哮喘高风险婴儿肠道菌群发育迟滞可通过补充乳酸菌改善

Delayed gut microbiota development in high-risk for asthma infants is temporarily modifiable by Lactobacillussupplementation

Nature Communications(2018) 

doi: 10.1038/s41467-018-03157-4

发达国家中很多孩子受过敏体质（特应性）的困扰，易发展为哮喘，肠道菌群扰动和代谢障碍可影响免疫系统发育，或是背后的潜在机制。UCSF的Lynch实验室主导的人体研究，对哮喘高遗传风险的婴儿的肠道菌群构成和代谢情况进行了追踪分析，并发现补充鼠李糖乳杆菌GG可使肠道菌群的发育滞后得到暂时性的部分改善。该研究于上周在Nature Communications[IF：12.124]上线，或为基于菌群的早期预防性干预提供启示。

论文摘要

Atopy, the failure to downregulate pro-inflammatory responses to typically innocuous stimuli, is among the most common affliction in the western world and fre-quently precedes childhood asthma development2,3. Independent birth cohorts indicate that the depletion of specific bacterial genera from the infant gut microbiota at 1 or 3 months old is associated with increased risk of atopy, recurrent wheeze, or asthma development in childhood4,5. One month old infants at significantly increased relative-risk for subsequent development of atopy or asthma in childhood, exhibit a distinct gut microbiota and fecal metabolome, characteristically depleted of dihomo-γ- linoleate, a precursor for anti-inflammatory prostaglandins, and docosapentanoic acid, an anti-inflammatory ω-3 polyunsaturated fatty acid5. Moreover, sterile fecal water from high-risk neonates promoted CD4+ IL4+ expansion and reduced CD4+ CD25+ FoxP3+ cell frequency ex vivo5, indicating that differences in infant gut microbiome composition and metabolites can induce immune dysfunction that precedes childhood atopy and asthma development. In mice, manipulation of the gut microbiome via a high-fiber dietary intervention (which increases concentrations of short chain fatty acids (SCFAs)), or oral Lactobacillus supple- mentation, promotes pro-resolving local and remote mucosal immunity, including induction of T-regulatory cell populations, and reprogramming of hematopoietic-derived immune cell pre- cursor populations6,7. This occurs, at least in part, via microbial production, or induction, of metabolites, which shape host immune cell effector phenotypes6–8. Thus, mounting evidence implicates a developmental origin for childhood atopy and asthma involving gut microbiome perturbation and associated metabolic dysfunction in very early-life. 

From an ecological perspective, founder species, those to first colonize a previously pristine environment, frequently dictate biome conditions and influence both the pace and subsequent pattern of species accumulation in the developing ecosystem9. Using this theoretical framework, we hypothesized that neonates at high risk for asthma (HR) exhibit meconium gut microbiota dysbiosis and a reduced rate of gut bacterial diversification over the first year of life. We also rationalized that early-life daily oral supplementation of HR infants with Lactobacillus rhamnosus GG (LGG), up to 6 months of age, would alter the microbiome development of high- risk infants, and promote both the bacterial taxa and metabolites necessary for the induction of immune tolerance. 

In this study, we show that children at HR for asthma, exhibit a distinct pioneer meconium microbiota, delayed gut microbial diversification and are depleted for a range of anti-inflammatory fecal lipids in infancy. These deficits are partly rescued following LGG supplementation, and the products of LGG-supplemented infant gut microbiomes at 6 months of age, were found to increase the number of regulatory T cells ex vivo. This tolerogenic effect appears to be contingent upon sustained supplementation, since these effects were lost 6 months after cessation of supplementa- tion. Our findings indicate that early-life gut microbiome per- turbation and delayed development are associated with increased risk of childhood atopy and asthma. Moreover, they indicate nascent gut microbiome manipulation offers a feasible approach for immunomodulation in humans, and offer a much-needed framework for therapeutic development and future studies. 

实验综述

① 哮喘高风险婴儿分为LGG组（10例）和安慰剂组（15例），前者出生后每天口服鼠李糖乳杆菌GG（LGG）持续6个月；

② 与哮喘低风险婴儿（29例）相比，高风险婴儿有明显不同的胎便菌群，肠杆菌科和拟杆菌科富集，Akk菌属、栖粪杆菌属和罗氏菌属等缺失；

③ 且肠道菌群多样性发育迟缓，菌群功能偏向糖酵解，缺乏多种抗炎性脂代谢物；

④ 这些不足在LGG组婴儿中得到部分补救，其菌群代谢物可在体外增加调节性T细胞，停止LGG补充后6个月这些效果消失。