9 P52290 Turn over 50. It has long been known that much of our supply of neurochemicals – an estimated 50 percent of the dopamine, for example, and a vast majority of the serotonin – originate in the intestine, where these chemical signals regulate appetite, feelings of fullness and digestion. But only in recent years has mainstream psychiatric research given serious consideration to the role microbes might play in creating those chemicals. Lyte’s own interest in the question dates back to his time as a postdoctoral fellow at the University of Pittsburgh in 1985, when he found himself immersed in an emerging field with an unwieldy name: psychoneuroimmunology, or PNI, for short. The central theory, quite controversial at the time, suggested that stress worsened disease by suppressing our immune system. 51. By 1990, at a lab in Mankato, Minn., Lyte distilled the theory into three words, which he wrote on a chalkboard in his office: Stress o Immune o Disease. In the course of several experiments, he homed in on a paradox. When he dropped an intruder mouse in the cage of an animal that lived alone, the intruder ramped up its immune system – a boost, he suspected, intended to fight off germ-ridden bites or scratches. Surprisingly, though, this did not stop infections. It instead had the opposite effect: stressed animals got sick. Lyte walked up to the board and scratched a line through the word ‘‘Immune.’’ Stress, he suspected, directly affected the bacterial bugs that caused infections. 52. To test how micro-organisms reacted to stress, he filled petri plates with a bovine-serum-based medium and laced the dishes with a strain of bacterium. In some, he dropped norepinephrine, a neurochemical that mammals produce when stressed. The next day, he snapped a Polaroid. The results were visible and obvious: the control plates were nearly barren, but those with the norepinephrine bloomed with bacteria that filigreed in frostlike patterns. Bacteria clearly responded to stress. 53. Then, to see if bacteria could induce stress, Lyte fed white mice a liquid solution of Campylobacter jejuni, a bacterium that can cause food poisoning in humans but generally doesn’t prompt an immune response in mice. To the trained eye, his treated mice were as healthy as the controls. But when he ran them through a plexiglass maze raised several feet above the lab floor, the bacteria- fed mice were less likely to venture out on the high, unprotected ledges of the maze. In human terms, they seemed anxious. Without the bacteria, they walked the narrow, elevated planks. 54. Each of these results was fascinating, but Lyte had a difficult time finding microbiology journals that would publish either. ‘‘It was so anathema to them,’’ he told me. When the mouse study finally appeared in the journal Physiology & Behavior in 1998, it garnered little attention. And yet as Stephen Collins, a gastroenterologist at McMaster University, told me, those first papers contained the seeds of an entire new field of research. ‘‘Mark showed, quite clearly, in elegant studies that are not often cited, that introducing a pathological bacterium into the gut will cause a change in behavior.’’ 55. Lyte went on to show how stressful conditions for newborn cattle worsened deadly E. coli infections. In another experiment, he fed mice lean ground hamburger that appeared to improve memory and learning – a conceptual proof that by changing diet, he could change gut microbes and change behavior. After accumulating nearly a decade’s worth of evidence, in July 2008, he flew to Washington to present his research. He was a finalist for the National Institutes of Health’s Pioneer Award, a $2.5 million grant for so-called blue-sky biomedical research. Finally, it seemed, his time had come. When he got up to speak, Lyte described a dialogue between the bacterial organ and our central nervous system. At the two-minute mark, a prominent scientist in the audience did a spit take. 56. ‘‘Dr. Lyte,’’ he later asked at a question-and-answer session, ‘‘if what you’re saying is right, then why is it when we give antibiotics to patients to kill bacteria, they are not running around crazy on the wards?’’