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• W2891057921 abstract "•Murine gut mucosal probiotic colonization is only mildly enhanced by antibiotics•Human gut mucosal probiotic colonization is significantly enhanced by antibiotics•Post antibiotics, probiotics delay gut microbiome and transcriptome reconstitution•In contrast, aFMT restores mucosal microbiome and gut transcriptome reconstitution Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host. Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host. Antibiotics have transformed medicine and the fight against common life-threatening bacterial infections (Van Boeckel et al., 2014Van Boeckel T.P. Gandra S. Ashok A. Caudron Q. Grenfell B.T. Levin S.A. Laxminarayan R. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data.Lancet Infect. Dis. 2014; 14: 742-750Abstract Full Text Full Text PDF PubMed Scopus (1406) Google Scholar). However, widespread antibiotic exposure is associated with the emergence of resistant strains and with a variety of gastrointestinal (GI) effects, hypersensitivity, and drug-specific adverse effects, most notably antibiotic-associated diarrhea (AAD) in 5% to 35% of treated humans (Wiström et al., 2001Wiström J. Norrby S.R. Myhre E.B. Eriksson S. Granström G. Lagergren L. Englund G. Nord C.E. Svenungsson B. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study.J. Antimicrob. Chemother. 2001; 47: 43-50Crossref PubMed Scopus (329) Google Scholar, McFarland, 1998McFarland L.V. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea.Dig. Dis. 1998; 16: 292-307Crossref PubMed Scopus (238) Google Scholar). Non-selective antibiotics-induced disruption of commensal microbiome community structure (“dysbiosis”) accounts for up to 20% of all AAD cases (Bartlett, 2002Bartlett J.G. Clinical practice. Antibiotic-associated diarrhea.N. Engl. J. Med. 2002; 346: 334-339Crossref PubMed Scopus (959) Google Scholar). Such dysbiosis occurs rapidly within days, leading to altered bacterial metabolism and impaired host proteome in mice and humans (Ferrer et al., 2014Ferrer M. Martins dos Santos V.A. Ott S.J. Moya A. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach.Gut Microbes. 2014; 5: 64-70Crossref PubMed Scopus (62) Google Scholar, Lichtman et al., 2016Lichtman J.S. Ferreyra J.A. Ng K.M. Smits S.A. Sonnenburg J.L. Elias J.E. Host-Microbiota Interactions in the Pathogenesis of Antibiotic-Associated Diseases.Cell Rep. 2016; 14: 1049-1061Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Human microbiome reconstitution from antibiotic treatment is often slow and incomplete (Dethlefsen et al., 2008Dethlefsen L. Huse S. Sogin M.L. Relman D.A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing.PLoS Biol. 2008; 6: e280Crossref PubMed Scopus (1728) Google Scholar, Dethlefsen and Relman, 2011Dethlefsen L. Relman D.A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.Proc. Natl. Acad. Sci. USA. 2011; 108: 4554-4561Crossref PubMed Scopus (1534) Google Scholar, Jernberg et al., 2007Jernberg C. Löfmark S. Edlund C. Jansson J.K. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota.ISME J. 2007; 1: 56-66Crossref PubMed Scopus (716) Google Scholar) and, in some cases, may take years to revert to naive configuration (Lankelma et al., 2017Lankelma J.M. Cranendonk D.R. Belzer C. de Vos A.F. de Vos W.M. van der Poll T. Wiersinga W.J. Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study.Gut. 2017; 66: 1623-1630Crossref PubMed Scopus (54) Google Scholar). Of note, studies in rodent models and humans suggest an association between antibiotic exposure, especially during early stages of life, and a host propensity for a variety of long-term disorders (Vangay et al., 2015Vangay P. Ward T. Gerber J.S. Knights D. Antibiotics, pediatric dysbiosis, and disease.Cell Host Microbe. 2015; 17: 553-564Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), including obesity (Shao et al., 2017Shao X. Ding X. Wang B. Li L. An X. Yao Q. Song R. Zhang J.A. Antibiotic Exposure in Early Life Increases Risk of Childhood Obesity: A Systematic Review and Meta-Analysis.Front. Endocrinol. (Lausanne). 2017; 8: 170Crossref PubMed Scopus (57) Google Scholar), allergy (Risnes et al., 2011Risnes K.R. Belanger K. Murk W. Bracken M.B. Antibiotic exposure by 6 months and asthma and allergy at 6 years: Findings in a cohort of 1,401 US children.Am. J. Epidemiol. 2011; 173: 310-318Crossref PubMed Scopus (199) Google Scholar, Hoskin-Parr et al., 2013Hoskin-Parr L. Teyhan A. Blocker A. Henderson A.J. Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent relationship.Pediatr. Allergy Immunol. 2013; 24: 762-771Crossref PubMed Scopus (91) Google Scholar), increased risk of autoimmunity (Arvonen et al., 2015Arvonen M. Virta L.J. Pokka T. Kröger L. Vähäsalo P. Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group’s greater susceptibility to infections?.J. Rheumatol. 2015; 42: 521-526Crossref PubMed Scopus (55) Google Scholar), and inflammatory bowel disease (Virta et al., 2012Virta L. Auvinen A. Helenius H. Huovinen P. Kolho K.L. Association of repeated exposure to antibiotics with the development of pediatric Crohn’s disease--a nationwide, register-based finnish case-control study.Am. J. Epidemiol. 2012; 175: 775-784Crossref PubMed Scopus (131) Google Scholar, Kronman et al., 2012Kronman M.P. Zaoutis T.E. Haynes K. Feng R. Coffin S.E. Antibiotic exposure and IBD development among children: a population-based cohort study.Pediatrics. 2012; 130: e794-e803Crossref PubMed Scopus (280) Google Scholar). Probiotics have been proposed to constitute an effective preventive treatment for antibiotics-induced dysbiosis and associated adverse effects in mice (Ekmekciu et al., 2017Ekmekciu I. von Klitzing E. Fiebiger U. Neumann C. Bacher P. Scheffold A. Bereswill S. Heimesaat M.M. The Probiotic Compound VSL#3 Modulates Mucosal, Peripheral, and Systemic Immunity Following Murine Broad-Spectrum Antibiotic Treatment.Front. Cell. Infect. Microbiol. 2017; 7: 167Crossref PubMed Scopus (39) Google Scholar) and in some (Hempel et al., 2012Hempel S. Newberry S.J. Maher A.R. Wang Z. Miles J.N. Shanman R. Johnsen B. Shekelle P.G. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis.JAMA. 2012; 307: 1959-1969Crossref PubMed Scopus (574) Google Scholar) but not all human studies (Olek et al., 2017Olek A. Woynarowski M. Ahrén I.L. Kierkuś J. Socha P. Larsson N. Önning G. Efficacy and Safety of Lactobacillus plantarum DSM 9843 (LP299V) in the Prevention of Antibiotic-Associated Gastrointestinal Symptoms in Children-Randomized, Double-Blind, Placebo-Controlled Study.J. Pediatr. 2017; 186: 82-86Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, Allen et al., 2013Allen S.J. Wareham K. Wang D. Bradley C. Hutchings H. Harris W. Dhar A. Brown H. Foden A. Gravenor M.B. Mack D. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial.Lancet. 2013; 382: 1249-1257Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). Importantly, adverse effects associated with probiotics consumption may be under-reported in clinical trials (Bafeta et al., 2018Bafeta A. Koh M. Riveros C. Ravaud P. Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota: A Systematic Review.Ann. Intern. Med. 2018; (Published online July 17, 2018)https://doi.org/10.7326/M18-0343Crossref PubMed Scopus (90) Google Scholar), further complicating the efficacy debate. The extent and pattern of probiotic gut mucosal colonization and impact on the indigenous gut microbiome following antibiotic use also remain unclear. While few small-scale culture-based studies attempted to quantify supplemented probiotics in the antibiotics-perturbed GI mucosa (Klarin et al., 2005Klarin B. Johansson M.L. Molin G. Larsson A. Jeppsson B. Adhesion of the probiotic bacterium Lactobacillus plantarum 299v onto the gut mucosa in critically ill patients: a randomised open trial.Crit. Care. 2005; 9: R285-R293Crossref PubMed Google Scholar), the vast majority of studies extrapolate their conclusions from stool samples, resulting in inconclusive findings regarding probiotics capability to restore the pre-antibiotics microbiome configuration (McFarland, 2014McFarland L.V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review.BMJ Open. 2014; 4: e005047Crossref PubMed Scopus (131) Google Scholar). Importantly, no in vivo studies have directly examined the global extent of human mucosal probiotic colonization following antibiotic treatment and their impact on reconstitution of the indigenous mucosal microbiome or the host gut transcriptome. Here, we explored the impact of probiotics consumption following antibiotic exposure on the gut luminal, mucosal, and fecal microbiome composition and function and the GI transcriptome in mice and humans. To this aim, mice and a cohort of human volunteers were treated with broad-spectrum antibiotics and then either were supplemented with probiotics, underwent autologous fecal microbiome transplantation (aFMT), or were allowed to spontaneously recover over time. We found significant differences between mice and humans with respect to post-antibiotic probiotics gut mucosal colonization. Mice featured only a mild improvement in colonization of the “human-compatible” probiotics regimen upon antibiotic treatment as compared to homeostatic conditions, while humans demonstrated a marked colonization improvement in this setting. Importantly, post-antibiotic probiotic supplementation significantly delayed the extent of reconstitution of the indigenous fecal and mucosal microbiome (in both mice and humans) and the reversion of the gut transcriptome toward homeostatic configuration (in humans) compared to either spontaneous reconstitution or aFMT. In contrast, post-antibiotic aFMT in both mice and humans achieved a rapid and near-complete gut mucosal microbiome recolonization associated with reversion of the human gut transcriptome toward its pre-antibiotic configuration. Under homeostatic conditions (Zmora et al., 2018Zmora N. Zilberman-Schapira G. Suez J. Mor U. Dori-Bachash M. Bashiardes S. Kotler E. Zur M. Regev-Lehavi D. Brik R.B.-Z. et al.Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.Cell. 2018; 174 (this issue): 1388-1405Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar), administration of a multi-strain probiotic preparation was associated with limited colonization in mice and with person-specific gut mucosal colonization resistance in humans. To study the post-antibiotic mucosal colonization capacity of probiotics and their impact on the indigenous mucosal microbiome as compared to aFMT or watchful waiting, we performed the MUcosal Search for Probiotic Impact and Colonization 3 (MUSPIC3) study in mice and in humans. In mice, we supplemented the drinking water of adult male wild-type (WT) C57BL/6 mice with a broad-spectrum antibiotic regimen of ciprofloxacin and metronidazole for 2 weeks. The immediate impact of antibiotic treatment on gut mucosal microbiome configuration was assessed in one group of mice sacrificed after the 2-week antibiotic exposure (Figure 1A, “Antibiotics”). The remaining animals (n = 30) were divided into three post-antibiotic intervention groups. In the first group (“Probiotics”), antibiotic treatment was followed by 4 weeks of daily administration by oral gavage of a commercially prescribed probiotics product involving 11 strains that was validated for composition and viability by multiple methods (Zmora et al., 2018Zmora N. Zilberman-Schapira G. Suez J. Mor U. Dori-Bachash M. Bashiardes S. Kotler E. Zur M. Regev-Lehavi D. Brik R.B.-Z. et al.Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.Cell. 2018; 174 (this issue): 1388-1405Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar): Lactobacillus acidophilus (LAC), L. casei (LCA), L. casei sbsp. paracasei (LPA), L. plantarum (LPL), L. rhamnosus (LRH), Bifidobacterium longum (BLO), B. bifidum (BBI), B. breve (BBR), B. longum sbsp. infantis (BIN), Lactococcus lactis (LLA), and Streptococcus thermophilus (STH). Each mouse of the second group (“aFMT”) received, on the day following cessation of antibiotics, an oral gavage of its own pre-antibiotics stool microbiome. A third group (“Spontaneous”) remained untreated following antibiotic therapy to assess the spontaneous recovery of the indigenous gut microbiome in this setting. An additional group of mice (“Control”) did not receive antibiotics or any other treatment and was followed throughout the study’s duration. We first assessed the fecal and mucosal colonization of probiotics following broad-spectrum antibiotic treatment in mice. 16S rDNA indicated that three of the four genera comprising the probiotics mix (Lactobacillus, Bifidobacterium, and Streptococcus) were present in stool samples even prior to antibiotic administration (Figures S1A–S1C). 1 day following probiotics administration, Lactobacillus (Figure S1A), Bifidobacterium (Figure S1B), and Lactococcus genera (Figure S1D) increased in relative abundance (RA). On day 4, only Bifidobacterium RA remained elevated, after which none of the genera RAs were significantly higher in the treated group (Figures S1A–S1D). Given the inability of 16S rDNA analysis to distinguish absolute abundance changes at the species level, we utilized a sensitive species-specific qPCR (Zmora et al., 2018Zmora N. Zilberman-Schapira G. Suez J. Mor U. Dori-Bachash M. Bashiardes S. Kotler E. Zur M. Regev-Lehavi D. Brik R.B.-Z. et al.Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.Cell. 2018; 174 (this issue): 1388-1405Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar) targeting each of the tested 11-probiotic species. A pooled qPCR analysis for all species in stool indicated >10,000-fold fecal enrichment of probiotic species on days 1 and 4 of probiotic supplementation (Figure 1B), which rapidly declined in the following days, thereby losing statistical significance, though the trend persisted throughout the experiment (incremental area under the curve [iAUC] p < 0.0001 versus each group). A per-species analysis indicated 9 of the 11 species (all but BBI and LAC) to be significantly enriched in stool during probiotics supplementation (Figure 1C). Like in stool, 16S rDNA assessment of mucosal gut surfaces did not detect a significant elevation in the RA of any of the probiotics genera in any of the regions (Figures S1E–S1H). A pooled qPCR analysis for all administered probiotic species indicated significantly higher abundance in the lumen of the lower GI (LGI), but not the LGI mucosa (Figure 1D) or the upper GI (UGI; Figure 1E). The species that were significantly elevated in the lumen of the LGI tissues and the stomach were consistent with those shed in stool, while only BBR, LRH, and STH were significantly elevated in the LGI mucosa (Figure 1F). In comparison, mice that received probiotics using the same experimental design but without antibiotics pre-treatment featured a significantly lower aggregated probiotics load of all targets in the GI lumen, but not the mucosa (Figure S2A). These results indicate that resistance to the presence of probiotic species in the murine GI lumen is contributed by the resident microbiome. This resistance is partially alleviated by antibiotics, although even after antibiotics pre-treatment, the tested probiotics demonstrated mild and sporadic mucosal presence, potentially reflecting lower colonization capacity of these human-compatible probiotics species in the murine gut mucosa. We next determined the impact of the probiotic formulation on reconstitution of the indigenous murine fecal and mucosal gut microbiome community following antibiotic treatment. Expectedly, antibiotic treatment resulted in a dramatic reduction in stool alpha diversity (>66% reduction; Figure 2A) and general disruption of the fecal bacterial community structure as evident by unweighted UniFrac distances to baseline (Figure 2B). Of the three post-antibiotic interventions, aFMT was most efficient in restoring fecal bacterial richness to that observed in the control, with alpha diversity becoming indistinguishable to control within 8 days following aFMT (p = 0.11). In contrast, both probiotics and spontaneous recovery did not restore fecal alpha diversity to baseline levels 4 weeks following antibiotic cessation. Importantly, probiotics significantly delayed the return to baseline microbiome richness even compared to spontaneous recovery as evident in all tested time points (Figure 2A). Delayed murine probiotics-induced microbiome reconstitution was also reflected in the kinetics of return to pre-antibiotics baseline fecal composition as expressed by UniFrac distances. Expectedly, all treatment groups were dramatically shifted from baseline stool composition upon antibiotic treatment. While aFMT returned to baseline by day 28 after antibiotic treatment (p = 0.83; Figure 2B), both the probiotics and spontaneous recovery groups failed to fully return to baseline within 4 weeks of antibiotics cessation, with microbiome in the probiotics-administered group featuring the slowest recovery rate (p = 0.0001). As a greater distance to baseline in the probiotics-supplemented group may be merely a result of new exogenous bacteria introduced into the microbiome, we repeated the measurement after removing the four probiotics genera from the analysis and renormalizing RAs to 1 and corroborated the greater distance to baseline of the probiotics-supplemented group, reflecting an impaired indigenous mucosal microbiome reconstitution in this group (Figure S2B). A pairwise comparison of fecal microbial composition between the last day of follow-up and baseline demonstrated 28 taxa significantly differentially represented in the probiotics group (Figure S2C) with a >10-fold increase in the abundance of Blautia and no significant increase in any of the probiotics genera. Fewer significant differences were observed in the spontaneous recovery (16 taxa; Figure S2D) and aFMT (6 taxa; Figure S2E) groups. Of all taxa significantly reduced by antibiotics, 13 taxa belonging to 4 different phyla returned to baseline levels in both the aFMT and spontaneous recovery groups, but not in the probiotics group (Figure 2C). In contrast, five taxa were over-represented in the stool samples of the probiotics and significantly inversely correlated with alpha diversity: Akkermansia, Vagococcus, Enterococcus, Blautia, and Lactococcus. Of these, only Blautia bloomed exclusively in the probiotics group after antibiotics cessation (Figure 2D). Interestingly, macroscopic differences were noted between the ceca of probiotics-administered and spontaneously recovering mice, with the former being larger (representatives in Figure S2F) and significantly heavier (Figure S2G), reminiscent of germ-free mice or mice treated with broad-spectrum antibiotics. Consistent with the findings in stool, the number of observed species in the probiotics group was comparable to the group dissected immediately after 2 weeks of antibiotics and significantly lower compared to the control, aFMT, and spontaneous recovery groups in both the lumen and the mucosa of the LGI (Figure 2E) and UGI (Figure 2F). No significant differences were noted between the aFMT and control groups in any of the regions, whereas the richness in the spontaneous group was in between that of aFMT and probiotics (Figures 2E and 2F). Reduced alpha diversity in the LGI of the probiotics group was at least partly due to a total reduction in LGI bacterial load (Figure 2G). In agreement, the UniFrac distance to control of the mucosal and luminal aFMT microbiome configuration was lower than that of the spontaneously recovering group, with the largest distance to control featured by the probiotics-administered group (Figures 2H–2I and S2H). As in stool, these colonization differences could not be explained by the mere presence of probiotics genera in probiotics-administered mice, as the result remained unchanged even if probiotics genera were excluded from the analysis (Figures S2I and S2J). Interestingly, microbiome composition of aFMT-treated mice was indistinguishable from controls both in the LGI and the UGI, suggesting that fecal microbiome was sufficient to recapitulate the distinct UGI microbiome (Figure S2H). Of the taxa significantly reduced in the LGI mucosa of the antibiotics group compared to control, 16 returned to control levels in both the aFMT and the spontaneous recovery groups, but not in the probiotics group, of which 11 belonged to the Clostridiales order; two genera (Blautia and Streptococcus) significantly bloomed exclusively in the probiotics group (Figure 2J). Four taxa predominant in the probiotics group had a high (Spearman r < −0.6) and significant (p < 0.0001) inverse correlation with the alpha diversity in the LGI mucosa: Vagococcus, Akkermansia muciniphila, Blautia producta, and Enterococcus casseliflavus (Figure S2K). These blooming taxa may thus play a role in probiotics-induced inhibition of microbiome reconstitution. To ascertain that the delayed return to homeostatic indigenous microbiome configuration following probiotics treatment was not a unique feature of the studied vivarium, we performed the same set of interventions in mice housed in a different specific-pathogen-free (SPF) animal facility with distinct baseline fecal microbiome (26 taxa significantly differentially represented; Figure S3A). In this vivarium as well, aFMT induced a rapid indigenous microbiome post-antibiotic reconstitution as compared to watchful waiting, while the 11-strain probiotic treatment delayed the speed and magnitude of the recolonization process (Figures S3B–S3K). Collectively, 4 weeks of spontaneous recovery following a broad-spectrum antibiotic treatment in mice partially restored baseline gut mucosal configuration and bacterial richness and load. Watchful waiting was superior—in its rate of induction of indigenous microbiome reconstitution—to consumption of probiotics, which demonstrated little improvement of the post-antibiotics microbiome configuration and delayed the restoration of homeostatic composition and richness of the pre-antibiotic gut mucosal microbiome. In comparison to both watchful waiting and probiotics administration, aFMT constituted the most efficient treatment modality, enabling rapid restoration of both upper- and lower-gut mucosal microbiome to homeostatic configuration following antibiotic treatment in mice. We next set out to determine how the 11-strain probiotics or aFMT would affect the post-antibiotic human luminal and mucosa-associated microbiome reconstitution. To this aim, we conducted a prospective longitudinal interventional study in 21 healthy human volunteers not consuming probiotics (Table S1 and STAR Methods) who were given an oral broad-spectrum antibiotic treatment of ciprofloxacin and metronidazole at standard dosages for a period of 7 days (Figure 3A). Following antibiotic treatment, seven participants were followed by watchful waiting for spontaneous microbiome reconstitution, six participants received aFMT (STAR Methods), and eight participants received the aforementioned 11-strain probiotics preparation administered bi-daily for a period of 4 weeks (Figure 3A). Endoscopic examinations were performed twice in each of the 21 participants. A first colonoscopy and deep endoscopy were performed after completion of the week-long antibiotic course, thereby characterizing the post-antibiotics dysbiosis throughout the GI tract. A second colonoscopy and deep endoscopy were performed 3 weeks later (day 21) to assess the degree of gut mucosal and luminal reconstitution in each of the three treatment arms (Figure 3A). Multiple stool samples were collected at intervals indicated in Figure 3A up to 6 months from antibiotics cessation. In total, 337 luminal, 702 mucosal, and 557 stool samples, as well as 362 regional biopsies, were collected. Expectedly, antibiotic treatment in humans triggered a profound fecal microbial depletion (Figure S4A) and disruption of microbial community composition (Figure S4B) as observed in stool (Figures S4C and S4D), LGI mucosa (Figures S4E and S4F), and UGI mucosa (Figure S4G), with the latter region the least affected by antibiotics (Figure S4H). Compositional changes were accompanied by alteration of microbiome function in the stool and LGI as assessed by shotgun metagenomic sequencing (Figures S4I–S4K). Fecal 16S rDNA analysis demonstrated that all probiotics-related genera were found in stools prior to probiotics supplementation, and Lactobacillus, Lactococcus, and Streptococcus significantly expanded in RA following antibiotics treatment. All four probiotics genera remained significantly elevated compared to baseline during probiotics supplementation, though none were further elevated to the post-antibiotics levels. Following cessation of probiotic treatment, none of the genera remained significantly elevated compared to baseline (Figures S5A–S5D). A fecal species-level metagenomic analysis (MetaPhlAn2) also demonstrated an antibiotics-induced expansion in RA of 6 of 11 species compared to baseline (BBI, BBR, BLO, LAC, LLA, and STH; Figure S5E), while during probiotic treatment, all species expanded compared to baseline, but only BBI and BLO reached statistical significance with this method (Figure S5E). A shotgun metagenomic sequencing strain-specific method (Sharon et al., 2013Sharon I. Morowitz M.J. Thomas B.C. Costello E.K. Relman D.A. Banfield J.F. Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization.Genome Res. 2013; 23: 111-120Crossref PubMed Scopus (306) Google Scholar) identified one of the probiotic strains in a single baseline day in stool, two of the probiotics strains (different than the one appearing at baseline) during antibiotic treatment, and six of the pill-specific strains (BBI, BBR, BLO, LLA, LPL, and LRH) in multiple days during probiotics exposure. BBI, BLO, and BBR were also shed after cessation by the same participants (Figure 3B). Fecal species-specific qPCR, the most sensitive method, revealed a significant fecal expansion during probiotics administration of the 11-probiotic species when considered together, with 7 of 11 species being significantly elevated from baseline when analyzed separately during consumption (BBR, BIN, LAC, LCA, LLA, LPL, and LRH; F" @default.
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• W2891057921 title "Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT" @default.
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• W2891057921 doi "https://doi.org/10.1016/j.cell.2018.08.047" @default.
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