Bifidobacterium animalis subsp. lactis BB-12 Protects against Antibiotic-Induced Functional and Compositional Changes in Human Fecal Microbiome

Daniel Merenstein, Claire M Fraser, Robert F Roberts, Tian Liu, Silvia Grant-Beurmann, Tina P Tan, Keisha Herbin Smith, Tom Cronin, Olivia A Martin, Mary Ellen Sanders, Sean C Lucan, Maureen A Kane, Daniel Merenstein, Claire M Fraser, Robert F Roberts, Tian Liu, Silvia Grant-Beurmann, Tina P Tan, Keisha Herbin Smith, Tom Cronin, Olivia A Martin, Mary Ellen Sanders, Sean C Lucan, Maureen A Kane

Abstract

The administration of broad-spectrum antibiotics is often associated with antibiotic-associated diarrhea (AAD), and impacts gastrointestinal tract homeostasis, as evidenced by the following: (a) an overall reduction in both the numbers and diversity of the gut microbiota, and (b) decreased short-chain fatty acid (SCFA) production. Evidence in humans that probiotics may enhance the recovery of microbiota populations after antibiotic treatment is equivocal, and few studies have addressed if probiotics improve the recovery of microbial metabolic function. Our aim was to determine if Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-containing yogurt could protect against antibiotic-induced fecal SCFA and microbiota composition disruptions. We conducted a randomized, allocation-concealed, controlled trial of amoxicillin/clavulanate administration (days 1-7), in conjunction with either BB-12-containing or control yogurt (days 1-14). We measured the fecal levels of SCFAs and bacterial composition at baseline and days 7, 14, 21, and 30. Forty-two participants were randomly assigned to the BB-12 group, and 20 participants to the control group. Antibiotic treatment suppressed the fecal acetate levels in both the control and probiotic groups. Following the cessation of antibiotics, the fecal acetate levels in the probiotic group increased over the remainder of the study and returned to the baseline levels on day 30 (-1.6% baseline), whereas, in the control group, the acetate levels remained suppressed. Further, antibiotic treatment reduced the Shannon diversity of the gut microbiota, for all the study participants at day 7. The magnitude of this change was larger and more sustained in the control group compared to the probiotic group, which is consistent with the hypothesis that BB-12 enhanced microbiota recovery. There were no significant baseline clinical differences between the two groups. Concurrent administration of amoxicillin/clavulanate and BB-12 yogurt, to healthy subjects, was associated with a significantly smaller decrease in the fecal SCFA levels and a more stable taxonomic profile of the microbiota over time than the control group.

Keywords: Bifidobacterium; abundance; antibiotic-induced perturbation; diversity; gut microbiota; probiotic; short-chain fatty acid.

Conflict of interest statement

MES has been compensated for speaking engagements or for consulting from Associated British Foods, California Dairy Research Foundation, Church & Dwight, Danone North America, Fairlife, GlaxoSmithKline, Kerry, Mead Johnson, PepsiCo, and Trouw Nutrition. She has served on scientific advisory boards for Cargill, Sanofi, Danone North America, Danone Research, Winclove Probiotics and Yakult. She serves as the executive science officer for the International Scientific Association for Probiotics and Prebiotics. DM has consulted for Bayer & Pfizer. SCL has been compensated both for speaking engagements and for serving on the Scientific and Nutritional Advisory Board of Epicure. SCL has also consulted for Danone North America. The other authors have no competing interests to declare. None of the companies listed above had any role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Additionally none have seen the results.

Figures

Figure 1
Figure 1
Participant timeline and sample/data collection schedule.
Figure 2
Figure 2
Consolidated standards of reporting trials (CONSORT) flow diagram of participants. Sixty-six participants were enrolled, 62 of which were randomized (42 to BB-12 group and 20 to control) after a 30-day run-in period. By day 7 of the intervention, 56 participants (38 BB-12 and 18 control) remained in the study.
Figure 3
Figure 3
Comparisons of fecal SCFA levels and Shannon diversity at baseline with multiple time points post amoxicillin/clavulanate administration. (A–C) % change in average SCFA levels as compared to post run-in (day 0) baseline. (A) Acetate, (B) propionate, (C) butyrate. The acetate control group (red) in (A) remains decreased at day 30 (−25.1%) whereas active (blue, BB-12) group returns to baseline at day 30 (−1.6%). (D) Correlation of Shannon diversity between pre- and post-baseline values (Spearman’s rank correlation coefficient R = 0.49, p < 0.05). (E) Differences in Shannon diversity between the control (red) and BB-12 (blue) groups at time points pre (baseline 1, day 30), post (baseline 2, day 0), day 7, day 14, day 21, and day 30.
Figure 4
Figure 4
Taxonomic shifts induced by amoxicillin/clavulanate administration with and without BB-12 over time. (A,B) Hierarchical dendrogram of participants and their predominant fecal bacterial genera; control group (A) and BB-12 (active) group (B). The heat map represents the relative abundance (range 0–1; 1 = 100%) of each bacterial genus. The predominant genera are represented along the right x-axis. The legend for the heat map is provided on the right side representing the relative abundance of each bacterial genus within each sample. (C) Percent community divergence (Bray–Curtis dissimilarity) over time with respect to the baseline (post run-in, day 0). Control group (blue bar graphs) exhibits overall greater increase in community dissimilarity when compared to BB-12 recipients (red bar graphs).

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