New strategy to protect healthy gut microbes from antibiotics

Gut microbes promote human health by fighting off pathogens, but they also contribute to diseases such as diabetes and cancer. A study published March 19th by Cell Reports reveals a potential strategy for tipping the balance in favor of good bacteria by altering the composition of the microbial community.

A group of Portuguese and Spanish researchers found that a chemical signal called autoinducer-2 (AI-2), which bacteria use to communicate with each other, can promote the right balance of gut microbes in antibiotic-treated mice. The findings pave the way for therapeutic strategies that harness the chemical language of bacteria to foster a healthy community of gut microbes.

"The bacteria in our intestines are extremely important for many aspects of our health," says senior study author Karina de Bivar Xavier of the Instituto Gulbenkian de Ciência in Portugal. "If we learn how to tailor their species composition and their functions in our favor, we will be able to use these bacteria to prevent infections and develop treatments for inflammatory bowel diseases and diet-induced microbial imbalances."

Antibiotic use and dietary factors can change the composition of gut microbes and strongly reduce bacterial diversity, posing a serious threat to human health by increasing host susceptibility to harmful pathogens such as Salmonella. In particular, shifts in the balance between Bacteroidetes and Firmicutes--the two predominant phyla in the mammalian gut--are associated with obesity, diabetes, chronic inflammatory bowel diseases, and gastrointestinal cancer. The ability to drive this community from a disease state to a healthy state, by manipulating the native signals and interactions that occur between its members, offers great potential for therapeutic benefit.

To test this idea, Xavier and her team focused on a small diffusible molecule called AI-2, which fosters interspecies communication throughout the bacterial kingdom. AI-2 produced by one species can influence gene expression in another species, enabling the entire population to synchronously regulate behaviors such as virulence and biofilm formation. These features make AI-2 an excellent candidate for mediating cell-cell interactions in the mammalian gut, where hundreds of bacterial species co-exist and interact.

To manipulate AI-2 levels in the mouse gut, the researchers constructed an Escherichia coli mutant that was deficient at absorbing AI-2 from the environment. When this mutant was introduced into the gastrointestinal tract of mice that were being treated with an antibiotic, the resulting increase in intestinal AI-2 levels altered the composition of gut microbes to favor the expansion of the Firmicutes phylum, which had been almost eliminated by the antibiotic.

"Because high AI-2 levels in the gut tipped the balance toward the healthy state during antibiotic treatment, it's possible that manipulation of this chemical signal may prevent the harmful effects of antibiotics, correct diet-induced microbial imbalances, and treat gastrointestinal diseases in humans," says co-first author Jessica Thompson of the Instituto Gulbenkian de Ciência.

Moving forward, the researchers will examine whether AI-2 accelerates the recovery of the protective functions of gut microbes against pathogens and infectious disease after antibiotic treatment. They will also determine the various functions of AI-2 signaling by examining how it affects gene expression in bacteria, as well as identify new bacterial receptors for AI-2 and other chemical signals.

"These receptors could be used as new drug targets to alter bacterial communication," says the study's co-first author Rita Almeida Oliveira of the Instituto Gulbenkian de Ciência. "This strategy to control bacteria may be a promising alternative to avoid the increasingly serious problem of bacterial resistance to antibiotics that are used today."

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The above story is based on materials provided by Cell Press . Note: Materials may be edited for content and length.

Special microbes make anti-obesity molecule in the gut

Microbes may just be the next diet craze. Researchers have programmed bacteria to generate a molecule that, through normal metabolism, becomes a hunger-suppressing lipid. Mice that drank water laced with the programmed bacteria ate less, had lower body fat and staved off diabetes -- even when fed a high-fat diet -- offering a potential weight-loss strategy for humans.

The team will describe their approach at the 249^th National Meeting & Exposition of the American Chemical Society (ACS).

Obesity strongly increases the risk for developing several diseases and conditions, such as heart disease, stroke, type 2 diabetes and some types of cancer. One in three Americans is obese, and efforts to stem the epidemic have largely failed. Lifestyle changes and medication typically achieve only modest weight loss, and most people regain the weight. In recent years, numerous studies have shown that the population of microbes living in the gut may be a key factor in determining the risk for obesity and related diseases, suggesting that strategically altering the gut microbiome may impact human health.

One advantage to microbial medicine would be that it's low maintenance, says Sean Davies, Ph.D. His goal is to produce therapeutic bacteria that live in the gut for six months or a year, providing sustained drug delivery. This is in contrast to weight-loss drugs that typically need to be taken at least daily, and people tend not to take their medications as directed over time. "So we need strategies that deliver the drug without requiring the patient to remember to take their pills every few hours," Davies says.

For a therapeutic molecule, Davies and colleagues at Vanderbilt University selected N-acyl-phosphatidylethanolamines (NAPEs), which are produced in the small intestine after a meal and are quickly converted into N-acyl-ethanolamines (NAEs), potent appetite-suppressing lipids. The researchers altered the genes of a strain of probiotic bacteria so it would make NAPEs. Then they added the bacteria to the drinking water of a strain of mice that, fed a high-fat diet, develop obesity, signs of diabetes and fatty livers.

Compared to mice who received plain water or water containing control, non-programmed bacteria, the mice drinking the NAPE-making bacteria gained 15 percent less weight over the eight weeks of treatment. In addition, their livers and glucose metabolism were better than in the control mice. The mice that received the therapeutic bacteria remained lighter and leaner than control mice for up to 12 weeks after treatment ended.

In further experiments, Davies' team found that mice that lacked the enzyme to make NAEs from NAPEs were not helped by the NAPE-making bacteria; but this could be overcome by giving the mice NAE-making bacteria instead. "This suggests that it might be best to use NAE-making bacteria in eventual clinical trials," says Davies, especially if the researchers find that some people don't make very much of the enzyme that converts NAPEs to NAEs. "We think that this would work very well in humans."

The main obstacle to starting human trials is the potential risk that a treated person could transmit these special bacteria to another by fecal exposure. "We don't want individuals to be unintentionally treated without their knowledge," says Davies. "Especially because you could imagine that there might be some individuals, say the very young or old or those with specific diseases, who could be harmed by being exposed to an appetite-suppressing bacteria. So, we are working on genetically modifying the bacteria to significantly reduce its ability to be transmitted."

Davies acknowledges funding from the National Institutes of Health.

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Chlorine use in sewage treatment could promote antibiotic resistance

Chlorine, a disinfectant commonly used in most wastewater treatment plants, may be failing to completely eliminate pharmaceuticals from wastes. As a result, trace levels of these substances get discharged from the plants to the nation's waterways. And now, scientists are reporting preliminary studies that show chlorine treatment may encourage the formation of new, unknown antibiotics that could also enter the environment, potentially contributing to the growing problem of antibiotic resistance.

The research, which will be presented today at the 249th National Meeting & Exposition of the American Chemical Society (ACS), suggests that a re-evaluation of wastewater treatment and disinfection practices is needed.

"Pharmaceuticals that get out into the environment can harm aquatic life, making them react slowly in the wild and disrupting their hormone systems," notes Olya Keen, Ph.D. She adds that increased antibiotic exposure, even at low levels in the environment, can lead to development of antibiotic-resistant microbes and a general weakening of antibiotics' abilities to fight bacterial infections in humans.

"Treated wastewater is one of the major sources of pharmaceuticals and antibiotics in the environment," says Keen. "Wastewater treatment facilities were not designed to remove these drugs. The molecules are typically very stable and do not easily get biodegraded. Instead, most just pass through the treatment facility and into the aquatic environment."

But besides failing to remove all drugs from wastewater, sewage treatment facilities using chlorine may have the unintended consequences of encouraging the formation of other antibiotics in the discharged water. Keen, graduate student Nicole Kennedy and others in her team at the University of North Carolina at Charlotte ran several lab experiments and found that exposing doxycycline, a common antibiotic, to chlorine in wastewater increased the antibiotic properties of their samples.

"Surprisingly, we found that the products formed in the lab sample were even stronger antibiotics than doxycycline, the parent and starting compound," she adds. Keen has not yet identified all the properties of these "transformation products," and that research is now underway. She notes that these compounds could turn out to be previously unidentified antibiotics.

Keen explains that the best solution may be to decrease the amount of these drugs that reach a treatment plant in the first place. Currently, disposal of pharmaceuticals is not regulated, however. So she urges a greater emphasis on collecting and incinerating old pharmaceuticals, rather than dumping them down the drain or placing them in the trash, which can lead to harmful environmental exposures.

In addition, this research has applications to drinking water treatment systems, most of which also use chlorine as a disinfectant, she says. To purify drinking water, chlorine must remain in the distribution piping system for hours, which blocks microbes from growing. But this also provides ample time for chlorine to interact with pharmaceuticals that may be in the water, encouraging development of new antibiotic compounds.

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Opossum-based antidote to venom from snake bites could save thousands of lives

Scientists will report in a presentation today that they have turned to the opossum to develop a promising new and inexpensive antidote for venomous snake bites. They predict it could save thousands of lives worldwide without the side effects of current treatments.

The presentation will take place here at the 249^th National Meeting & Exposition of the American Chemical Society (ACS).

Worldwide, an estimated 421,000 cases of venomous snake bites and 20,000 deaths from these bites occur yearly, according to the International Society on Toxicology.

Intriguingly, opossums shrug off snake bite venom with no ill effects. Claire F. Komives, Ph.D., who is at San Jose State University, explains that initial studies showing the opossum's immunity to snake venom were done in the 1940s. In the early 1990s, a group of researchers identified a serum protein from the opossum that was able to neutralize snake venoms. One researcher, B. V. Lipps, Ph.D., found that a smaller chain of amino acids from the opossum protein, called a peptide, was also able to neutralize the venom.

But Komives says it appears that no one has followed up on those studies to develop an antivenom therapy -- at least not until she and her team came along. Armed with this information, they had the peptide chemically synthesized. When they tested it in venom-exposed mice, they found that it protected them from the life threatening effects of bites from U.S. Western Diamondback rattlesnakes and Russell's Viper venom from Pakistan.

The exact mechanism is not known, but recently published computer models have shown that the peptide interacts with proteins in the snake venom that are toxic to humans, she says. "It appears that the venom protein may bind to the peptide, rendering it no longer toxic."

Komives' team showed that they could program the bacteria E. coli to make the peptide. Producing the peptide in bacteria should enable the group to inexpensively make large quantities of it. The peptide should also be easy to purify from E. coli.

"Our approach is different because most antivenoms are made by injecting the venom into a horse and then processing the serum," says Komives. "The serum has additional components, however, so the patient often has some kind of adverse reaction, such as a rash, itching, wheezing, rapid heart rate, fever or body aches. The peptide we are using does not have those negative effects on mice."

Because the process is inexpensive, the antivenom has a good chance of being distributed to underserved areas across the globe, according to Komives. That includes India, Southeast Asia, Africa and South America, where venomous snakes bite thousands of people every year.

Komives says that based on the original publications, the antivenom would probably work against venoms from other venomous snakes, as well as against scorpion, plant and bacterial toxins.

The new antivenom has another potential advantage: It likely could be delivered in just one injectable dose. "Since when a snake bites, it injects venom into the victim in different ways, depending on which part of the body is bitten and the angle of the bite, it is likely that each snake bite would need to be treated differently," says Komives. "It is common that additional antivenom needs to be injected if the patient continues to show the effects of the venom." But because the new antidote appears to have no side effects, at least in mice, it probably could be given in one large dose to attack all of the venom, making additional injections unnecessary, she explains. The team plans to test this theory soon. They also will make large quantities of the antivenom and test it on mice, using a wide variety of venoms and toxins.

Komives acknowledges funding from a Fulbright-Nehru fellowship and private sources.

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