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Comment by Dr. Krishna Kumari Challa on January 5, 2024 at 9:23am

There is so much organic matter in the gut that comes from the food we eat. It's chemically complex, and you need more enzymes to accommodate it in that environment. Scientists think this variety of genes enables gut bacteria to use a lot of different things that come their way.

Some of the metabolites they use also have interesting implications for human health in the gut. People with type 2 diabetes, for example, have higher levels of an amino acid byproduct called imidazole propionate in their blood. Another metabolite, resveratrol, impacts several metabolic and immune system processes, and itaconate is produced by macrophages in response to infections. Researchers hope that more research like this will help us understand the function of different microbes in the gut, which can in turn be leveraged to improve health.

Understanding of these different metabolisms and how they work will enable us to come up with strategies to intervene—either through the diet or pharmacologically—to modulate the flow of metabolites through these various pathways. So, in whatever context, like type 2 diabetes or following an infection, we could control which metabolites are being produced to have a therapeutic benefit.

Dietary- and host-derived metabolites are used by diverse gut bacteria for anaerobic respiration, Nature Microbiology (2024). DOI: 10.1038/s41564-023-01560-2 www.nature.com/articles/s41564-023-01560-2

Part 3

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Comment by Dr. Krishna Kumari Challa on January 5, 2024 at 9:20am

At the organism level, we typically think of respiration as the process of breathing in oxygen. At the cellular level, respiration describes an energy-generating biochemical process. Most cells use oxygen for respiration, but in anaerobic environments like the inside of the intestine, cells have evolved to use other molecules.

Cells possess two main types of metabolism to produce energy: fermentation and respiration. In fermentation, the cell breaks down molecules to generate energy directly.

Respiration involves two molecules: an electron donor and an electron acceptor. A classic example of this process uses glucose as a donor and oxygen as the acceptor. The cells break down the glucose by shuttling extracted electrons through a series of steps before their final transfer to an oxygen molecule. This prompts the cell to generate ATP, or adenosine triphosphate : the basic source of energy for use and storage at the cellular level.

Most of the microbes living in the gut use fermentation, but there are also several known types of bacteria with respiratory metabolisms, including those that use carbon dioxide and sulfate electron acceptors.

For the new study, researchers analyzed a database of more than 1,500 genomes from a database of human gut bacteria. They saw a surprising distribution of genes that produce reductases, which are enzymes that use different respiratory electron acceptors. While most of the genomes encode just a few reductases, a small subset encodes more than 30 different ones.

These bacteria weren't closely related; they came from three distinct and distantly related families (Burkholderiaceae, Eggerthellaceae, and Erysipelotrichaceae) separated by hundreds of millions of years of evolutionary history.

These bacteria appear to be more resourceful than bacteria with respiratory metabolisms that live outside of a host organism, which mostly use inorganic compounds. The respiratory gut bacteria Light and team identified specialize in various organic metabolites, which makes sense given the constant food supply.

Par t2

Comment by Dr. Krishna Kumari Challa on January 5, 2024 at 9:18am

The  resourceful ways bacteria thrive in the human gut

The gut microbiome is so useful to human digestion and health that it is often called an extra digestive organ. This vast collection of bacteria and other microorganisms in the intestine helps us break down foods and produce nutrients or other metabolites that impact human health in a myriad of ways.

New research  shows that some groups of these microbial helpers are amazingly resourceful too, with a large repertoire of genes that help them generate energy for themselves and potentially influence human health as well.

The paper, published January 4, 2024, in Nature Microbiology, identified 22 metabolites that three distantly related families of gut bacteria use as alternatives to oxygen for respiration in the anaerobic environment of the gut.

These bacteria also have up to hundreds of copies of genes for producing the enzymes that process these alternate metabolites—many more than have been measured in bacteria that live outside the gut. These results suggest that anaerobic gut bacteria may have the ability to produce energy from hundreds of other compounds as well. These are examples of some of the peculiar metabolisms that act on all these different metabolites produced by the gut microbiome.

This is interesting because one of the main ways the microbiome impacts our health is by making or modifying these small molecules that can then enter our bloodstream and act like drugs.

Part 1

Comment by Dr. Krishna Kumari Challa on January 5, 2024 at 9:11am

Cognitive maps in some brain regions are compressed during goal-seeking decision-making

Human decision-making has been the focus of a wide range of research studies. Collectively, these research efforts could help to understand better how people make different types of everyday choices while also shedding light on the neural processes underpinning these choices.

Findings suggest that while making instantaneous decisions, or in other words, choices that need to be made quickly based on the information available at a given moment, humans greatly rely on contextual information. This contextual information can also guide so-called sequential decisions, which entails making a choice after observing the sequential unfolding of a process.

Researchers' findings, published in Neuron, suggest that goal-seeking 'compresses' spatial maps in the hippocampus and orbitofrontal cortices in the brain.

To explore what happens in the brain during goal-directed decision-making, the researchers carried out an experiment involving 27 human participants. The  results shed new light on the neural underpinnings of goal-directed decision-making, suggesting that the brain could utilize compression mechanisms to contextually modulate sensory information during decision-making to achieve a specific goal. In the future, new studies could further investigate these compression processes, which could lead to fascinating new discoveries.

Paul S. Muhle-Karbe et al, Goal-seeking compresses neural codes for space in the human hippocampus and orbitofrontal cortex, Neuron (2023). DOI: 10.1016/j.neuron.2023.08.021. www.sciencedirect.com/science/ … ii/S0896627323006323

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 1:20pm

Surprising Study Links 'Good' Cholesterol With Up to 42% Higher Dementia Risk

When it comes to cholesterol, it's usually sorted into the 'good' kind and the 'bad' kind based on their effects on heart health – but now a new study has shown that the 'good' type of cholesterol could have other health risks attached.

This is High-Density lipoprotein cholesterol (HDL-C), and the latest research links an abundance of it with a higher risk of dementia in older adults. For those above 75 years of age, the risk increases by 42 percent, the analysis showed. The research, led by a team from Monash University, looked at data on 18,668 adults aged over 65 from Australia and the US. Overall, for those diagnosed as having high HDL-C levels the risk of dementia increased by 27 percent on average, with individuals followed for an average of 6.3 years. "This is the most comprehensive study to report high HDL-C and the risk of dementia in older people," write the researchers in their published paper. "Findings showed that high HDL-C was associated with dementia risk and the risk increased with age."

Most of the cholesterol in our bodies is the Low-Density lipoprotein (LDL) or 'bad' type, and if there's a lot of it in the blood, it can clog up arteries, increasing the risk of heart disease and strokes. The main benefit of HDL-C is keeping LDL-C levels in check. A normal level of HDL-C in the blood is considered to be 40–50 milligrams per deciliter (or mg/dL) for men, and 50–60 mg/dL for women – roughly 40–60 parts per thousand. Almost 15 percent of the participants (2,709 people) had what was regarded as high HDL-C levels as the study started, which is 80 mg/dL or above.

The increase in risk is quite a jump, and the association remained significant when adjusted for factors such as age, sex, education, alcohol consumption, and daily exercise. However, this doesn't prove the cholesterol is causing the increase in dementia – only that there's evidence of a link. "While we know HDL cholesterol is important for cardiovascular health, this study suggests that we need further research to understand the role of very high HDL cholesterol in the context of brain health.

https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(23)00281-X/fulltext

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 11:39am

Study demonstrates potency of synthetic antibiotic against serious chronic infections

A new synthetic antibiotic developed by  researchers is shown to be more effective than established drugs against "superbugs" such as MRSA, a new study shows.

The study, "Development of teixobactin  analogs containing hydrophobic, nonproteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms," is published in the European Journal of Medicinal Chemistry.

The study demonstrates the potent activity of the antibiotic, teixobactin, against bacterial biofilms. Biofilms are clusters of bacteria that are attached to a surface and/or to each other—which are associated with serious chronic infections in humans.

Nearly 5 million people lose their lives due to antibiotic resistance-associated infections and millions more live with poor quality of life due to treatment failures. Antimicrobial resistance (AMR) is increasing and an AMR review commissioned by the UK Government has predicted that by 2050 an additional 10 million people will succumb to drug-resistant infections each year.

 A team of researchers  developed simplified synthetic versions of the natural molecule teixobactin, which is used by producer bacteria to kill other bacteria in soil.

They have tested a unique library of synthetic versions of the "game-changing" antibiotic, optimizing key features of the drug to enhance its efficacy and safety, plus enabling it to be inexpensively produced at scale. For this latest study, the researchers designed and synthesized highly potent teixobactin analogs but swapped out key bottleneck building block L-allo-enduracididine with the commercially available low-cost simplified building blocks such as non-proteogenic amino acids. As a result, the analogs are now effective against a broad range of resistant bacterial pathogens including bacterial isolates from patients and bacterial biofilms.

This is another important step in adapting the natural teixobactin molecule to make it suitable for human use.

Teixobactin molecules have the potential to provide new treatment options against multi-drug resistant bacterial and biofilm-related infections to improve and save lives globally. 

Anish Parmar et al, Development of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms, European Journal of Medicinal Chemistry (2023). DOI: 10.1016/j.ejmech.2023.115853

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 11:31am

Complex, unfamiliar sentences make the brain's language network work harder, study reveals

With help from an artificial language network, MIT neuroscientists have discovered what kind of sentences are most likely to fire up the brain's key language processing centers.

The new study reveals that sentences that are more complex, either because of unusual grammar or unexpected meaning, generate stronger responses in these language processing centers. Sentences that are very straightforward barely engage these regions, and nonsensical sequences of words don't do much for them either.

The input has to be language-like enough to engage the system. And then within that space, if things are really easy to process, then you don't have much of a response. But if things get difficult, or surprising, if there's an unusual construction or an unusual set of words that you're maybe not very familiar with, then the network has to work harder.

In this study, the researchers focused on language-processing regions found in the left hemisphere of the brain, which includes Broca's area as well as other parts of the left frontal and temporal lobes of the brain.

To figure out what made certain sentences drive activity more than others, the researchers analyzed the sentences based on 11 different linguistic properties, including grammaticality, plausibility, emotional valence (positive or negative), and how easy it is to visualize the sentence content.

This analysis revealed that sentences with higher surprisal generate higher responses in the brain. This is consistent with previous studies showing people have more difficulty processing sentences with higher surprisal, the researchers say.

Another linguistic property that correlated with the language network's responses was linguistic complexity, which is measured by how much a sentence adheres to the rules of English grammar and how plausible it is, meaning how much sense the content makes, apart from the grammar.

Sentences at either end of the spectrum—either extremely simple, or so complex that they make no sense at all—evoked very little activation in the language network. The largest responses came from sentences that make some sense but require work to figure them out.

Researchers  found that the sentences that elicit the highest brain response have a weird grammatical thing and/or a weird meaning. There's something slightly unusual about these sentences.

Greta Tuckute et al, Driving and suppressing the human language network using large language models, Nature Human Behaviour (2024). DOI: 10.1038/s41562-023-01783-7

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Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 11:16am

Pathogenic bacteria use molecular 'shuttle services' to fill their injection apparatus with the right product

Disease-causing bacteria of the genus Salmonella or Yersinia can use tiny injection apparatuses to inject harmful proteins into host cells, much to the discomfort of the infected person. However, it is not only with a view to controlling disease that researchers are investigating the injection mechanism of these so-called type III secretion systems also known as "injectisomes."

If the structure and function of the injectisome were fully understood, researchers could hijack it to deliver specific drugs into cells, such as cancer cells. In fact, the structure of the injectisome has already been elucidated. However, it remained unclear how the bacteria load their syringes so that the right proteins are injected at the right time.

In a study published in Nature Microbiology, a team of scientists  has now been able to answer this question: mobile components of the injectisome comb through the bacterial cell in search of the proteins to be injected, so-called effectors. When they encounter an effector, they transport it like a shuttle bus to the gate of the injection needle.

How proteins of the sorting platform in the cytosol bind to effectors and deliver the cargo to the export gate of the membrane-bound injectisome is comparable to the processes at a freight terminal.

Scientists think that this shuttle mechanism helps to make the injection efficient and specific at the same time—after all, the bacteria have to inject the right proteins quickly to avoid being recognized and eliminated by the immune system. 

 Cytosolic sorting platform complexes shuttle type III secretion system effectors to the injectisome in Yersinia enterocolitica., Nature Microbiology (2024). DOI: 10.1038/s41564-023-01545-1

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 10:55am

What makes urine yellow? Scientists discover the enzyme responsible

Researchers at the University of Maryland and National Institutes of Health have identified the microbial enzyme responsible for giving urine its yellow hue, according to a new study published in the journal Nature Microbiology.

The discovery of this enzyme, called bilirubin reductase, paves the way for further research into the gut microbiome's role in ailments like jaundice and inflammatory bowel disease.

This enzyme discovery finally unravels the mystery behind urine's yellow colour. It's remarkable that an everyday biological phenomenon went unexplained for so long.

When red blood cells degrade after their six-month lifespan, a bright orange pigment called bilirubin is produced as a byproduct. Bilirubin is typically secreted into the gut, where it is destined for excretion but can also be partially reabsorbed. Excess reabsorption can lead to a buildup of bilirubin in the blood and can cause jaundice—a condition that leads to the yellowing of the skin and eyes. Once in the gut, the resident flora can convert bilirubin into other molecules.

Gut microbes encode the enzyme bilirubin reductase that converts bilirubin into a colourless byproduct called urobilinogen. Urobilinogen then spontaneously degrades into a molecule called urobilin, which is responsible for the yellow color we are all familiar with.

Urobilin has long been linked to urine's yellow hue, but the research team's discovery of the enzyme responsible answers a question that has eluded scientists for over a century.

Aside from solving a scientific mystery, these findings could have important health implications. The research team found that bilirubin reductase is present in almost all healthy adults but is often missing from newborns and individuals with inflammatory bowel disease. They hypothesize that the absence of bilirubin reductase may contribute to infant jaundice and the formation of pigmented gallstones.

Now that we've identified this enzyme, we can start investigating how the bacteria in our gut impact circulating bilirubin levels and related health conditions like jaundice. This discovery lays the foundation for understanding the gut-liver axis.

In addition to jaundice and inflammatory bowel disease, the gut microbiome has been linked to various diseases and conditions, from allergies to arthritis to psoriasis. This latest discovery brings researchers closer to achieving a holistic understanding of the gut microbiome's role in human health.

BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen, Nature Microbiology (2024). DOI: 10.1038/s41564-023-01549-x

Comment by Dr. Krishna Kumari Challa on January 4, 2024 at 10:37am

Mouse study shows gut biome plays a role in social anxiety disorder

A large team of medical, psychological and social researchers has found that certain microbes in the gut biome may play a role in social anxiety disorder. In their study reported in the Proceedings of the National Academy of Sciences the group conducted experiments with fecal transplants in mice and tested them for anxiety.

Social anxiety disorder (SAD) is a condition in which a person experiences higher than normal levels of anxiety when exposed to people in a social setting, particularly people they don't know. Such settings can include parties, participating in classroom discussions or even standing in line at the grocery store.

Prior research has suggested that conditions in the gut microbiome can have an impact on emotions, which led the team on this new effort to wonder if certain microbes in the gut microbiome might play a role in SAD. To find out, they designed and carried out an experiment with lab mice.

The researchers gave the mice drugs to kill their gut microbiomes and then gave some of them fecal transplants from people with SAD. Others were given fecal transplants from people who did not have the disorder to serve as a control. After administering the transplants, the researchers exposed the test mice to a variety of social environments, which included interacting with groups of mice they knew and groups that they did not know. They found that the test mice given the SAD fecal transplants displayed symptoms of SAD, while those given the control did not. They also noted that they saw no differences in anxiety between the groups when the mice were interacting with mice they already knew.

The research team also found what they describe as substantial differences in the mix of microbes in the microbiomes of the two groups—most specifically, they found lower numbers of three types of bacteria in the mice who had been given SAD fecal transplants. They also found different levels of brain chemicals (such as oxytocin) in the two groups, and differences that appeared to promote inflammation in the SAD group.

Nathaniel L. Ritz et al, Social anxiety disorder-associated gut microbiota increases social fear, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2308706120

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