Transplanting elderly human microbiota weakened the gut barrier in young piglets
Transplanting elderly human microbiota weakened the gut barrier in young piglets
On 23 September, Aging Cell published a study using 18 two-month-old Bama piglets. Two groups of six animals, pretreated with antibiotics, received gut microbiota from healthy human donors aged 22–29 or 70–85; a further six piglets served as controls. Each donor group comprised five individuals. After one week of microbial colonization the authors compared the animals' intestines, blood, and mucosal gene activity.
The gut barrier in older people is generally weaker, and the composition of intestinal bacteria shifts with age, but it was unclear whether the altered microbiota itself causes the weakened barrier or both phenomena are simply independent consequences of the same aging process. To tease apart these explanations the authors transplanted microbiota into young piglets that were identical in age, breed, and housing conditions and differed only in whose microbiota they received. Piglets were chosen because their intestinal anatomy is closer to that of humans than the gut of rodents. A similar transplant had already been tested in mice: aged microbiota in young animals impaired their memory through an inflammatory signal traveling from the gut to the brain. In that experiment the effect was recorded far from the intestine; here, it is examined at its source.
In animals that received microbiota from elderly donors, the villi of the ileum (the finger-like projections through which nutrients are absorbed) became shorter. Plasma levels of diamine oxidase rose, an enzyme whose increase in the blood indicates heightened permeability of the intestinal wall. In several segments of the intestine, tight-junction protein levels fell. These proteins seal neighboring epithelial cells together and keep the contents of the gut on the correct side of the wall. Routine blood panels (liver, kidney, lipid, and carbohydrate markers) remained unchanged across all groups; only neutrophils and basophils increased in piglets that received elderly microbiota. The effect stayed concentrated in the gut.
In piglets with elderly microbiota, the bacterium Blautia obeum expanded sharply, circulating prostaglandin E3 was higher, and the dipeptide Tyr-Phe (a compound of two amino acids) was lower; the bacterium and both metabolites were statistically associated with tight-junction protein levels. In cultured pig intestinal epithelial cells, Tyr-Phe raised and prostaglandin E3 lowered the transepithelial electrical resistance of the cell layer, a direct measurement of barrier integrity, confirming that both substances can mediate between the microbiota and the barrier.
Separately, in the same piglets, the activity of seven genes forming a single interferon-stimulated gene cluster dropped. Interferons are signaling proteins that prime cells for viral encounter. Some of these genes correlated statistically with tight-junction protein levels: the aged microbiota produced two distinct consequences, a weakened barrier and suppressed antiviral defense in the epithelium.
The piglets were identical in every respect except donor microbiota, so the differences in the gut, blood, and mucosal genes were created by the microbiota itself. This causal evidence supports the rationale behind the ongoing human trial ARMOR, in which elderly participants receive microbiota from young athletes precisely because the aging gut barrier becomes permeable and fuels chronic inflammation. How much of the effect is attributable to Blautia obeum itself and how much to a specific metabolite is something the authors propose to resolve next, in experiments with pure cultures and individual compounds.