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Identification and characterisation of an iron-responsive candidate probiotic.

Bailey JR, Probert CS, Cogan TA - PLoS ONE (2011)

Bottom Line: 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.Therefore, we offer an alternative paradigm which considers that probiotics should be able to be competitive during periods of intestinal bleeding, trauma or stress.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Microbiology, School of Veterinary Sciences, University of Bristol, Bristol, United Kingdom.

ABSTRACT

Background: Iron 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 findings: Here, 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/significance: We 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.

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Effect of probiotics on the adaptive immune response.Percent change in expression of T-box21 (Th1), RORC (Th17) and Foxp3 (Treg) transcription factor mRNA in response to E. coli and the effect of probiotics on their expression (A). Percent change in cytokine mRNA levels induced by T cells in response to E. coli with and without probiotic (B). Results are expressed as mean±S.E.M. * p≤0.05 and ** p≤0.01.
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pone-0026507-g005: Effect of probiotics on the adaptive immune response.Percent change in expression of T-box21 (Th1), RORC (Th17) and Foxp3 (Treg) transcription factor mRNA in response to E. coli and the effect of probiotics on their expression (A). Percent change in cytokine mRNA levels induced by T cells in response to E. coli with and without probiotic (B). Results are expressed as mean±S.E.M. * p≤0.05 and ** p≤0.01.

Mentions: Leukocytes were isolated from the intestinal lamina propria and challenged with bacterial antigens from E. coli K12 and AIEC HM615 to determine the effect of competing probiotic antigens from L. acidophilus ASF360, S. thermophilus NCIMB 41856 and E. coli Nissle 1917. Both E. coli K12 and AIEC HM615 induced a Th1 response, indicated by upregulation of mRNA encoding the Th1-specific transcription factor T-box21 in the population of cultured leukocytes (16% (p = 0.003) and 13% (p = 0.007) respectively); this was significantly reduced by the addition of L. acidophilus ASF360 or S. thermophilus NCIMB 41856. L. acidophilus ASF360 reduced the response to E. coli K12 and AIEC HM615 by 13% (p = 0.003) and 11% (p = 0.02), respectively. S. thermophilus NCIMB 41856 reduced the Th1 response to E. coli K12 and AIEC HM615 by 10% (p = 0.03) and 13% (p = 0.04), respectively. E. coli Nissle 1917 also downregulated the Th1 response to AIEC HM615 by 21% (p = 0.009). Furthermore, S. thermophilus NCIMB 41856 reduced the baseline level of transcription of T-box21 in untreated cells by 6% (p = 0.03). Neither E. coli strain induced a significant Th2 response but the Th17-specific transcription factor, RORC, was also upregulated following treatment with E. coli K12 or AIEC HM615 antigens (9% and 13% (p = 0.02), respectively). The Th17 response to E. coli K12 was reduced by 12% following the addition of L. acidophilus ASF360 antigens (p = 0.009) and the response to AIEC HM615 was reduced by the addition of any of the three potential probiotic strains: L. acidophilus ASF360 reduced the response by 18% (p = 0.0002), S. thermophilus NCIMB 41856 by 15% (p = 0.003) and E. coli Nissle 1917 by 26% (p = 0.003). In addition, both L. acidophilus ASF360 and S. thermophilus NCIMB 41856 were capable of reducing the baseline level of RORC transcription in untreated cells by 10% (p = 0.003 and p = 0.04, respectively). AIEC HM615 also induced a strong Treg response, shown by the upregulation of Foxp3 by 30% (p = 0.0009) in cultured leukocytes. However, this was reduced by the addition of any of the three potential probiotic strains: L. acidophilus ASF360 caused an 18% reduction in Foxp3 expression (p = 0.02), S. thermophilus NCIMB 41856 a 21% reduction (p = 0.03) and E. coli Nissle 1917 a 27% reduction (p = 0.02) (Figure 5A).


Identification and characterisation of an iron-responsive candidate probiotic.

Bailey JR, Probert CS, Cogan TA - PLoS ONE (2011)

Effect of probiotics on the adaptive immune response.Percent change in expression of T-box21 (Th1), RORC (Th17) and Foxp3 (Treg) transcription factor mRNA in response to E. coli and the effect of probiotics on their expression (A). Percent change in cytokine mRNA levels induced by T cells in response to E. coli with and without probiotic (B). Results are expressed as mean±S.E.M. * p≤0.05 and ** p≤0.01.
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Related In: Results  -  Collection

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pone-0026507-g005: Effect of probiotics on the adaptive immune response.Percent change in expression of T-box21 (Th1), RORC (Th17) and Foxp3 (Treg) transcription factor mRNA in response to E. coli and the effect of probiotics on their expression (A). Percent change in cytokine mRNA levels induced by T cells in response to E. coli with and without probiotic (B). Results are expressed as mean±S.E.M. * p≤0.05 and ** p≤0.01.
Mentions: Leukocytes were isolated from the intestinal lamina propria and challenged with bacterial antigens from E. coli K12 and AIEC HM615 to determine the effect of competing probiotic antigens from L. acidophilus ASF360, S. thermophilus NCIMB 41856 and E. coli Nissle 1917. Both E. coli K12 and AIEC HM615 induced a Th1 response, indicated by upregulation of mRNA encoding the Th1-specific transcription factor T-box21 in the population of cultured leukocytes (16% (p = 0.003) and 13% (p = 0.007) respectively); this was significantly reduced by the addition of L. acidophilus ASF360 or S. thermophilus NCIMB 41856. L. acidophilus ASF360 reduced the response to E. coli K12 and AIEC HM615 by 13% (p = 0.003) and 11% (p = 0.02), respectively. S. thermophilus NCIMB 41856 reduced the Th1 response to E. coli K12 and AIEC HM615 by 10% (p = 0.03) and 13% (p = 0.04), respectively. E. coli Nissle 1917 also downregulated the Th1 response to AIEC HM615 by 21% (p = 0.009). Furthermore, S. thermophilus NCIMB 41856 reduced the baseline level of transcription of T-box21 in untreated cells by 6% (p = 0.03). Neither E. coli strain induced a significant Th2 response but the Th17-specific transcription factor, RORC, was also upregulated following treatment with E. coli K12 or AIEC HM615 antigens (9% and 13% (p = 0.02), respectively). The Th17 response to E. coli K12 was reduced by 12% following the addition of L. acidophilus ASF360 antigens (p = 0.009) and the response to AIEC HM615 was reduced by the addition of any of the three potential probiotic strains: L. acidophilus ASF360 reduced the response by 18% (p = 0.0002), S. thermophilus NCIMB 41856 by 15% (p = 0.003) and E. coli Nissle 1917 by 26% (p = 0.003). In addition, both L. acidophilus ASF360 and S. thermophilus NCIMB 41856 were capable of reducing the baseline level of RORC transcription in untreated cells by 10% (p = 0.003 and p = 0.04, respectively). AIEC HM615 also induced a strong Treg response, shown by the upregulation of Foxp3 by 30% (p = 0.0009) in cultured leukocytes. However, this was reduced by the addition of any of the three potential probiotic strains: L. acidophilus ASF360 caused an 18% reduction in Foxp3 expression (p = 0.02), S. thermophilus NCIMB 41856 a 21% reduction (p = 0.03) and E. coli Nissle 1917 a 27% reduction (p = 0.02) (Figure 5A).

Bottom Line: 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.Therefore, we offer an alternative paradigm which considers that probiotics should be able to be competitive during periods of intestinal bleeding, trauma or stress.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Microbiology, School of Veterinary Sciences, University of Bristol, Bristol, United Kingdom.

ABSTRACT

Background: Iron 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 findings: Here, 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/significance: We 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.

Show MeSH
Related in: MedlinePlus