Identification and Characterisation of an Iron-Responsive Candidate Probiotic

BackgroundIron is an essential cofactor in almost all biological systems. The lactic acid bacteria (LAB), frequently employed as probiotics, are unusual in having little or no requirement for iron. Iron in the human body is sequestered by transferrins and lactoferrin, limiting bacterial growth. An increase in the availability of iron in the intestine by bleeding, surgery, or under stress leads to an increase in the growth and virulence of many pathogens. Under these high iron conditions, LAB are rapidly out-competed; for the levels of probiotic bacteria to be maintained under high iron conditions they must be able to respond by increasing growth rate to compete with the normal flora. Despite this, iron-responsive genera are poorly characterised as probiotics.
Methodology/Principal FindingsHere, we show that a panel of probiotics are not able to respond to increased iron availability, and identify an isolate of Streptococcus thermophilus that can increase growth rate in response to increased iron availability. The isolate of S. thermophilus selected was able to reduce epithelial cell death as well as NF-κB signalling and IL-8 production triggered by pathogens. It was capable of crossing an epithelial cell barrier in conjunction with E. coli and downregulating Th1 and Th17 responses in primary human intestinal leukocytes.
Conclusions/SignificanceWe propose that an inability to compete with potential pathogens under conditions of high iron availability such as stress and trauma may contribute to the lack of efficacy of many LAB-based probiotics in treating disease. Therefore, we offer an alternative paradigm which considers that probiotics should be able to be competitive during periods of intestinal bleeding, trauma or stress.

背景：铁几乎是所有生物系统必需的辅因子。常被用作益生菌的乳酸菌（LAB）却颇为特殊，它们对铁的需求极少甚至完全无需。人体内的铁会被转铁蛋白和乳铁蛋白螯合，从而限制细菌的生长。当肠道内铁的可利用性因出血、手术或应激状态升高时，众多病原体的生长与毒力都会随之增强。在此高铁环境下，乳酸菌会迅速被淘汰；若要在高铁条件下维持益生菌的活菌水平，益生菌必须能够通过加快生长速率来与正常菌群竞争。尽管如此，铁响应属益生菌的相关特性仍鲜有研究。
材料与方法/主要结果：本研究证实，多数益生菌无法响应铁可利用性的升高，并筛选出一株能够在高铁环境下加快生长速率的嗜热链球菌（Streptococcus thermophilus）分离株。该嗜热链球菌分离株不仅能够减少病原体诱导的上皮细胞死亡，还可抑制NF-κB信号通路活化与IL-8的产生。此外，它可与大肠杆菌（E. coli）协同穿越上皮细胞屏障，并在原代人肠道白细胞中下调Th1与Th17免疫应答。
结论与意义：我们提出，在出血、创伤或应激等高铁环境下无法与潜在病原体竞争，或许是众多基于乳酸菌的益生菌临床疗效欠佳的原因之一。据此，我们提出全新的研究范式：益生菌应当能够在肠道出血、创伤或应激时期保持竞争优势。