A recent Twitter study reviewed the content of postings over a fixed period of time. It revealed that people are less happy than in years past. This is not surprising, but I choose to look at the doughnut, not the hole. There is much to be unhappy about these days of economic turmoil; yet, these travails are encouraging us to do an inventory of how we have been living as a society. Introspection and self analysis are very likely to cause some regrets and unhappiness. But, doing so may lead all of us to making the necessary changes to correct the factors that have lead to these dire conditions.
Forgiving ourselves and all of those who have contributed to our unhappiness is the only sane way to retain our health and be happy. As we start 2012, let us commit to living a more holistic and spiritual life. Our economic and political wellbeing depend on it (See my blog “Will the Mayans Get Us?”) Hugo Rodier, MD
Whence allergies? Your gut!
This newsletter has been reporting on this simple concept for over a decade (good studies published in peer review journals.) Still, no journal has caught on as the journal Nature has. Its reports are so concise and clear that it is best to quote directly from commentators reviewing the last two studies on this field. The implications are enormous, which is why I chose these two articles to start the new year:
The title of the first article is “Microbiome: Gut reaction.”
The twists and turns of the human gut support an active and diverse microbial ecosystem. The tens of trillions of bacteria aren’t just hitchhikers; they interact intimately with the immune system, and are so integral to our health that some scientists have deemed them the “forgotten organ”. Today scientists are trying to unravel the relationship between changes in lifestyles in recent decades, changes in our microbiota, and the skyrocketing prevalence of allergies in the developed world. Establishing a link between these phenomena could lead to treatments for allergies and asthma.
It was the ‘hygiene hypothesis’ (see ‘When allergies goes west’, page S2) that first posited a causal link between Western lifestyles and allergy. Scientists found that zealous use of antibacterials, from cleaning products to antibiotics, had limited exposure to pathogens in early childhood. They suggested that the regulation of immune responses was compromised by this limited exposure. In the late 1990s, Agnes Wold, a bacteriologist at the University of Gothenburg in Sweden, brought gut microbes into the equation. Wold and her colleagues observed that typical gut bacteria colonize infants in Pakistan earlier than they colonize infants in Sweden. This delay, Wold suggested, could compromise immune tolerance – affecting the ability to cope with harmless antigens such as food and pollen.
Huffnagle, a microbiologist at the University of Michigan in Ann Arbor, has built on this concept of the hygiene hypothesis. He proposes that the Western lifestyle can dramatically alter our gut microflora leading to allergies and other inflammatory diseases, an idea he calls the ‘microflora hypothesis’.
The theory is supported by observational evidence. City dwellers, increasingly the predominant demographic, are exposed to a narrower range of microbes than people in rural areas – and they get more allergies. Children in rural Burkina Faso, where allergies are rare and the typical diet is high in fibre, have a different profile of microbes in their faeces than children living in Europe. The rapid increase in allergic diseases in the West has coincided with widespread use of antibiotics, especially broad-spectrum drugs. Antibiotics can profoundly alter the microbial composition of the gut, and studies show that children who are given antibiotics in their first year are more susceptible to allergies. “More and more of these smoking guns point to the role of the microbiota affecting immune development,” says Brett Finlay, a microbiologist at the Michael Smith Laboratories, University of British Colombia in Vancouver.
Bugging the immune system: The immune cells in the gut are in constant contact with a diverse microbial milieu, and the human gut “has more immune cells than the rest of the body put together,” says David Artis, a microbiologist at the University of Pennsylvania in Philadelphia. To an immune cell, beneficial or harmless bacteria (known as commensals) look much like harmful ones, but the beneficial bugs have developed methods of shaping the function of the immune system, so that their presence doesn’t provoke an immune attack. “These bugs are flipping switches,” says Sarkis Mazmanian, a microbiologist at the California Institute of Technology in Pasadena. If these beneficial microbes fail to colonize our guts early in life, or if they succumb to a course of antibiotics, then switches don’t get flipped and the immune system can become hypersensitive, attacking harmless microbes and other substances such as pollen, pet dander or shellfish – or so the thinking goes.
Scientists are still trying to figure out which switches are flipped, how the commensal bacteria flip them, and what the consequences are. “I think there will probably be multiple pathways through which commensals can influence allergic disease,” Artis says.
Several of these pathways appear to involve regulatory T cells: immune cells that suppress inflammation by keeping the immune system in check. “Our immune system is sort of like a loaded gun, and as soon as there’s a microbe, it wants to fire,” says Mazmanian. Mice lacking regulatory T cells develop allergies or autoimmune diseases, and research suggests that some microbes can increase their abundance or boost their activity. Kenya Honda, an immunologist at the University of Tokyo, has been investigating this link.
Honda’s research focuses on bacteria in the Clostridium genus, many species of which live symbiotically in the intestines of mice and humans (although others, like C. dificile, are highly pathogenic). His team took mice that had been bred to be free of microbes, and inoculated them with a mixture of 46 different Clostridium strains. Sure enough, this was a catalyst for the production of regulatory T cells in the colon; inoculation with other types of bacteria had little or no such impact2. The team then used the same 46 Clostridium strains to boost the microbiota of standard laboratory mice, which typically already have Clostridium bacteria at a low level, and subjected them to tests that would ordinarily provoke an allergic response. They found that the Clostridium-boosted mice exhibited much more muted allergic responses than a control group, suggesting that microflora rich in Clostridium can provide at least partial protection against allergies.”Mice treated with antibiotics designed to eliminate Clostridium species had more food allergies than untreated mice.”
Another mouse study, yet to be published, reinforces Honda’s findings. A team led by Cathryn Nagler, an immunologist at the University of Chicago in Illinois, found that mice treated with antibiotics designed to eliminate Clostridium species had more food allergies than untreated mice. Nagler’s team also found fewer regulatory T cells in the lining of the colons of these mice. “One of our challenges now is to see how those regulatory cells get out of the colon to mediate protection against allergic disease,” Nagler says.
The title of the second article is “Peripheral education of the immune system by colonic commensal microbiota.”
Researchers at the University of Toronto have found an explanation for how the intestinal tract influences a key component of the immune system to prevent infection, offering a potential clue to the cause of autoimmune disorders like rheumatoid arthritis and multiple sclerosis.
“The findings shed light on the complex balance between beneficial and harmful bacteria in the gut,” said Prof. Jennifer Gommerman, an Associate Professor in the Department of Immunology at U of T, whose findings were published online by the scientific journal, Nature. “There has been a long-standing mystery of how certain cells can differentiate between and attack harmful bacteria in the intestine without damaging beneficial bacteria and other necessary cells. Our research is working to solve it. The researchers found that some B cells-a type of white blood cell that produces antibodies-acquire functions that allow them to neutralize pathogens only while spending time in the gut. Moreover, this subset of B cells is critical to health.
“When we got rid of that B-cell function, the host was unable to clear a gut pathogen and there were other negative outcomes, so it appears to be very important for the cells to adopt this function in the gut,” said Prof. Gommerman, whose lab conducted the research in mice. Textbook immunology-based mostly on research done in the spleen, lymph nodes or other sterile sites distant from gut microbes-has suggested that B cells develop a specific immune function and rigidly maintain that identity. Over the last few years, however, some labs have shown the microbe-rich environment of the gut can induce flexibility in immune cell identity.
Prof. Gommerman and her colleagues, including trainees from her lab Drs. Jörg Fritz, Olga Rojas and Doug McCarthy, found that as B cells differentiate into plasma cells in the gut, they adopt characteristics of innate immune cells-despite their traditional association with the adaptive immune system. Specifically, they begin to look and act like inflammatory cells called monocytes, while maintaining their ability to produce a key antibody called Immunoglobulin A.
“What intrigued us was that this theme-B cells behaving like monocytes-had been seen before in fish and in vitro. But now we have a living example in a mammalian system, where this kind of bipotentiality is realized,” said Prof. Gommerman. This B-cell plasticity provides a potential explanation how cells dedicated to controlling pathogens can respond to a large burden of harmful bacteria without damaging beneficial bacteria and other cells essential for proper function of the intestine.
It also may explain how scientists had failed to appreciate the multi-functionality of some B cells. “There are classical markers immunologists use to identify B cells-receptors that are displayed on their surface-and most of them are absent from plasma cells,” said Prof. Gommerman. “So in some cases, what people thought was a monocyte could have been a plasma cell because it had changed its surface identity, although monocytes play an important role in innate immunity as well.This transformational ability, the researchers also found, is dependent on bacteria called commensal microflora that digests food and provides nutrients. That relationship highlights the importance of the gut in fighting infection, and begs the question of whether plasma cells trained in the gut to secrete specific anti-microbial molecules can play a role in other infectious disease scenarios, such as food-borne listeria infection.
It also opens a line of investigation into whether a systemic relationship exists between those anti-microbial molecules and healthy cells in sites remote from the intestine. Understanding the nature of that relationship could improve understanding of inflammatory mechanisms in autoimmune disorders such as lupus, rheumatoid arthritis and multiple sclerosis, in which immune cells attack and eventually destroy healthy tissue.But the next step, said Prof. Gommerman, is to look at human samples for the same type of multi-potentiality they saw in rodent plasma cells that acquired their anti-microbial properties in the gut.
“We’re really at the early stages of understanding what we call the microbiome in the gut,” said Prof. Gommerman. “There is a role for plasma cells in many autoimmune diseases, and B cells can do a lot more than just make antibodies. We need to understand the full spectrum of their effects within the immune response.”
Practical tip, if you have not heard it before: maximize microbiota health by eating lots of fiber (plant based foods,) and get rid of milk, processed sugars and fatty red meats. Limit the use of antibiotics, and acid blocking pills, and get a water filter.
 J. Nature 2011;479:S5
 J. Nature 2011;478; 250