason, the researchers propose that the SLYM is the brain’s mesothelium, lining the connective tissue and blood vessels in the gap between the brain and skull. “Physiological pulsations induced by the cardiovascular system, respiration, and positional changes of the head are constantly shifting the brain within the cranial cavity,” the scientists explain in their whitepaper. “SLYM may, like other mesothelial membranes, reduce friction between the brain and skull during such movements.” Adding to the SLYM’s already extensive immune functionality, experiments in mice also suggest that these diminutive membranes block most proteins, including amyloid plaques that cause Alzheimer’s, from crossing from the ‘contaminated’ CSF compartment to the ‘clean’ CSF compartment–although it allows tiny molecules like electrolytes to pass through. But the large role it plays in neuroprotection has its downsides: The group theorizes that damage to the shield may disrupt its ability to direct these potentially harmful proteins out of the brain. Any damage may also result in immune cells from the skull’s bone marrow flooding the brain’s sterile surface, an interesting finding that could help explain why traumatic brain injuries can cause prolonged brain inflammation and disrupt the normal flow of cleansing CSF. However, they concede that understanding how this disruption impacts the healthy brain “will require more detailed studies.”  “We conclude that SLYM fulfills the characteristics of a mesothelium by acting as an immune barrier that prevents exchange of small solutes between the outer and inner subarachnoid space compartments and by covering blood vessels in the subarachnoid space,” the group write in their paper. Finally, these new findings could uncover vital information pertaining to a host of brain disorders affecting millions of people across the globe – which, the researchers hope, will lead to new targets and therapeutics to aid in their treatment.

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New nanonets target, trap, and kill specific bacteria

The nanonets could be used instead of antibiotics once fully developed. The microscopic nets consist of antimicrobial peptides (AMPs) that form a mesh when they detect certain chemicals in the bacterial cell membrane. Once the AMPs have attached themselves to the bacteria via these chemical sites, they attract other peptides, self-organizing to project long, interwoven tendrils to surround the bacteria – trapping and killing them in infected mice. In a major breakthrough, National University of Singapore (NUS) researchers have developed prolongated bacteria busters as a way to treat antibiotic-resistant bacteria. A burgeoning public health crisis, the United Nations recently projected that these superbugs will kill 10 million people by 2050-causing more deaths than cancer and posing an imminent threat to humanity.  As misuse and overprescribing of antimicrobials are the main drivers in developing drug-resistant pathogens, it stands to reason that using more antibiotics to treat them will be highly detrimental to society. Therefore, major organizations have prioritized the development of alternative therapies to fight the illnesses caused by these stubborn strains of bacteria that are getting harder to shake. Professor Rachel Ee from NUS, who co-led the team with Professor Rajamani Lakshminarayanan, says: “Faced with the rapid emergence of antimicrobial resistance globally, there is an urgent demand for innovative strategies to ‘outwit’ the microbes’ ability to evolutionarily adapt through mutations.” In her team’s whitepaper published in Advanced Functional Materials, a new nanonet platform is described that self-assembles to ensnare and kill specific bacteria in mice without using antimicrobials. The system comprises synthetic AMPs, which cluster to form a sticky web once they come into contact with either lipopolysaccharide or lipoteichoic acid in bacterial cell membranes–an action that also disrupts these structures, killing the microbes. In their whitepaper, the team state, considering all data, “the findings in this work hold potential to advance the development of synthetic nanonets as anti-infective biomaterials that can help tackle the antibiotic resistance crisis.” Professor Ee added that the next challenge “is to optimize the design for clinical application in humans.”  Proposed mechanistic pathways of bacteria-induced formation of peptide nanonets. Credit: Advanced Functional Materials (2022). Nanonet chemistry In nature, trap-and-kill is a common immune reaction employed in sites such as the small intestine, urinary tract, and blood vessels in response to the presence of a foreign body. Once the immune system recognizes these trespassers, it deploys native peptides, which form nanonets incapacitating the bacteria: causing them to clump together, making it easier for white blood cells to kill them. In past research, scientists have explored the development of synthetic nanonets to address widespread antibiotic resistance. However, according to Professor Ee, these AMP nanonets failed as they could only form short, disjointed strands unable to encompass or disable bacteria. To overcome this, the team used ‘click chemistry,’ changing one or two amino acids in the peptide sequences for a preferred function: “By modifying the chemical compositions of the AMPs previously used, our team’s peptides could self-assemble into extensive, cross-linked nanonets, which are more suitable for physically entrapping and immobilising bacteria cells,” says Prof Ee in an interview with The Strait Times. “In addition, most of the synthetic peptide nanonets that have been developed so far can only trap bacteria, whereas the modifications we made allowed our nanonets to both trap and kill them,” she adds. The team made these changes to the short peptide sequence by adding a special group of peptides shaped like a loop called a ‘β-hairpin turn’ to the end of the backbone amides. As the β-hairpin isn’t part of the backbone, researchers can rearrange them to recognize and react to certain chemicals in bacteria or stick to other peptides while the backbone remains unreactive and unchanged. Once the group had tweaked the AMP’s hairpin, they tackled E.coli infections in mice. The bacteria, which causes food poisoning, presents a challenge as it is known to resist even the most potent last-resort antibiotics. Trap-and-kill E.coli First, the team established the action of their peptide arrangement against gram-positive and negative bacteria in glassware. They then moved on to toxicity tests in a mouse model of peritonitis – an infection of the abdominal cavity lining that the E.coli had caused. They began slowly, only giving the animals one AMP injection, running tests after 2 hours to ensure the creature’s systems weren’t overloaded. Blood tests post-injection showed that the AMPs had an almost immediate effect, lowering the bacteria load and peritoneal fluid in the animal’s abdomens. However, the group observed issues with the treatment reaching and treating distant infected organs. Once the researchers completed low-dosage toxicity tests, they evaluated the efficacy of a multiple-injection regimen over 24 hours, noting that the E. coli-infected mice showed no signs of discomfort or distress during this time. After 24 hours, tests showed negligible changes to the animal’s body weight, with urine tests indicating healthy renal functions and no damage to any other vital murine organs. Overall, the team says their nanonets displayed excellent in vivo efficacy. Commenting on the promising results, Prof Ee highlighted that even if the bacteria become resistant to the killing functionality of the nanonets, their immobilizing effect alone can already render them vulnerable to the immune system’s antimicrobial defenses: “This means that the bacteria cannot just mutate and alter their proteins to evade detection by the nets, which is one of the ways germs become resistant to antibiotics.” Regarding the initial limitations of their platform, in their whitepaper, the group writes that further improvement to the formulation is required to achieve greater antimicrobial efficacy at distant organs; however, overall, the findings are promising. To end, the scientists hope health organizations worldwide will use their nanoscale bacterial trawler to wage war on superbugs. In the future, they plan to reformulate the AMPs into a hydrogel that can be injected directly into the infected part of the body before beginning human trials.

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Injectable tissue provides relief from chronic back pain in humans–could cut out the need for opioids

The new treatment cures the source of back pain, not just the symptoms. An injection comprising pulverized vertebral discs has successfully been used to treat degenerative disc disease, one of the world’s most common medical conditions. The therapy was shown to regrow the discs while reducing inflammation and pain, significantly improving the patient’s mobility and quality of life without surgical intervention. If rolled out to the general population, the team says their treatment could finally alleviate the suffering of millions of chronic lower back pain patients, possibly curbing the rampant opioid epidemic that kills thousands of Americans every year. The nonsurgical intervention from Summit Medical Center, Oklahoma, tackles chronic low back pain: the most common cause of disability worldwide and the sole cause of more than half of all opioids prescribed in the United States, helping to cripple the global economy. As there is no gold standard for diagnosing or treating degenerative disc disease, therapies derived from natural materials found in the body called biologics are being explored to regrow these degenerated discs. However, as the disc loses vital liquids as it deteriorates and cracks, to end the pain, the treatment would need to rehydrate these structures as it repopulates native cells to gain the desired height restoration- no easy feat. In the current study, researchers used a biological platform known as viable disc allograft supplementation, a human tissue graft (allograft) containing micronized or pulverized vertebral discs injected directly into a patient’s damaged disc. The investigation, involving 50 participants, is part of the larger Viable Allograft Supplemented Disc Regeneration in the Treatment of Patients With Low Back Pain (VAST) Trial, following 220 patients with chronic lower back pain over three years. Researchers injected forty-six volunteers with the allograft in this extension, and four received a saline placebo. Using radiography and Magnetic Resonance Imaging (MRI), the scientists saw that the therapy encourages the cells in the damaged discs to regenerate, leaving healthy tissue. These results were also validated using various pain and disability indices which record patient-reported symptoms, functional outcomes, and quality of life. In this way, the group obtained a complete picture of the pain relief gained by the patients, which imaging alone cannot always depict. The group states the allograft, acquired from cadavers, requires no incisions and can be administered by a clinician using a mild sedative – meaning patients can go home the same day. “The significant improvement in pain and function is promising for patients living with chronic low back pain – a condition that can greatly impact a person’s quality of life,” said lead author Douglas Beall, chief of radiology at Clinical Radiology of Oklahoma. “Back pain is the leading cause of limited activity and workplace absenteeism. This treatment may help patients return to a normal activity level for a longer period time.” Images at 12 months demonstrated improvement in morphology, disc height, and patient indices of pain and functional improvement followed. Credit: Beall et al. Int J Spine Surg. 2020 Why does the back degenerate? The spine has 26 vertebrae bones cushioned by small gel-filled sacs known as vertebral discs, which act like shock absorbers to allow the flexible movement of the spine. The discs comprise a firm, tough outer layer called the annulus fibrosis, surrounding a soft, jellylike layer, the nucleus pulposus. Degenerative disc disease occurs when these layers show wear and tear due to aging, injury, or disease. As these structures lose their integrity and dry out, the vertebrae drop to come closer together, reducing the disc’s ability to act like a buttress and provide support. A lack of blood supply means damaged discs do not repair themselves – as a consequence, they can bulge, tear or slip out of place, causing chronic pain and problems with mobility. The problem with treating this condition is that existing therapies treat the symptoms of the disease rather than the causes. In the present study, the researchers developed a biologic consisting of a nucleus pulposus allograft, saline components, and a cryopreserved vial of cells (VIA Disc Matrix). According to their past whitepapers, once they thaw the vial, all the ingredients are mixed together and injected using a 22-gauge spinal needle into 1 or 2 degenerated intervertebral discs in the lower spine. To ensure the participants incur no injuries, the scientists use continuous fluoroscopic imaging or computed tomography to guide the procedure, which takes 10-11 minutes for one disc and roughly 15 minutes for two. Sturdy results in humans Appearing sound in theory, the researchers have trialed their allograft multiple times. They first ran a one-year pilot study involving 24 patients; next came the larger VAST trial, which followed 220 participants over 12 months; and finally, the newest 50-patient VAST extension study running over three years, whose results the team reported at the Society of Interventional Radiology Annual Scientific Meeting in Phoenix. In the pilot and large-scale VAST trial, scientists compared the results from participants receiving the allograft to those from the saline placebo and nonsurgical management (NSM) cohorts.  In the pilot study, subjects receiving the allograft exhibited a more considerable reduction of pain and a significant increase in functional improvement than the placebo group over the 12 months. In the 224 patients aged 19 to 73 years, pain improved by fifty-four percent at the one-year mark in patients receiving the allograft – accompanied by a fifty-three percent improvement in the self-reported Oswestry Disability Index (ODI): indicating that disc tissue allograft may be a beneficial nonsurgical treatment for patients who have chronically painful lumbar degenerative discs. The extension further validates these results by showing that after three years, sixty percent of patients who received the allograft injection for chronic low back pain reported a fifty percent reduction in pain, with seventy percent of this group reporting more than a 20-point improvement in their ODI scores.  Limitations and future plans Despite the positive results of the studies, the group remains realistic, voicing concerns about the small number of reported adverse events as they lost many participants in the follow-up. And

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Human brain organoids successfully integrate into the mouse cortex and respond to visual stimuli

Could these mini-brain ‘grafts’ be used to repair brain injuries in the future? In a world’s first, researchers have shown that human brain organoids transplanted into live animals’ brains successfully formed human-mouse synaptic connections and reacted to visual stimuli. The results, made possible by an unprecedented multi-faceted technology, show the cross-species transplant merged with the animal’s visual cortex and tapped into the local blood supply. The study from UC San Diego revolves around brain organoids or mini-brains – structures designed to resemble a specific brain region or to simulate isolated changes caused by a neurological disorder. To date, scientists have successfully implanted human brain organoids into animal tissue, hoping these structures can repair or replace damaged tissue in the brain to act as a neural prosthesis. And although these studies hold promise for neuroscientific research, scientists have still been unable to prove that human brain organoids implanted in the animal brain could merge with their native structures and react to stimuli along with them–Until now. In the new study, the UC San Diego researchers developed a new type of ultra-sensitive electrode to record neuronal activity and combined it with a technology called two-photon imaging, which captures live cell activity in biological tissue. Using the electrodes, they recorded neural activity from the implanted organoid, showing that it had formed functional connections with the mouse cortex and reacted to external stimuli. Through the two-photon imaging, they were able to observe that mouse blood vessels grew into the organoid, providing it with nutrients and oxygen– a big deal as organoids do not contain vascular cells. “No other study has been able to record optically and electrically at the same time,” states Madison Wilson, the paper’s first author and Ph.D. candidate in Professor Duygum Kuzum’s group at UC San Diego. “Our experiments reveal that visual stimuli evoke electrophysiological responses in the organoids, matching the responses from the surrounding cortex.” Unprecedented imaging The organoids used in this study were human cortical organoids designed to typify some, but not all, of the features of the cerebral cortex. The team grew the mini-brains from differentiated human induced pluripotent stem cells: special cells created from adult cells (in this case, skin cells) exposed to a chemical cocktail to revert them back to their embryonic state. To measure the activity of the organoid once transplanted into the mouse cortex, the team used platinum nanoparticles to lower a special property of graphene electrodes known as impedance – which blocks or ‘resists’ the flow of electricity. Once they had achieved this, 100 times more of the electrical potential created by neurons could flow through the electrodes, enabling this activity to be recorded and analyzed. Amazingly, the scientists achieved this while keeping the electrodes transparent to lower the electrical resistance and increase conductivity while viewing the activity of neurons directly beneath the arrays. Duygu Kuzum, a professor of electrical and computer engineering at UC San Diego, says, “By lowering impedance, we can shrink electrode dimensions down to single cell size and record neural activity with single cell resolution.” In tests on mice, these highly sensitive graphene electrodes could record and image neuronal activity at both the macroscale and single-cell levels. Accordingly, the data indicated that the neurons within the organoids became synchronized with the surrounding tissue. At the same time, the two-photon imaging clearly showed the organoid’s integration with the mouse’s cortex and blood supply to back these results. Live brain implants Taken together, the team states their multi-modal imaging platform indicates that human and mouse cortical tissues established functional connections enabling the organoid to react to external sensory stimuli. They later verified their findings during dissection, where the organoid was stained with two different types of antibodies – one that ‘traces’ human cells and the other that marks synaptic connections. Via this investigation, the team confirmed that the human cells had traveled as far as 4mm away from the boundary of the graft site migrating along the mouse’s corpus callosum, a thick nerve tract just below the cerebral cortex – providing further proof of integration. In their white paper, the team writes this combination of stem cell and neurorecording technologies could herald the next generation of disease models, drug screening and personalized medicine platforms, and transplantable neural prosthetics to restore specific lost, degenerated, or damaged brain regions. “We envision that, further along the road, this combination of stem cells and neurorecording technologies will be used for modeling disease under physiological conditions; examining candidate treatments on patient-specific organoids; and evaluating organoids’ potential to restore specific lost, degenerated or damaged brain regions,” Kuzum concludes.

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