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Sleep Deprivation Death Linked Causally to the Gut

Reporter : Irina Robu, PhD

Neuroscientists at Harvard Medical School identified an unexpected link between sleep deprivation and premature death. Their findings show that the possibility that animals might be able to survive without sleep, under certain circumstances. Their study with sleep-deprived fruit flies found that death was continuously by the accumulation of reactive oxidative species in the gut. And when the flies were given antioxidant compounds that neutralized and cleared ROS from the gut, the sleep-deprived animals remained active and had normal lifespans. Extra experiments in mice confirmed that ROS accumulated in the gut when they didn’t get enough sleep.
Yet, in spite of decades of study, researchers still haven’t revealed why animals die when they don’t sleep. In attempts to answer how sleep deprivation culminates in death, most research has focused on the brain, where sleep originates. However, studies have yet to yield conclusive results. In addition to impairing cognition, sleep loss leads to dysfunction of the gastrointestinal, immune, metabolic, and circulatory systems.
The Harvard Medical School team carried out a sequence of experiments in fruit flies to search throughout the body for signs of damage caused by sleep deprivation. Fruit flies share many sleep-regulating genes with humans. To screen sleep, the investigators used infrared beams to constantly track the movement of flies housed in individual tubes. Scientist show that flies can sleep through physical shaking, so they genetically manipulated fruit flies to express a heat-sensitive protein in specific neurons, the activity of which are known to suppress sleep. When flies were housed at 29°C the protein induced neurons to remain constantly active, thus preventing the flies from sleeping.
The scientists discovered that fruit fly mortality spiked after 10 days of temperature-induced sleep deprivation and all of the flies died by around day 20 and control flies that had normal sleep lived up to approximately 40 days in the same environmental conditions. Since mortality increased around day 10, the scientists looked for markers of cell damage on that and the preceding days. They noticed that the guts of sleep-deprived flies had a dramatic build-up of ROS. The buildup of ROS in the fruit fly guts peaked around day 10 of sleep deprivation, and when deprivation was stopped, ROS levels decreased.
To find out if ROS in the gut plays a causal role in sleep deprivation-induced death, the researchers next looked at whether preventing ROS accumulation could prolong survival. They tested dozens of compounds with antioxidant properties known to neutralize ROS and identified 11 that, when given as a food supplement, allowed sleep-deprived flies to have a normal or near-normal lifespan. These compounds, such as melatonin, lipoic acid, and NAD, were particularly effective at clearing ROS from the gut. Notably, the supplements did not extend the lifespan of non-sleep-deprived flies.
The role of ROS removal in preventing death was also confirmed by experiments in which flies were genetically manipulated to overproduce antioxidant enzymes in their guts. These flies had normal to near-normal lifespans when sleep deprived, but flies that overproduced antioxidant enzymes in their nervous systems weren’t protected from sleep-deprivation-related death.
While the results demonstrated that ROS build up in the gut plays a central role in causing premature death from sleep deprivation, the researchers acknowledged that many questions are still without answers. At the same time, they found that insufficient sleep is identified to restrict with the body’s hunger signaling pathways, which lead to measure the fruit fly food intake to analyze whether there were potential associations between feeding and death. They found that some sleep-deprived flies ate more throughout the day compared with non-deprived controls.
The researchers are now working to identify the biological pathways that lead to ROS accumulation in the gut and subsequent physiological disruptions.

SOURCE

Death Due to Sleep Deprivation Linked Causally to the Gut, and is Preventable in Flies

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Obesity is a global concern that is associated with many chronic complications such as type 2 diabetes, insulin resistance (IR), cardiovascular diseases, and cancer. Growing evidence has implicated the digestive system, including its microbiota, gut-derived incretin hormones, and gut-associated lymphoid tissue in obesity and IR. During high fat diet (HFD) feeding and obesity, a significant shift occurs in the microbial populations within the gut, known as dysbiosis, which interacts with the intestinal immune system. Similar to other metabolic organs, including visceral adipose tissue (VAT) and liver, altered immune homeostasis has also been observed in the small and large intestines during obesity.

 

A link between the gut microbiota and the intestinal immune system is the immune-derived molecule immunoglobulin A (IgA). IgA is a B cell antibody primarily produced in dimeric form by plasma cells residing in the gut lamina propria (LP). Given the importance of IgA on intestinal–gut microbe immunoregulation, which is directly influenced by dietary changes, scientists hypothesized that IgA may be a key player in the pathogenesis of obesity and IR. Here, in this study it was demonstrate that IgA levels are reduced during obesity and the loss of IgA in mice worsens IR and increases intestinal permeability, microbiota encroachment, and downstream inflammation in metabolic tissues, including inside the VAT.

 

IgA deficiency alters the obese gut microbiota and its metabolic phenotype can be recapitulated into microbiota-depleted mice upon fecal matter transplantation. In addition, the researchers also demonstrated that commonly used therapies for diabetes such as metformin and bariatric surgery can alter cellular and stool IgA levels, respectively. These findings suggested a critical function for IgA in regulating metabolic disease and support the emerging role for intestinal immunity as an important modulator of systemic glucose metabolism.

 

Overall, the researchers demonstrated a critical role for IgA in regulating intestinal homeostasis, metabolic inflammation, and obesity-related IR. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease. This research further emphasized the importance of the intestinal adaptive immune system and its interactions with the gut microbiota and innate immune system within the larger network of organs involved in the manifestation of metabolic disease.

 

Future investigation is required to determine the impact of IgA deficiency during obesity in humans and the role of metabolic disease in human populations with selective IgA deficiency, especially since human IgA deficiency is associated with an altered gut microbiota that cannot be fully compensated with IgM. However, the research identified IgA as a critical immunological molecule in the intestine that impacts systemic glucose homeostasis, and treatments targeting IgA-producing immune populations and SIgA may have therapeutic potential for metabolic disease.

 

References:

 

https://www.nature.com/articles/s41467-019-11370-y?elqTrackId=dc86e0c60f574542b033227afd0fdc8e

 

https://www.jci.org/articles/view/88879

 

https://www.nature.com/articles/nm.2353

 

https://diabetes.diabetesjournals.org/content/57/6/1470

 

https://www.sciencedirect.com/science/article/pii/S1550413115001047?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1550413115002326?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1931312814004636?via%3Dihub

 

https://www.nature.com/articles/nature15766

 

https://www.sciencedirect.com/science/article/pii/S1550413116000371?via%3Dihub

 

https://www.nature.com/articles/nm.2001

 

https://www.sciencedirect.com/science/article/abs/pii/S1550413118305047?via%3Dihub

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The trillions of microbes in the human gut are known to aid the body in synthesizing key vitamins and other nutrients. But this new study suggests that things can sometimes be more adversarial.

 

Choline is a key nutrient in a range of metabolic processes, as well as the production of cell membranes. Researchers identified a strain of choline-metabolizing E. coli that, when transplanted into the guts of germ-free mice, consumed enough of the nutrient to create a choline deficiency in them, even when the animals consumed a choline-rich diet.

 

This new study indicate that choline-utilizing bacteria compete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donor metabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels of choline-consuming bacteria showed increased susceptibility to metabolic disease in the context of a high-fat diet.

 

DNA methylation is essential for normal development and has been linked to everything from aging to carcinogenesis. This study showed changes in DNA methylation across multiple tissues, not just in adult mice with a choline-consuming gut microbiota, but also in the pups of those animals while they developed in utero.

 

Bacterially induced reduction of methyl-donor availability influenced global DNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations. This study reveal an underappreciated effect of bacterial choline metabolism on host metabolism, epigenetics, and behavior.

 

The choline-deficient mice with choline-consuming gut microbes also showed much higher rates of infanticide, and exhibited signs of anxiety, with some mice over-grooming themselves and their cage-mates, sometimes to the point of baldness.

 

Tests have also shown as many as 65 percent of healthy individuals carry genes that encode for the enzyme that metabolizes choline in their gut microbiomes. This work suggests that interpersonal differences in microbial metabolism should be considered when determining optimal nutrient intake requirements.

 

References:

 

https://news.harvard.edu/gazette/story/2017/11/harvard-research-suggests-microbial-menace/

 

http://www.cell.com/cell-host-microbe/fulltext/S1931-3128(17)30304-9

 

https://www.ncbi.nlm.nih.gov/pubmed/23151509

 

https://www.ncbi.nlm.nih.gov/pubmed/25677519

 

http://mbio.asm.org/content/6/2/e02481-14

 

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