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Tarmfloran spelar en viktig roll för människorshälsa genom att bl.a. reglera värdens immunitet, producera näringsämnen och stärkatarmbarriären. Dysbios i tarmfloran har associerats med flera sjukdomar,inklusive diabetes typ 2. Metformin är förstahandsvalet av läkemedel mot diabetestyp 2 och har en pleotropisk effekt. Det finns stöd för att tarmarna är ettbetydande målorgan för metformin, dels för att intravenös administrering av metforminger sämre effekt än oral. Syftet med denna litteraturstudie var därför attundersöka om metformin har effekter på tarmflorans sammansättning hos människormed diabetes typ 2. Resultatet är baserat på fem olika studier hämtade frånPubmed. Alla studierna ger stöd åt att metformin förändrar tarmfloranssammansättning och indikerar även att tarmfloran är involverad i metforminsbehandlingseffekter och biverkningar. Hur omfattande förändringarna var ochvilka taxa som påverkades varierade, troligen p.g.a. olika studiedesigner. Resultatentyder på att metformin ökar den relativa förekomsten av Escherichia, Akkermansiamuciniphila och SCFA-producerande taxa, inklusive Blautia. Indikationer fanns också på att metformin minskar den relativaförekomsten av Intestinibacter.Slutsatsen är att metformin förändrar tarmflorans sammansättning, men att flerstudier krävs för att bekräfta både de taxonomiska och funktionella förändringarna.Det finns också ett behov av mer kunskap om hur resultat påverkas avsekvenserings- och statistikmetoder för att lättare kunna göra jämförelser mellan studier. / The gut microbiota has important impact on hosthealth by regulating host immunity, providing nutrients and strengthening ofthe gut integrity. A gut microbiota dysbiosis has been associated with severaldiseases, including type 2 diabetes. Metformin is the drug of first choiceagainst type 2 diabetes and has pleiotrophic effects. It has been suggestedthat the intestines is a important target of metformin because intravenousadministration exerts smaller therapeutic effects than oral. The aim of thislitterature study was to investigate if metformin alters the gut microbiotacomposition in humans. The result is based on five studies collected from Pubmed.All studies support that metformin treatment is associated with an altered gutmicrobiota and may be involved in terapeutic and side effects of metformin. Theamplitude of the metformin-induced alterations and affected taxa differed amongthe studies, probably due to large differences in study designs. Main findingssuggest that metformin increase the relative abundance of Escherichia, Akkermansiamuciniphila and SCFA-producing taxa as Blautia.Metformin also might decrease the relative abundance of Intestinibacter. In conclusion, metformin alters the gutmicrobiota, but more studies are needed to determine the taxonomic andfunctional alterations during metformin treatment. There is also a need of moreknowledge of how results are affected by sequencing and statistical methods.

Submitted by PPG Odontologia (odontologia-pg@pucrs.br) on 2018-03-23T12:20:59Z No. of bitstreams: 1 CAUANA_OLIVA_TAVARES_TES.pdf: 7981094 bytes, checksum: f72aed348b44d9575861b810913cc7c3 (MD5) / Approved for entry into archive by Tatiana Lopes (tatiana.lopes@pucrs.br) on 2018-04-06T11:47:44Z (GMT) No. of bitstreams: 1 CAUANA_OLIVA_TAVARES_TES.pdf: 7981094 bytes, checksum: f72aed348b44d9575861b810913cc7c3 (MD5) / Made available in DSpace on 2018-04-06T11:50:47Z (GMT). No. of bitstreams: 1 CAUANA_OLIVA_TAVARES_TES.pdf: 7981094 bytes, checksum: f72aed348b44d9575861b810913cc7c3 (MD5) Previous issue date: 2017-12-18 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Infection and dysbiosis present a close relationship with metabolic diseases, although the influence of apical periodontitis (AP) in this context needs further investigation. This thesis includes a review and an experimental study that evaluated the influence of AP in a rat model of metabolic disorder induced by 10% fructose supplementation. 60 male Wistar rats were used. Animals that received high fructose diet (HFD; N=30) or filtered water (control; N=30) were subdivided into additional groups: (i) without induction of AP (N=20); (ii) with AP induction 2 weeks before euthanasia (14 days; N=20); (iii) with AP induction 4 weeks before euthanasia (28 days; N=20). HFD triggered obesity-related type2 diabetes, as indicated by induction of overweight and hyperglycemia, besides polydipsia, regardless of the AP induction. There was no variation in the serum or intestinal levels of TNF, IL-1? and IL-6 among the experimental groups. Serum leptin and adiponectin levels were significantly elevated in the HFD group, without AP induction. The intestinal levels of leptin were significantly increased in the groups with 28 days of AP induction, despite HFD. A significant elevation of liver glutathione levels was observed in animals submitted to HFD and AP for 14 days. AP induction (14 or 28 days) led to pulp and periapical tissue inflammation, without any influence of HFD. Either HFD or AP induction led to dysbiosis, as indicated by a significant reduction of fecal A. muciniphila expression. Conluding, we provide novel evidence that AP can have systemic impacts on metabolic disorders, likely by modulating intestinal metabolism and microbiota. / Infec??o e disbiose est?o correlacionadas com a s?ndrome metab?lica. Por?m, ainda ? necess?rio que haja investiga??es sobre a influ?ncia da periodontite apical neste contexto. Esta tese contempla uma revis?o de literatura acerca do tema e um trabalho experimental que avaliou a influ?ncia da periodontite apical em um modelo de desordem metab?lica induzido por suplementa??o com frutose 10% (HFD) durante 8 semanas. Foram utilizados 60 ratos wistar machos, os quais foram subdivididos em: G1- controle (ingest?o de ?gua filtrada e sem indu??o les?o periapical); G2- controle HFD (ingest?o de frutose e sem indu??o les?o periapical); G3- controle 14 dias PA (ingest?o de ?gua filtrada e com indu??o les?o periapical por 14 dias); G4- HFD 14 dias PA (ingest?o de frutose e com indu??o les?o periapical por 14 dias); G5- controle 28 dias PA (ingest?o de ?gua filtrada e com indu??o les?o periapical por 28 dias); G6- HFD 28 dias PA (ingest?o de frutose e com indu??o les?o periapical por 28 dias). Durante as 8 semanas de experimento, os animais foram pesados a cada 2 dias. Os consumos de ra??o e ?gua foram medidos diariamente. Ap?s as 8 semanas, foi realizada a medi??o da glicemia e coleta de fezes de cada animal para avalia??o da bact?ria Akkermansia muciniphila atrav?s de PCR. Em seguida, os animais foram eutanasiados. Foram removidas as mand?bulas, para an?lise histol?gica; o soro do sangue e o intestino para an?lise de citocinas (TNF, IL-1? e IL-6) e adipocinas (leptina e adiponectina) atrav?s de ELISA; o f?gado e o cora??o para an?lise de estresse oxidativo (catalase e glutationa) atrav?s de espectrofotometria. Os resultados demonstraram que houve aumento de peso, de ingesta de ?gua (polidipsia) e de glicemia nos grupos submetidos ao HFD, independente de indu??o de PA, confirmando que o modelo experimental foi capaz de induzir diabetes tipo2 relacionada ? obesidade. N?o houve varia??o nos n?veis de TNF, IL-1? e IL-6 entre os grupos experimentais. Os n?veis de leptina e de adiponectina estavam significantemente aumentados no G2. Os n?veis intestinais de leptina estavam aumentados nos grupos 5 e 6. Um aumento nos n?veis de glutationa foi observado nos animais do G4. Ocorreu indu??o de periodontite apical nos grupos 3, 4, 5 e 6, sem altera??es provocadas pela HFD. Tanto a PA quanto o HFD foram capazes de provocar disbiose, diminuindo significativamente os n?veis de express?o de A. muciniphila. Concluindo, o presente estudo demonstra, pela primeira vez, que a PA exerce influ?ncia sist?mica e impacta desordens metab?licas modulando o metabolismo intestinal e a microbiota.

abstract: The transition to college has been identified as a vulnerable period for weight gain and the onset of obesity. Research has shown that the gut microbiota is different in obese compared to lean individuals, but a period of weight gain has never been studied in free-living individuals. The objective of this longitudinal, observational study was to assess the association between changes in the intestinal microbiota and weight-related outcomes in healthy college students living in on-campus dormitories at Arizona State University (n=39). Anthropometric measures and fecal samples were collected at the beginning and end of the school year, and microbial relative abundance for A. muciniphila, F. prausnitzii, R. gnavus, and L. acidophilus was measured through qPCR analyses. In this population, body mass index (BMI) and waist circumference (WC) increased by 0.97 ± 1.28 kg/m2 and 2.64 ± 4.90 cm, respectively. Wilcoxon-Rank tests revealed that R. gnavus fold change was significantly different between groups of weight loss/maintenance and weight gain ≥ 5% body weight (0.14 [-0.21, 0.64], n=24 vs. -0.14 [-0.92, 0.05], n=15, respectively; p=0.028). Correlation analyses suggested a significant negative association between A. muciniphila fold change and both % WC change and % BMI change (r= -0.66; p<0.01 and r= -0.33; p=0.04, respectively). However, multivariate regression analysis controlling for sex and race/ethnicity showed a significant association between A. muciniphila and % WC change, but not % BMI change (R2= 0.53; p<0.01 and R2= 0.24; p=0.15). F. prausnitzii was not associated with weight-related outcomes in this sample. L. acidophilus was excluded from study analyses after subsequent qPCR trials revealed no amplification in participant samples. Overall, this was the first study to show a relationship between A. muciniphila fold change and weight-related outcomes over a period of weight gain. Specifically, A. muciniphila was strongly negatively associated with WC in this sample. Further research is needed to more accurately describe these associations and potential mechanisms associated with the shift in gut microbiota observed with weight gain. Findings from future research may be used to develop interventions for college students aiming to shift the gut microbiota to prevent weight gain. / Dissertation/Thesis / Masters Thesis Nutrition 2017

We have previously demonstrated that long-term dietary Se deficiency in old Terc-/- mice with humanized telomeres induces type-2 diabetes and exacerbates age-dependent increases in the abundance of A. muciniphila and Lachnospiraceae, which are related to obesity and metabolic syndromes. The objectives of this dissertation are: 1) to determine the minimum intake of Se required for type 2 diabetes prevention in middle-aged mice; 2) to evaluate the efficacy of A. muciniphila and R. torques (a Lachnospiraceae family member) to intervene dietary Se deficiency-induced type 2 diabetes and the underlying mechanisms; 3) to assess sex differences in the responses to dietary Se deficiency and oral gavage of such bacteria. Our results demonstrated that mice fed diets containing ≤0.10 mg Se/kg developed glucose intolerance and insulin resistance at middle-aged stage. To address objectives 2 and 3, we showed that dietary Se deficiency exacerbated type-2 diabetes-like phenotypes in males but the extent was less in females aged 7 and 13 months. Oral gavage of A. muciniphila into either antibiotics-treated or conventional mice ameliorated these phenotypes and elevated beneficial bacteria (Lactobacillus, F. prausnitzii, and Roseburia spp./E. rectale) abundance, but reduced E. coli abundance. Dietary Se deficiency decreased intestinal barrier functions and induced intestinal inflammation. In conventional mice, A. muciniphila oral gavage reversed such intestinal defects but did not affect the expression of selenoproteins. By contrast, oral gavage of R. torques did not restore dietary Se deficiency-induced type 2 diabetes-like phenotypes in female mature mice and showed opposite impacts on the change of the 4 specific genera in comparison with A. muciniphila oral gavage. Taken together, our findings demonstrate that suboptimal body Se status induces type 2 diabetes and reshapes gut microbiota in an age- and sex-dependent manner. Such metabolic defects in conventional Se-deficient mice can be alleviated by A. muciniphila but not R. torques supplement, which may counteract common intestinal defects in metabolic syndrome. In conclusion, optimal Se at nutritional level of intake is necessary to prevent type 2 diabetes. A. muciniphila is a promising supplement for alleviation of type 2 diabetes and possibly other metabolic diseases in relation to intestinal inflammation and glucose dysregulation.

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