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A gut feeling about immunity As it becomes evident that the microbiome exerts an influence on the human immune system, scientists have begun to ponder therapies that might act on intestinal microbes to reduce harmful inflammation. Roxanne Khamsi reports. For Stanley Hazen, success doesn’t smell sweet— it often stinks. At various points in recent months, Hazen, a cardiologist at the Cleveland Clinic in Ohio, has housed a group of very stinky mice in the research facility where he works. By no fault of their own, the rodents have high levels of trimethylamine (TMA), a compound produced when gut bacteria break down certain nutrients such as choline, which is derived from eggs and other cholesterol-rich foods. “TMA smells like rotting fish, and TMA levels are very high in these animals,” Hazen explains. “The animal facility put them in their own room, they were so stinky.” Hazen and his colleagues have found that these animals, which cannot further metabolize TMA into a more harmful compound called trimethylamine N-oxide, are protected against certain cardiovascular ailments associated with inflammation—and he’d like to exploit this finding to one day help humans as well. He is far from alone in his quest. In the past few years, scientists around the world have tinkered with metabolites and the gut microbes that make them to try to mitigate inflammatory disorders ranging from inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative 674

colitis, to heart disease and liver disorders. They’ve also gained insight in laboratory studies as to how gut microbes can influence ailments that involve aberrant immune signaling in distant organs, such as asthma, gout and diabetes. “I think that the role of the microbiota cannot be overstated,” says Samuli Rautava of University of Turku in Finland. “We’re in the very early stages of actually knowing what goes on in the gut and how the intestine and mostly the gut microbiota control the development of inflammatory responses. We don’t have the whole picture yet, but the more we know, more and more things point to the importance of the gut microbiota.” As of now, it’s unclear how to best alter the microbiome to modulate inflammation. Some scientists are trying to treat inflammatory conditions with a probiotic approach, essentially adding microbes to the milieu, whereas others are giving nutrients such as sugars in a ‘prebiotic’ treatment to foster the abundance of the desired organisms in the gut. When it comes to the approval and marketing of probiotics, the picture becomes even murkier. Rautava notes that probiotic effects are extremely strain specific. “People often jump to the

conclusion that if one [strain of] Lactobacillus is great for something, all the other Lactobacilli should be as well.” He notes that even though probiotic products are marketed widely, many of them bypass the pharmaceutical regulatory path in places such as Europe. In the US, where probiotics have come under regulatory scrutiny in the last few years and cannot be sold as curing a specific disease, companies still sell these products with claims that they rid the body of toxins and boost general immunity. “I think that the commercialized products have come way before we have the scientific evidence," Rautava says. "I’m confident that there are great probiotics for things like allergies and perhaps IBD but we need to be very careful in teasing out which probiotics should be used for what purpose and in whom, and that data is not there yet.” Momentous metabolites A wide range of diet-derived metabolites, such as fatty acids, can cause changes to the immune system. Increasingly, research has suggested that microbes in the gut mediate which metabolites are produced and when. Some of the most detailed information about this relationship comes, perhaps unsurprisingly,

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news from inflammatory disorders that affect the gut itself. Notably, research has found that the intestinal microbial makeup of some people with IBD is disrupted. This so-called dysbiosis in the gut in IBD is linked to lower levels of secondary bile acids, which are thought to influence at least some immune cells such as monocytes through the G protein–coupled bile acid receptor 1 (GPBAR1) and nuclear receptor subfamily 1, group H, member 4 (NR1H4)1. Research has found reduced NR1H4 activity in the ileum among individuals with Crohn’s disease, for example, suggesting that this pathway might perhaps be a target for therapeutics. But bile acids are only part of the story. Other metabolites thought to mitigate inflammation are short-chain fatty acids, including acetate, propionate and butyrate, produced when microbes break down fiber. These fatty acid metabolites are thought to produce an effect on immune cells by binding to receptors such as G protein-coupled receptors GPR41 and GPR432. Furthermore, short-chain fatty acids may perhaps dampen inflammation by modulating peroxisome proliferator-activated receptor-γ (PPAR-γ) in cells lining the gut, which in turn influences the activation of NF-κB, a protein with many functions, including immune-system regulation. This is no small point. Among the many inflammatory diseases linked to excess NF-κB activation are ulcerative colitis and IBD. As far back as the early 1990s, researchers have found evidence that giving butyrate enemas to patients ameliorated gut disorders. For example, in one study3 published in 1992, ten individuals with ulcerative colitis who had not responded to other treatments received two weeks of treatment with butyrate enemas. The treatment reduced the discharge of blood from the colon in nine out of ten patients. Follow-up studies have continued to look at this treatment approach, but some have shown minor or little benefit from the enemas; larger trials are still needed. More recently, a diet-swap study between a group of 20 African-American volunteers and 20 people in rural South Africa found that alterations in what people ate affected not only butyrate levels, but also cellular changes associated with abnormal growths in the colon, known as polyps, that sometimes develop into cancer. At the beginning of the study, about half of the African-American participants had polyps, but none of the volunteers in South Africa had these growths. After two weeks on the South African diet, which is lower in fat and proteins and higher in fiber than the American diet, the participants in the US had more than twice as much butyrate in their fecal samples as before, and reduced signs of cancer-associated

changes in the colon such as inflammation that provides a gain of function,” which, in and cell proliferation. In contrast, markers of other words, would introduce bacteria that inflammation increased in the South Africans have a positive effect. Luckily for Cani and his placed on the American diet. The findings were colleagues, the bacteria they study seem to be doing good work in the gut, and adding more of reported in April in Nature Communications4. Rather than depend wholly on bacteria for them to the gut through probiotics could offer butyrate, it’s possible to get short-chain fatty benefits. He notes that scientists have linked acids directly from the diet, from sources such gastric bypass surgery—which has reversed as flaxseed oil. However, the Western diet is type 2 diabetes in some obese individuals—to thought to have disproportionately low levels of an increase in the relative abundance of certain short-chain fatty acids relative to the long-chain intestinal microbes such as Akkermansia6. Last fatty acids found in sources such as palm oil (and year, Cani patented A. muciniphila as a potential which are thought to have pro-inflammatory treatment for metabolic disorders. effects). The recommended ratio of these acids The probiotic strain of Escherichia coli Nissle is, respectively 1:4. By comparison, the Western 1917, named after the German doctor Alfred diet has a ratio closer to 1:16 (ref. 5). Nissle, who discovered the bacterium during Nathalie Delzenne of the Louvain Drug World War I, has also garnered interest for its Research Institute at the Catholic University anti-inflammatory effects. One study found, of Louvain in Belgium for example, that oral and her former postdoc doses of E. coli Nissle 1917 “I’m not yet convinced Patrice Cani, who now reduced inflammation in has his own lab at the a mouse model of sepsis7. that we will be able to same university, have set Follow-up research has reverse the phenotype their sights on developing shed light on how this of inflammation by therapeutics based on microbial strain exerts the gut bacteria that its influence. In an using only one [type generate short-chain fatty experiment published of] bacteria or one acids such as butyrate. last year, intestinal cells In particular, they are co-cultured with E. coli component.” looking at butyrateNissle 1917 had lower producing strains such levels of ‘inflammasome as Akkermansia muciniphila, which also helps activation’—referring to protein complexes that make mucus that maintains the gut lining. turn on other signaling molecules that promote One idea is keep gut bacteria such as inflammation—than intestinal cells exposed to Akkermansia churning out butyrate by giving another commensal type of E. coli8. The findings these microbes the energy sources they thrive hint that certain strains of E. coli may perhaps on, such as oligofructose, a form of dietary have anti-inflammatory characteristics. fiber. “We can propose that when you give Probiotic supplements containing E. coli certain dietary fibers you can really change the Nissle 1917 have been taken by patients composition of the gut microbiota as a whole with ulcerative colitis, some of whom claim in order to promote several bacteria that play it helps with their condition. But in the US, a beneficial role in the gut,” Delzenne explains. increasingly close scrutiny by the Food and “That’s the prebiotic concept.” Drug Administration (FDA) of probiotic “If I had to choose and guess, I would say health claims has changed the landscape of that a prebiotic is going to be more potent than available products such as E. coli Nissle 1917. a probiotic, actually, in terms of shifting the Because it is no longer available in the US, microbial composition,” Hazen says. He points online chat forums for patients with ulcerative out that it might be simpler from a biological colitis indicate that some individuals with the stance to give people compounds that alter the disorder have sought this probiotic by traveling populations of bacteria already present in the gut across the border to Canada where it is sold by rather than trying to introduce new bacteria. But the Ontario, Canada–based company Medical knowing which approach is superior is tough at Futures as Mutaflor. However, although E. coli this early stage. “We’re trying all of them and I Nissle 1917 has shown promise, a 100-person don’t know what is best,” he notes, adding that, study led by Danish researchers found no ultimately, the best one “is the one that makes it benefit in using it as an add-on treatment to to the finish line.” conventional therapies for active ulcerative colitis. (Another trial is currently underway Gut gain to see if Mutaflor can assist in the treatment Hazen says that influencing the immune system of diabetes.) with a probiotic might prove harder than a Among researchers there is the growing prebiotic, “unless you’re providing a probiotic idea that probiotics should contain multiple

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news strains—ideally, tailored to specifically supplement the gut of each individual in a personalized fashion. “I’m not yet convinced that we will be able to reverse the phenotype of inflammation by using only one [type of] bacteria or one component,” Cani says. Kenya Honda of the RIKEN Center for Integrative Medical Science in Japan and his collaborators at the Boston-based company PureTech Ventures examined a combination of 17 strains of Clostridia bacteria—selected on the basis of their ability to enhance the abundance of regulatory T (Treg) cells (a subset of cells known to keep the immune system in check) that produce anti-inflammatory molecules such as interleukin-10—and found that oral doses of the combination reduced symptoms of colitis and allergic diarrhea in mice9. The mixture of 17 strains of Clostridia, dubbed VE202, was studied by Vedanta, which was founded by PureTech Ventures, and subsequently outlicensed to Johnson & Johnson. “VE202 seems to act as a community to help polarize the T cells to become Treg [cells]," Honda notes. He adds that "although short chain fatty acids, such as butyrate, produced by VE202 appear critical for the Treg cell induction, other metabolites may also contribute.” Beyond the gut It’s not just intestinal inflammatory disorders that seem affected by the gut microbiome: as Hazen’s research suggests, intestinal microbes can influence blood vessels and organs such as the heart. At the center of his research is the conversion of TMA to trimethylamine N-oxide (TMAO), a process that normally takes place in the liver. Previously, Hazen and his colleagues found evidence suggesting that TMAO may contribute ailments such as atherosclerosis in humans. The stinky mice Hazen works with have been genetically engineered to lack a protein called FMO3, which is short for flavin-containing monooxygenase 3. Without this protein, the animals are unable to metabolize the TMA into TMAO, and levels of the former accumulate. The problem is exacerbated when the engineered mice are fed a diet rich in choline—a nutrient that humans get from foods such as eggs. And the higher the TMA levels, the worse the stink. “If you knock down FMO3 and put that animal on a high-choline diet, it makes your eyes water,” Hazen says. In mouse studies, silencing the FMO3 gene makes the animals stinky, but it also blocks the development of atherosclerosis, which refers to plaque buildup in the arteries resulting in part from inflammation, “even though the cholesterol levels [in the rodents] are super, super high,” Hazen explains. The ultimate 676

goal, he adds, is to protect humans one day from diet-induced atherosclerosis and other inflammation-linked diseases. In February, Hazen and his colleagues reported that among 112 people, those individuals with high blood levels of TMAO— which is produced from TMA made by gut bacteria—had a greater risk of certain types of heart failure than their counterparts with low levels of TMAO10. Another study from Hazen and his collaborators has shown that high levels of TMAO and the related metabolites choline and betaine predict greater risk of cardiovascular disease11. In a recent paper he co-authored, transplanting a high-TMAproducing microbial strain into mice increased the animals’ susceptibility to atherosclerosis more than a low-TMA-producing strain12. The findings further support the notion that bacteria producing TMA in the gut can influence inflammation-linked cardiovascular disorders. Meanwhile, Philip Calder, who researches nutritional immunology at the University of Southampton, UK, is exploring the connection between microbial metabolites in the body and non-alcoholic fatty liver disease (NAFLD), a condition that can occur when inflammation scars the organ, making it unable to properly break down fats13. He and his collaborators reported in October that 15–18 months of treatment with the fatty acids docosahexaenoic acid and eicosapentaenoic acid decreased liver fat buildup in people taking the supplement. He is now helping to conduct a trial that combines a prebiotic approach with a probiotic to achieve a beneficial effect on the liver. The examples of immune-related diseases affected by gut bacteria continue to grow. Last year, for example, a study showed that diet alterations could protect mice prone to inflammatory bone disease against this disorder; the same study also found that these genetically prone mice typically show an overgrowth of Prevotella bacteria in the gut, suggesting that these microbes might contribute to the disease (though a causal link is not yet established)14. A 2013 paper, meanwhile, described how mice fed a high-fiber diet had high levels of shortchain fatty acids circulating in their blood and were protected against allergic inflammation in the lung, suggesting that the intestinal ecosystem of bacteria might perhaps influence asthma in humans15. (It’s worth noting that the lung, like many human organs, appears to have its own bacterial inhabitants, dubbed the ‘lung microbiome,’ which is distinct from the intestinal microbiome.) Yet another paper about mice, published in May, suggested that gut microbes have a role in gout, a common form of inflammatory arthritis seen in people16. “In terms of excitement, what people are

talking about a lot at the moment is how the gut microbiota, and how things that alter the gut microbiota, might influence inflammation,” says Parveen Yaqoob of the University of Reading, UK. “I think the challenges are really clearly establishing cause and effect, because when you’re doing this work in humans there are so many factors that could be influencing the question that you’re trying to answer.” And some researchers even hope that rather than using probiotics to quiet detrimental immune activity, they might one day be able to use probiotics to help boost immune system activity. For example, to explore how probiotics might mitigate the decline of immune function seen in aging, Yaqoob and her colleagues examined how four different types of probiotics affected dendritic cells of the immune system from young and old individuals. The study, published last year, showed that all four probiotics enhanced the production of certain receptors on the surface of dendritic cells (ultimately, however, it concluded that pretreatment of young or old dendritic cells with probiotics failed to enhance the proliferation of T cells derived from older donors)17. Although details about the relationship between intestinal microbes and immunity are only just beginning to emerge, some of the scientists in the field have taken their early discoveries to heart. “I’m convinced that we have to feed our microbes correctly, so based on my background and on what we discovered, I’m one guy eating a lot of nondigestible carbohydrates, from vegetable and fruit sources,” Cani says. “My motto is ‘In Gut We Trust’.” Roxanne Khamsi is the chief news editor of Nature Medicine in New York. Published online 29 June 2015; doi.10.1038/nm.3906 1. Brestoff, J.R. & Artis, D. Nat Immunol. 14, 676–684 (2013). 2. Trompette, A. et al. Nat. Med. 20, 159–166 (2014). 3. Scheppach, W. et al. Gastroenterology 103, 51–56 (1992). 4. O’Keefe, S.J.D. et al. Nat. Commun. 6, 6342 (2015). 5. Wall, R., Ross, R.P., Fitzgerald, G.F. & Stanton, C. Nutr. Rev. 68, 280–289 (2010). 6. Liou, A.P. et al. Sci. Trans. Med. 5, doi: 10.1126/scitranslmed.3005687 (2013). 7. Arribas, B. et al. Br. J. Pharmacol. 157, 1024–1033 (2009). 8. Becker, H.M., Apladas, A., Scharl, M., Fried, M. & Rogler, G. Digestion 82, 110–118 (2014). 9. Atarashi, K. et al. Nature 500, 232–236 (2013). 10. Tang, W.H. et al. J. Card. Fail. 21, 91–96 (2015). 11. Wang, Z. et al. Nature 472, 57–63 (2011). 12. Gregory, J.C. et al. J. Biol. Chem. 290, 5647–5660 (2015). 13. Scorletti, E. et al. Hepatology 60, 1211–1221 (2014). 14. Lukens, J.R. et al. Nature 516, 246–249 (2014). 15. Trompette, A. et al. Nat. Med. 20, 159–166 (2014). 16. Vieira, A.T. et al. Arthritis Rheumatol. 67,1646–1656 (2015). 17. You, J., Dong, H., Mann, E.R., Knight, S.C. & Yaqoob, P. Immunobiology 219, 138–148 (2014).

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A gut feeling about immunity.

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