Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome- a pilot study

Van T Pham, Sophie Fehlbaum, Nicole Seifert, Nathalie Richard, Maaike J Bruins, Wilbert Sybesma, Ateequr Rehman, Robert E Steinert, Van T Pham, Sophie Fehlbaum, Nicole Seifert, Nathalie Richard, Maaike J Bruins, Wilbert Sybesma, Ateequr Rehman, Robert E Steinert

Abstract

An increasing body of evidence has shown that gut microbiota imbalances are linked to diseases. Currently, the possibility of regulating gut microbiota to reverse these perturbations by developing novel therapeutic and preventive strategies is being extensively investigated. The modulatory effect of vitamins on the gut microbiome and related host health benefits remain largely unclear. We investigated the effects of colon-delivered vitamins A, B2, C, D, and E on the gut microbiota using a human clinical study and batch fermentation experiments, in combination with cell models for the assessment of barrier and immune functions. Vitamins C, B2, and D may modulate the human gut microbiome in terms of metabolic activity and bacterial composition. The most distinct effect was that of vitamin C, which significantly increased microbial alpha diversity and fecal short-chain fatty acids compared to the placebo. The remaining vitamins tested showed similar effects on microbial diversity, composition, and/or metabolic activity in vitro, but in varying degrees. Here, we showed that vitamins may modulate the human gut microbiome. Follow-up studies investigating targeted delivery of vitamins to the colon may help clarify the clinical significance of this novel concept for treating and preventing dysbiotic microbiota-related human diseases. Trial registration: ClinicalTrials.gov, NCT03668964. Registered 13 September 2018 - Retrospectively registered, https://ichgcp.net/clinical-trials-registry/NCT03668964.

Keywords: Vitamins; dysbiosis; gut microbiome; targeted delivery.

Figures

Figure 1.
Figure 1.
Alpha diversity of gut microbiota before and after colon-delivered vitamin intervention.Diversity indices, including evenness (a), Shannon’s index (b), observed number of species (c) and Simpson’s index (d) were compared before and after colon-delivered vitamin intervention, using a paired Wilcoxon test. Absolute changes between the intervention group and the placebo were compared using a Wilcoxon test. Values are shown as median and interquartile range. NS, not significant, p > .05
Figure 1.
Figure 1.
Alpha diversity of gut microbiota before and after colon-delivered vitamin intervention.Diversity indices, including evenness (a), Shannon’s index (b), observed number of species (c) and Simpson’s index (d) were compared before and after colon-delivered vitamin intervention, using a paired Wilcoxon test. Absolute changes between the intervention group and the placebo were compared using a Wilcoxon test. Values are shown as median and interquartile range. NS, not significant, p > .05
Figure 2.
Figure 2.
Effect of vitamin treatments on microbial composition in humans and in vitro. Values are shown as absolute difference in relative abundance at the phylum (p), family (f), genus (g), and species (s) level versus placebo (for human study), or versus the control (for in vitro study), using different bubble size. Direction of change is depicted by color. Significant differences are marked as bold
Figure 2.
Figure 2.
Effect of vitamin treatments on microbial composition in humans and in vitro. Values are shown as absolute difference in relative abundance at the phylum (p), family (f), genus (g), and species (s) level versus placebo (for human study), or versus the control (for in vitro study), using different bubble size. Direction of change is depicted by color. Significant differences are marked as bold
Figure 3.
Figure 3.
Short-chain fatty acid concentrations before and after colon-delivered vitamin intervention. Concentrations (mM) of acetate (a), propionate (b), butyrate (c) and total SCFA (d) before and after colon-delivered vitamin intervention were compared using the paired t-test when parametric assumptions were met, or a paired Wilcoxon test when parametric assumptions were not met. Absolute changes between the intervention group and the placebo were compared using the t-test when parametric assumption was met, or a Wilcoxon test when parametric assumptions were not met. Values are shown as mean ± SEM. NS, p > .05
Figure 3.
Figure 3.
Short-chain fatty acid concentrations before and after colon-delivered vitamin intervention. Concentrations (mM) of acetate (a), propionate (b), butyrate (c) and total SCFA (d) before and after colon-delivered vitamin intervention were compared using the paired t-test when parametric assumptions were met, or a paired Wilcoxon test when parametric assumptions were not met. Absolute changes between the intervention group and the placebo were compared using the t-test when parametric assumption was met, or a Wilcoxon test when parametric assumptions were not met. Values are shown as mean ± SEM. NS, p > .05
Figure 4.
Figure 4.
Vitamin treatments induced changes in the composition of the gut microbiome invitro. (a) Non-metric multidimensional scaling (nMDS) analysis of microbiome profiles generated via fermentation supernatant samples. An additional sample was taken from vitamin B2 0.2x fermentation vessel at baseline to assess the consistency of microbiome profiling procedure. (b) The number of species in fermentation supernatant samplesEach vitamin was tested at 3 doses (0.2x, 1x, and 5x) (Table S2) .
Figure 4.
Figure 4.
Vitamin treatments induced changes in the composition of the gut microbiome invitro. (a) Non-metric multidimensional scaling (nMDS) analysis of microbiome profiles generated via fermentation supernatant samples. An additional sample was taken from vitamin B2 0.2x fermentation vessel at baseline to assess the consistency of microbiome profiling procedure. (b) The number of species in fermentation supernatant samplesEach vitamin was tested at 3 doses (0.2x, 1x, and 5x) (Table S2) .
Figure 5.
Figure 5.
Vitamin treatments induced changes in the metabolic activity of the gut microbiome invitro. SCFA production after 48 h fermentation upon/after addition of vitamins. Data are expressed as mM. Each vitamin was tested at 3 doses (0.2x, 1x, and 5x) (Table S2) .
Figure 5.
Figure 5.
Vitamin treatments induced changes in the metabolic activity of the gut microbiome invitro. SCFA production after 48 h fermentation upon/after addition of vitamins. Data are expressed as mM. Each vitamin was tested at 3 doses (0.2x, 1x, and 5x) (Table S2) .
Figure 6.
Figure 6.
Vitamin treatments improved immune function and barrier integrity in vitro. (a) Effect of vitamin E on IL-8-CXCL8 production by HT29 cells. Data are expressed as pg/mL. (b-c) Effects of vitamins C and E on gut barrier integrity using a cellular intestinal model. Data are expressed as the ratio between TEER at the end of the incubation period and initial TEER. TEER ratios and IL-8-CXCL8 concentrations of samples taken before and after fermentation were compared using unpaired t-tests and unpaired Wilcoxon tests. Absolute changes between vitamin treatment groups and the control (between reactors) were compared using a linear model. Values are shown as median and interquartile range. # = p < .05; before fermentation group; * = p < .05; control. Each vitamin was tested at 3 doses (0.2x, 1x, and 5x) (Table S2)
Figure 6.
Figure 6.
Vitamin treatments improved immune function and barrier integrity in vitro. (a) Effect of vitamin E on IL-8-CXCL8 production by HT29 cells. Data are expressed as pg/mL. (b-c) Effects of vitamins C and E on gut barrier integrity using a cellular intestinal model. Data are expressed as the ratio between TEER at the end of the incubation period and initial TEER. TEER ratios and IL-8-CXCL8 concentrations of samples taken before and after fermentation were compared using unpaired t-tests and unpaired Wilcoxon tests. Absolute changes between vitamin treatment groups and the control (between reactors) were compared using a linear model. Values are shown as median and interquartile range. # = p < .05; before fermentation group; * = p < .05; control. Each vitamin was tested at 3 doses (0.2x, 1x, and 5x) (Table S2)

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