short-chain fatty acids

Researchers explore stroke's effects on microbiome

March 12, 2019

Science Daily/West Virginia University

Researchers are investigating how having a stroke can disrupt the community of bacteria that lives in the gut. These bacteria -- known collectively as the microbiome -- can interact with the central nervous system and may influence stroke patients' recovery.

 

Tumult in the bacterial community that occupies your gut -- known as your microbiome -- doesn't just cause indigestion. For people recovering from a stroke, it may influence how they get better.

 

A recent study by Allison Brichacek and Candice Brown, researchers in the West Virginia University School of Medicine, suggests that stroke patients' microbiomes -- and even the structure of their guts -- may still be out of kilter a month after the stroke has passed.

 

"We're interested in the gut-brain axis -- how the gut influences the brain and vice versa," said Brichacek, a doctoral student in the immunology and microbial pathogenesis graduate program. She presented her findings at the International Stroke Conference in February.

 

Previous studies indicated the immediate effects a stroke can have on someone's microbiome, but they didn't explore whether these effects lingered. To find out, Brichacek, Brown and their colleagues -- including Sophia Kenney, an undergraduate majoring in immunology and medical microbiology, and Stan Benkovic, a researcher in Brown's lab -- induced a stroke in animal models. Other models -- the control group -- didn't have a stroke. The researchers compared the two groups' microbiomes three days, 14 days and 28 days post-stroke. They also scrutinized their intestines for microscopic disparities.

 

Bacterial friend or foe?

 

One of the researchers' discoveries was that a certain family of bacteria -- Bifidobacteriaceae -- was less prominent in post-stroke models than in healthy ones both 14 and 28 days out. If the name of the family sounds familiar, that's probably because Bifidobacterium -- a genus within the Bifidobacteriaceae family -- is a common ingredient in yogurt and probiotics. These bacteria are known for supporting digestive health and may be associated with better outcomes in stroke patients.

 

Thatmay sound like bad news for people who have had a stroke, but the loss of Bifidobacteriaceae bacteria isn't the only long-term change their microbiomes undergo. Another family associated with worse outcomes -- Helicobacteraceae -- was also more common in post-stroke models 28 days out. The practical implications of these microbiotic shifts are still unknown.

 

The team also found that the ratio of one type of bacteria -- Firmicutes -- to another -- Bacteriodetes -- was higher in post-stroke models. After 14 days, the ratio in the experimental group was almost six times higher than in the control group. After 28 days, the experimental group's ratio had fallen, but it was still more than triple that of the control group. Having a high Firmicutes-to-Bacteriodetes ratio can be concerning because of its link to obesity, diabetes and inflammation.

 

Intestinal disorganization

 

The gut-brain axis seems to distribute a stroke's effects in another way, too. The research team discovered that a stroke can cause intestinal abnormalities. Under magnification, the intestinal tissues of healthy models resembled an orderly colony of coral. The branches of "coral" were actually villi -- tiny projections that increase the surface area of the intestinal wall and multiply the amount of nutrients it can absorb.

 

But in post-stroke models, the intestinal tissue looked scrambled, even a month after researchers triggered the stroke. "There's disorganization here," Brichacek said. "There's also less space between the villi to allow nutrients to move around." Poor circulation of nutrients can lead to compromised stroke recovery.

 

Treating the brain by treating the gut

 

What does all of this mean for stroke recovery? "Big picture: seeing a persistent, chronic change 28 days after stroke that is associated with this increase in some of the negative bacteria means that this could have negative effects on brain function and behavior. Ultimately, this could slow or prevent post-stroke recovery," said Brown, an assistant professor in Department of Neuroscience and faculty member in the Rockefeller Neuroscience Institute.

 

Her and Brichacek's findings may point to new therapeutic options for stroke. "If it ends up being that the gut has an influence on the repair of the brain, maybe our stroke treatments shouldn't just be focused on what we can do for the brain. Maybe we need to think about what can we do for the gut," Brichacek said.

 

For example, some bacteria in the gut produce short-chain fatty acids that affect brain function. "Some of these short-chain fatty acids are good, and some are bad," said Brown. "If the bacteria that produce some of the bad short-chain fatty acids are proliferating, that could have a negative outcome for brain function." Could nudging a stroke patient's microbiome in a healthier direction -- using probiotic supplements or prebiotic foods, for instance -- help prevent emotional or cognitive decline?

 

Likewise, might it be possible to lower a stroke patient's Firmicutes-to-Bacteriodetes ratio and promote weight loss, decrease diabetes risk and make subsequent strokes less likely?

 

The researchers' next step is to study intestinal changes in more depth. Just as the blood-brain barrier isolates the brain from the blood circulating elsewhere in the body, a barrier seals off the intestine from its surroundings. Brown and Brichacek want to know how a breach in the intestinal barrier could affect the central nervous system. Protecting this barrier is critical for the function of the enteric nervous system -- a part of the peripheral nervous system that includes the gut and often is called our "second brain" or "little brain."

 

"People don't appreciate the gut. It controls much more than digestion," Brown said. "Our results suggest that stroke targets both brains -- the brain in our head and the brain in our gut."

https://www.sciencedaily.com/releases/2019/03/190312123714.htm

Anti-inflammatory protein promotes healthy gut bacteria to curb obesity

New approach to weight loss and diabetes prevention published

September 19, 2018

Science Daily/University of North Carolina Health Care

Scientists have discovered that the anti-inflammatory protein NLRP12 normally helps protect mice against obesity and insulin resistance when they are fed a high-fat diet. The researchers also reported that the NLRP12 gene is underactive in people who are obese, making it a potential therapeutic target for treating obesity and diabetes, both of which are risk factors for cardiovascular disease and other serious conditions.

 

The study, published in Cell Host & Microbe, showed that NLRP12's anti-inflammatory effect promotes the growth of a "good" family of gut-dwelling bacteria, called Lachnospiraceae, that produce small molecules butyrate and propionate, which in turn promote gut health and protect mice against obesity and insulin resistance.

 

"Obesity is influenced by inflammation, not just by overeating and lack of exercise, and this study suggests that reducing inflammation promotes 'good' bacteria that can help maintain a healthy weight," said study senior author Jenny P-Y Ting, PhD, a William R. Kenan, Jr. Distinguished Professor of Genetics. "In mice, we showed that NLRP12 reduces inflammation in the gut and in adipose fat tissues. Although a direct causal effect is difficult to show in humans, our collaborators did help us show there are reduced expression levels of NLRP12 in individuals who are considered obese."

 

In humans, NLRP12 is produced by several types of immune cells and appears to function as a brake on excessive inflammation. Ting and colleagues in recent years have published studies showing that mice lacking the NLRP12 gene are highly susceptible to excessive inflammation, including experimental colon inflammation (colitis) and associated colon cancer.

 

In recent years, researchers have found evidence that inflammation in the gut and in where fat is deposited promotes obesity. About 40 percent of adults and 20 percent of children and teens age 2 to 19 in the United States are considered obese, according to recent government estimates. Being obese or even overweight can lead to a host of other conditions, including heart disease, stroke, cancers, and diabetes. Ting and colleagues in this study therefore sought to determine whether mice lacking the NLRP12 gene are more susceptible to obesity. The findings showed that they are.

 

The scientists fed mice that lacked the NLRP12 gene (NLRP12-knockout mice) and ordinary mice a high-fat diet for several months. The NLRP12-knockout mice ate and drank no more than their healthy cousins but accumulated significantly more fat and became heavier. The knockout mice also showed signs of insulin resistance, which involves a reduced ability to clear glucose from the bloodstream and tends to follow the development of obesity.

 

The absence of NLRP12 in these mice led to increased signs of inflammation in the gut and in fat deposits, but it wasn't clear how this led to extra weight gain until the researchers moved the animals from one facility to another. Following standard safety protocols to prevent disease spread, the researchers dosed the mice with antibiotics before the move.

 

"We noticed that the mice treated with antibiotics gained less weight than the mice that stayed in the old facility," said study co-first author Agnieszka Truax, PhD, a postdoctoral researcher in the Ting lab during the study. "That led us to suspect that gut bacteria were involved in promoting obesity."

 

Further tests showed that when NLRP12-knockout mice were kept in a bacteria-free condition, the mice did not gain weight because there were no bacteria. The deficiency of NLRP12 didn't matter as much. This suggested that "bad" bacteria had been driving the excess weight gain during a high-fat diet.

 

Remarkably, the knockout mice were also protected from excess weight gain when they were co-housed with control mice, hinting that "good" bacteria from the control mice were getting into them and helping to protect them.

 

Scientists have known that high-fat diets, as compared to low-fat diets, tend to reduce the diversity of bacterial species in the gut by suppressing some species and allowing a few others to proliferate abnormally. The UNC researchers confirmed this in their high-fat-eating mice, and they observed that the loss of bacterial diversity was much worse in the Nlrp12-knockout mice.

 

The experiments suggested that inflammation caused by a high-fat diet and worsened by the absence of NLRP12 was a major cause of this shift. Killing off rival bacterial species allowed a sharp rise in the levels of a bacterial family called Erysipelotrichaceae. These microbes became more prominent as gut inflammation worsened and exacerbated the weight-gain from a high-fat diet when put into the guts of otherwise germ-free mice.

 

By contrast, the Lachnospiraceae family of bacteria, which tended to die off in mice fed a high-fat diet, appeared to be highly beneficial. The researchers fed Lachnospiraceae to NLRP12-knockout mice prior to and during three weeks of high-fat eating and found that these "good" bacteria reduced gut inflammation, eliminated the hegemony of harmful Erysipelotrichaceae, and promoted more bacterial diversity. The Lachnospiraceae also significantly protected the animals against obesity and associated insulin-resistance.

 

"All the inflammatory and metabolic changes we had seen in the NLRP12-knockout mice during a high-fat diet were essentially reversed when we re-supplied Lachnospiraceae," Truax said.

 

Lachnospiraceae contain enzymes that convert carbs and fiber into small molecules called short-chain fatty acids (SCFAs). The scientists observed that two in particular, butyrate and propionate, appeared in significantly greater abundance when Lachnospiracea levels rose. Butyrate and propionate are known to have anti-inflammatory properties that promote gut health. The UNC team fed these SCFAs to the NLRP12-knockout mice and found that SCFAs protected the animals from the absence of NLRP12 just as well as the Lachnospiraceae had done.

 

Butyrate, propionate, and other SCFAs are already widely available as health supplements. But are these results in mice relevant to humans? A further test suggested that they are. Collaborating scientists Mihai Netea, MD, PhD, and Rinke Stienstra, PhD, from Radboud University Medical Center in the Netherlands examined fat cells from obese human patients and observed that the higher the measure of obesity -- the body-mass index -- the lower the activity of the NLRP12 gene tended to be.

 

Thus, treating people with "good" bacteria or the beneficial SCFAs they produce might one day be a relatively inexpensive strategy to combat obesity as well as diabetes and other obesity-driven conditions. Ting and colleagues plan to continue their investigations in that direction.

https://www.sciencedaily.com/releases/2018/09/180919133616.htm

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