James Jamaurie, Santos Renato Ers, Watnick Paula I
bioRxiv. 2025 Jan 2:2024.12.31.630902. doi: 10.1101/2024.12.31.630902.
The intestinal diarrheal pathogen colonizes the host terminal ileum, a microaerophilic, glucose-poor, nitrate-rich environment. In this environment, respires nitrate and increases transport and utilization of alternative carbon sources via the cAMP receptor protein (CRP), a transcription factor that is active during glucose scarcity. Here we show that nitrate respiration in aerated cultures is under control of CRP and, therefore, glucose availability. nitrate respiration results in extracellular accumulation of nitrite because does not possess the machinery for nitrite reduction. This nitrite inhibits biofilm formation via an as yet unelucidated mechanism that depends on the high cell density master regulator HapR. The genome of , an intestinal microbe shown to enhance biofilm accumulation in the neonatal mouse gut and predispose household contacts to cholera, encodes enzymes that reduce nitrite to nitrogen gas. We report that, in nitrate-supplemented co-cultures, metabolizes the nitrite generated by and, thereby, enhances surface accumulation. We propose that biofilm formation in the host intestine is limited by nitrite production but can be rescued by intestinal microbes such as that have the capacity to metabolize nitrite. Such microbes increase colonization of the host ileum and predispose to infection.
colonizes the terminal ileum where both oxygen and nitrate are available as terminal electron acceptors. biofilm formation is inhibited by nitrate due to its conversion to nitrite during respiration. When co-cultured with a microbe that can further reduce nitrite, surface accumulation in the presence of nitrate is rescued. The contribution of biofilm formation to ileal colonization depends on the composition of the microbiota. We propose that the intestinal microbiota predisposes mammalian hosts to cholera by consuming the nitrite generated by in the terminal ileum. Differences in the intestinal abundance of nitrite-reducing microbes may partially explain the differential susceptibility of humans to cholera and the resistance of non-human mammalian models to intestinal colonization with .
肠道腹泻病原体定殖于宿主回肠末端，这是一个微需氧、葡萄糖含量低、硝酸盐含量丰富的环境。在这种环境中，该病原体利用硝酸盐进行呼吸，并通过环磷酸腺苷受体蛋白（CRP）增加对替代碳源的转运和利用，CRP是一种在葡萄糖缺乏时发挥作用的转录因子。我们在此表明，在通气培养物中，该病原体的硝酸盐呼吸受CRP控制，因此也受葡萄糖可用性的控制。该病原体的硝酸盐呼吸导致细胞外亚硝酸盐积累，因为它不具备亚硝酸盐还原机制。这种亚硝酸盐通过一种尚未阐明的机制抑制该病原体的生物膜形成，该机制依赖于高细胞密度主调节因子HapR。一种肠道微生物的基因组显示，它能增强新生小鼠肠道中的生物膜积累，并使家庭接触者易患霍乱，该基因组编码将亚硝酸盐还原为氮气的酶。我们报告称，在添加硝酸盐的共培养物中，这种微生物代谢该病原体产生的亚硝酸盐，从而增强该病原体的表面积累。我们提出，宿主肠道中该病原体的生物膜形成受到亚硝酸盐产生的限制，但可以被具有代谢亚硝酸盐能力的肠道微生物（如上述微生物）拯救。此类微生物增加了该病原体在宿主回肠末端的定殖，并使其易受感染。
该病原体定殖于回肠末端，在那里氧气和硝酸盐均可作为末端电子受体。该病原体的生物膜形成因硝酸盐在呼吸过程中转化为亚硝酸盐而受到抑制。当与一种能够进一步还原亚硝酸盐的微生物共培养时，在有硝酸盐存在的情况下，该病原体的表面积累得以恢复。生物膜形成对回肠定殖的贡献取决于微生物群的组成。我们提出，肠道微生物群通过消耗该病原体在回肠末端产生的亚硝酸盐，使哺乳动物宿主易患霍乱。肠道中亚硝酸盐还原微生物丰度的差异可能部分解释了人类对霍乱易感性的差异以及非人类哺乳动物模型对该病原体肠道定殖的抗性。
