Skylar Steinberg
Sabine Hazan

Skylar Steinberg, BS, Health Promotion and Disease Prevention, Research Assistant, Ventura Clinical Trials Sabine Hazan, MD, Gastroenterology/Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Ventura, CA

Probiotics have grown in popularity in recent years, marketed as a healthy dietary supplement and placed in popular foods such as yogurt, kombucha, kimchi and more. In 2014, Sales of probiotics in the United States exceeded more than $1 billion, constituting a $25 billion market worldwide. Display footnote number: 1 The media and proclaimed health magazines have been quick to push the consumption of these products into our everyday lifestyle and diet. However, there is some confusion on the background and potential risks involved with an increased intake of probiotics that needs to be addressed. Furthermore, “probiotic,” has become increasingly misused, with many companies exploiting the term’s popularity without meeting the requisite criteria.

Probiotic is a general term for live, nonpathogenic microorganisms, many of which exist in a symbiotic relationship within the normal human gut flora. Display footnote number: 1 They have been used to treat Gastrointestinal (GI) and non-GI medical conditions, but data demonstrating their effectiveness has been conflicting. The Federal Drug Administration also views probiotics as a health food, not a drug, and does not regulate these products. Display footnote number: 1 One major issue is the fact that selection and dosing vary among products and the specific, beneficial effects of each probiotic strain cannot be generalized. Display footnote number: 1 Not all species of probiotics are a part of the normal human gut bacteria and the benefits associated with one strand cannot be generalized to others. Display footnote number: 1 Therefore, not all brands should promise equal effectivity and choosing a probiotic can be incredibly confusing and potentially harmful, Display footnote number: 1 especially in immunosuppressed individuals or critically ill patients. For example, two cases of Lactobacillus Bacteremia during probiotic treatment of short gut syndrome have been discovered demonstrating that probiotics may not be as benign a treatment as generally thought. Display footnote number: 2 Yet, as a result of media and marketing, most consumers now believe that probiotics are key to helping remedy a variety of health issues, keeping the demand for these products high. Display footnote number: 1

Evidence has shown, however, that probiotics have been beneficial for the treatment of acute diarrhea, pouchitis, atopic eczema, and some genitourinary infections. Display footnote number: 1 A 2010 analysis of 63 studies, totaling 8014 participants, concluded that probiotics helped decrease the duration and severity of acute infectious diarrhea. Display footnote number: 3 In fact, Irritable Bowel Syndrome (IBS) is one of the most common reasons that probiotics are consumed in clinical practice and also one of the most commonly studied with over 80 clinical trials of probiotics for IBS. The main reason for use of probiotics for both IBS constipation or IBS diarrhea is lack of pharmacologic treatment options. Display footnote number: 4

There has been no evidence or even weak evidence that probiotics help in conditions of Crohn’s disease or ulcerative colitis. Display footnote number: 5,6,7 In fact, Rolfe et. al. in 2006 showed that out of 160 participants with Crohn’s disease, probiotics were not superior to a placebo or aminosalicylates for the maintenance of remission in patients. Display footnote number: 8 In 2007, Lirussi et al. conducted further studies on liver disease that showed no benefit or harm from probiotics in patients with end-stage liver disease. Display footnote number: 9 However, Xu and al. showed probiotics “significantly reduced the development of overt hepatic encephalopathy” in patients with liver cirrhosis. Display footnote number: 10

With regards to metabolic diseases, probiotics have shown to significantly decrease plasma glucose and glycosylated hemoglobin. However, there is no agreement that they reduce blood insulin levels in diabetes patients. Display footnote number: 11,12,13,14,15 For patients with cardiovascular and cholesterol conditions, studies found that probiotics decreased LDL, but did not raise HDL. Although Cho and Kim, like several others, emphasized, “both the efficacy of probiotics for cholesterol lowering and safety should be investigated further in well-designed clinical trials.” Display footnote number: 16,17,18,19

When looking at the role of probiotics in GI infections like Helicobacter pylori and Clostridium difficile, the data has been controversial. Chao et al. in 2016 showed that probiotics, plus standard therapy, did not improve the eradication rate of H. pylori compared to placebo, however, probiotics did improve the side effects of diarrhea and nausea from the antibiotics. Display footnote number: 20 When given with antibiotics, probiotics did decrease the risk of developing CDAD by 64%. Display footnote number: 21

There is also inadequate evidence recommending probiotics for respiratory tract infection, Display footnote number: 22 Bacterial vaginosis, Display footnote number: 23,24 UTI, Display footnote number: 25 or chronic periodontitis. Display footnote number: 26

Overlooking the literature, it is evident that some effects of probiotics are well-documented, and their use alone or in combination with other therapies can be considered “evidence-based,” such as antibiotic-associated diarrhea, and C. diffassociated diarrhea, and yield positive results. In other conditions, however, further studies are crucial to determine the benefits of probiotics, because the available evidence is insufficient to show the efficacy of probiotics themselves and the studies included a wide swath of participants with varying degrees of ailments. Careful trials are needed to validate the effects of particular strains of probiotics given at specific dosages and for specific durations Display footnote number: 27 but more importantly, probiotics need to be specific to the individual because, clearly, microbiome profiling has demonstrated speciesspecific patterns. Display footnote number: 28,29

References

1. Saif Ul Islam, MD, RPh. Clinical Uses of Probiotics. Medicine: Volume 95, Number 5, February 2016. 1-5
2. Kunz, Anjali N., Noel, James M., Fairchok, Mary P. Two cases of Lactobacillus Bacteremia during Probiotic Treatment of Short Gut Syndrome. J of Pediatric Gastroenterology and Nutrition: April 2004-Volume 38- Issue 4.457-458.
3. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev; 2010:CD003048.
4. Elizabeth A Parker Ph.D., RD, Tina Roy B.S., Christopher R. D’Adamo Phd., L. Susan Wieland Ph.D. Probiotics and Gastrointestinal conditions: An overview of evidence from the Cochrane Collaboration: Nutrition 45 (2018) 125-134.
5. Doherty G, Bennett G, Patil S, Cheifetz A, Moss AC. Interventions for prevention of post-operative recurrence of Crohn’s disease. Cochrane Database Syst Rev; 2009:CD006873.
6. Naidoo K, Gordon M, Fagbemi AO, Thomas AG, Akobeng AK. Probiotics for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev; Dec. 7, 2011:CD007443.
7. Mallon P, McKay D, Kirk S, Gardiner K. Probiotics for induction of remission in ulcerative colitis. Cochrane Database Syst Rev; Oct. 17, 2007:CD005573.
8. Rolfe VE, Fortun PJ, Hawkey CJ, Bath-Hextall F. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev; Oct. 18, 2006:CD004826.
9. Lirussi F, Mastropasqua E, Orando S, Orlando R. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev; Jan. 24, 2007:CD005165.
10. Xu J, Ma R, Chen LF, Zhao LJ, Chen K, Zhang RB. Effects of probiotic therapy on hepatic encephalopathy in patients with liver cirrhosis: An updated meta-analysis of six randomized controlled trials. Hepatobiliary Pancreat Dis Int Aug. 13, 2014; 13:354-60
11. Zhang Q, Wu Y, Fei X. Effect of probiotics on glucose metabolism in patients with type 2 diabetes mellitus: A metaanalysis of randomized controlled trials. Medicina (Kaunas) 2016; 52:28-34; PMID:26987497
12. Samah S, Ramasamy K, Lim SM, Neoh CF. Probiotics for the management of type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract August 2016; 118:172-82;
13. Kasinska MA, Drzewoski J. Effectiveness of probiotics in type 2 diabetes: A meta-analysis. Pol Arch Med Wewn 2015; 125:803-13; PMID:26431318
14. Ruan Y, Sun J, He J, Chen F, Chen R, Chen H. Effect of probiotics on glycemic control: A systematic review and meta-analysis of randomized, controlled trials. PLoS One Jul. 10, 2015; 10:e0132121; PMID:26161741
15. Sun J, Buys NJ. Glucose- and glycaemic factor-lowering effects of probiotics on diabetes: A meta-analysis of randomised placebo-controlled trials. Br J Nutr April 14, 2016; 115:1167- 77
16. Shimizu M, Hashiguchi M, Shiga T, Tamura HO, Mochizuki M. Meta-analysis: Effects of probiotic supplementation on lipid profiles in normal to mildly hypercholesterolemic individuals. PLoS One Oct. 16, 2015; 10: e0139795; PMID:26473340
17. Sun J, Buys N. Effects of probiotics consumption on lowering lipids and CVD risk factors: A systematic review and meta-analysis of randomized controlled trials. Ann Med 2015; 47:430-40
18. Guo Z, Liu XM, Zhang QX, Shen Z, Tian FW, Zhang H, Sun ZH, Zhang HP, Chen W. Influence of consumption of probiotics on the plasma lipid profile: A meta-analysis of randomised controlled trials. Nutr Metab Cardiovasc Dis Nov. 21, 2011; 21:844-50
19. Cho YA, Kim J. Effect of probiotics on blood lipid concentrations: A meta-analysis of randomized controlled trials. Medicine (Baltimore) Oct. 2015; 94:e1714; PMID:26512560
20. Chao L, Jianzhong S, Haijian H, Xingyong W, Yiming L, Lan L, Youming L, Chaohui Y. Probiotic supplementation does not improve eradication rate of Helicobacter pylori infection compared to placebo based on standard therapy: A meta-analysis. Sci Rep 2016; 6:23522; PMID:26997149
21. Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev May 31, 2013; CD006095; PMID:23728658
22. Gu WJ, Wei CY, Yin RX. Lack of efficacy of probiotics in preventing ventilator-associated pneumonia probiotics for ventilator-associated pneumonia: A systematic review and meta-analysis of randomized controlled trials. Chest 2012; 142:859-68; PMID:22797719
23. Huang H, Song L, Zhao W. Effects of probiotics for the treatment of bacterial vaginosis in adult women: A meta- analysis of randomized clinical trials. Arch Gynecol Obstet June 2014; 289:1225-34
24. Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotics for the treatment of bacterial vaginosis. Cochrane Database Syst Rev Oct. 7, 2009; CD006289; PMID:19821358
25. Schwenger EM, Tejani AM, Loewen PS Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev Dec. 23, 2015; CD008772; PMID:26695595
26. Martin-Cabezas R, Davideau JL, Tenenbaum H, Huck O. Clinical efficacy of probiotics as an adjunctive therapy to non-surgical periodontal treatment of chronic periodontitis: A systematic review and meta-analysis. J Clin Periodontol June 2016; 43:520-30
27. Mariangela Rondanelli, Milena Anna Faliva, Simone Perna, Attilio Giacosa, Gabriella Peroni, and Anna Maria Castellazzi. Using probiotics in clinical practice: Where are we now? A review of existing meta-analyses. Gut Microbes 2017, VOL. 8, NO. 6, 521–543.
28. McCord, A.I. et al. Fecal microbiomes of non-human primates in Western Uganda reveal species-specific communities largely resistant to habitat perturbation. Am. J. Primatol. 76, 347–354 Jul. 15, 2014.
29. Amato, K.R. et al. Variable responses of human and non-human primate gut microbiomes to a Western diet. Microbiome 3, 53 Nov. 2015.

The Microbiome and Obesity

The Microbiome And Disease, Series #3

Sabine Hazan

Skylar Steinberg

Sabine Hazan, MD, Gastroenterology/Hepatology/ Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Skylar Steinberg, BS, Health Promotion and Disease Prevention, Research Assistant, Ventura Clinical Trials, Ventura, CA

In 2016, the World Health Organization (WHO) estimated that, globally, over 1.9 billion adults and 340 million children and adolescents (between the ages of 5 and 19 years), were overweight or obese. Since 1975, the worldwide prevalence of obesity has tripled, and, currently, the majority of the world’s population lives in countries where being overweight or obese kills more than being underweight.21 An increased body mass index (BMI) is a risk factor for cardiovascular disease, musculoskeletal disorders, diabetes, and a number of malignancies, including endometrial, breast, ovarian, prostate, liver, gallbladder, kidney, and colon cancers.21 Traditional weight loss therapies have proven largely ineffective, and given the dire consequences of obesity on general health, the development of better treatment modalities has become a scientific imperative. There is a growing body of research suggesting that obesity, metabolic syndrome, and insulin resistance are associated with predictable phyla and gene level compositional changes in the intestinal microbiome of humans and mice; 8,9 with a better understanding of these changes, we can develop new, robust therapeutic strategies. In this article, we will briefly discuss some of the definitive research related to the microbiome and its impact on obesity and other metabolic derangements.

Contemporary, culture-independent techniques for microbial DNA sequencing have identified four dominant bacterial phyla which reside in the mammalian gut.17 They are the Gram-negative Bacteroidetes and Proteobacteria and the Grampositive Actinobacteria and Firmicutes.17 In two foundational studies, one by Ley et al. and another by Turnbaugh et al., researchers used 16S rRNA gene sequencing to demonstrate that the microbial composition of the distal gut of leptin-deficient ob/ob mice was reduced in Bacteroidetes and enriched in Firmicutes when compared to their lean ob/+ and wild-type siblings, despite being fed the same diet.15,17,19 In subsequent research, Ley et al. corroborated the findings in the murine studies, observing a similar increase in the Firmicute/Bacteroidetes ratio in obese humans.13,14,18 However, other researchers have not noted the same pattern of colonization and more recent literature stresses biomarker composition and host-microbe genetics over phyla level profiles.10,16

One way by which the microbiome affects body weight is through its link to fat storage and energy extraction. For example, Flint et al. showed that the gut microbiota enables energy extraction from otherwise indigestible polysaccharides.12 Backhed et al. demonstrated that germ-free mice, once conventionalized, exhibited increased triglyceride content in their livers and adipose tissue, as well as increased luminal monosaccharide uptake.4 They hypothesized that this change was due to the microbial modulation of Fiaf, also known as angiopoietin-like protein 4, and its inhibitory effect on lipoprotein lipase (LPL). LPL is an enzyme that increases cellular uptake of fatty acids. During feeding, Fiaf is induced in germfree mice; however, in conventionalized mice, it is functionally suppressed.1,4 Years later, Backhed et al. shed light on another possible mechanism of microbe-mediated energy capture. They identified Ampk as a “fuel gauge” enzyme and found that the phosphorylated form was increased in the skeletal muscle of lean, germ-free mice.3,17 Yet another pathway of the microbiome’s influence on host metabolism is through its production of hydrolases, which digest carbohydrates to short-chain fatty acids (SCFA). SCFAs like acetate and propionate are not only energy sources, but also interact with G protein-coupled receptors in the gut, altering motility and affecting inflammatory pathways.15,17

In addition to the direct effects on host metabolism, it has been proposed that the microbiota composition may cause low-grade, systemic inflammation and play a role in the development of insulin resistance.1,7 Researchers have determined that lipopolysaccharide (LPS), a proinflammatory molecule, derived from Gram-negative bacteria in the mammalian microbiome is increased in the plasma of mice on a high-fat diet; this has also been observed in human studies.1,7 Furthermore, it has been noted that the gut permeability of obese mice is increased secondary to expressional changes in tight-junction proteins. This, coupled with increased LPS production, elucidates a possible pathway to the generalized inflammation associated with metabolic diseases.1,5,6,7 From a microbial ecology perspective, there has been an association of diabetic patients with a core microbiota rich in Proteobacteria.1 Vrieze et al. found that the introduction of intestinal microbes from lean donors resulted in temporary improvements in insulin sensitivity in patients with metabolic syndrome.1,20 This would lead one to think that fecal microbiota transplantation (FMT) is not a modality restricted to the treatment of C. difficile infection, but could possibly be used to treat obese and/or diabetic patients as well. As we discuss various biomarker-disease associations, it is appropriate to point to a microbiome classification paradigm associated with microbiota composition and biomarker levels. Arumugam et al. found that three energy-modulating molecules correlate with a host’s BMI, which may mean that there are common microbiome compositions associated with various disease states; this would potentially enable intervention through diet, pre- and probiotics, and medication.1,2 Lastly, more recent literature has highlighted the interaction between host genes and the microbiome, noting the relationship between leptin (“the satiety hormone”) and commensal bacterial populations, the declines and rises in various bacteria associated with the apolipoprotein A1 gene, and the phospholipase D1 gene, which may offer insight into host genotypic effects on microbiome.11

Obviously, there is a strong body of science linking obesity and other metabolic disease states to changes in the gut microbiome; however, our understanding of the relationship between microbe and host must continue to be refined. Expanding research and interest in the human microbiome could lead to improved treatment strategies for obesity and its long list of comorbidities. With the increasing complexity of the microbe-host relationship, new ground must be broken with new ideas.

References

1. Amandine, E. aßd Patrice D. Cani. “Diabetes, obesity and gut microbiota.” Best Practice and Research Clinical Gastroenterology, vol 27, no. 1, 2013, pp. 73-83., doi: 10.1016/j.bpg.2013.03.007.
2. Arumugam, M., et al. “Enterotypes of the human gut microbiome.” Nature, vol 473, 2011, pp. 174-180., doi: 10.1038/nature09944.
3. Blackhed, F., et al. “Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.” Proceedings of the National Academy of Sciences of the United States of America, vol 104, no. 3, 2007, pp. 979-984., doi: 10.1073/pnas.0605374104.
4. Backhed, F. et al. “The gut microbiota as an environmental factor that regulates fat storage.” Proceedings of the National Academy of Sciences of the United States of America, vol 101, no. 44, 2004, pp. 15718-23., doi: 10.1073/pnas.0407076101.
5. Cani, P.D., et al. “Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.” Gut, vol 58, no. 8, 2009, pp. 1091-103., doi: 10.1136/gut.2008.165886.
6. Cani, P.D., et al. “Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat dietinduced obesity and diabetes in mice.” Diabetes, vol 57, no. 6, 2008, pp. 1470-81., doi: 10.2337/db07-1403.
7. Cani, P.D., et al. “Metabolic endotoxemia initiates obesity and insulin resistance.” Diabetes, vol 56, no. 7, 2007, pp. 1761-72., doi: 10.2337/db06-1491.
8. Chen, J., et al. “Diet effects in gut microbiome and obesity.” Journal of Food Science, vol 79, no. 4, 2014, pp. R442-51., doi: 10.1111/1750-3841.12397.
9. Devaraj, S., et al. “The human gut microbiome and body metabolism: implications for obesity and diabetes.” Clinical Chemistry, vol 59, no. 4, 2013, pp. 617-28., doi: 10.1373/clinchem.2012.187617.
10. Duncan, S.H., et al. “Human colonic microbiota associated with diet, obesity and weight loss.” International Journal of Obesity (London), vol 32, no. 11, 2008, pp. 1720-24., doi: 10.1038/ijo.2008.155.
11. Duranti, S., et al. “Obesity and microbiota: an example of an intricate relationship.” Genes and Nutrition, vol 12, no. 18., doi: 10.1186/s12263-017-0566-2.
12. Flint, H.J., et al. “Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis.” Nature Reviews Microbiology, vol 6, no. 2, 2008, pp. 121-131., doi: 0.1038/nrmicro1817.
13. Ley, R.E., et al. “Microbial ecology: human gut microbes associated with obesity.” Nature, vol 444, no. 7122, 2006, pp. 1022-23., doi: 10.1038/441022a.
14. Ley, R.E. et al. “Obesity alters gut microbial ecology.” Proceedings of the National Academy of Sciences of the United States of America, vol 102, no. 31, 2005, pp. 11070-5., doi: 10.1073/pnas.0504978102.
15. Samuel, B.S., et al. “Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.” Proceedings of the National Academy of Sciences of the United States of America, vol 105, no. 43, 2008, pp. 16767-72., doi: 10.1073/pnas.0808567105.
16. Schwiertz, A., et al. “Microbiota and SCFA in lean and overweight healthy subjects.” Obesity (Silver Spring), vol 18, no. 1, 2010, pp. 190-195., doi: 10.1038/oby.2009.167.
17. Tilg, H. and Arthur Kaser. “Gut microbiome, obesity, and metabolic dysfunction.” Journal of Clinical Investigation, vol 121, no. 6, 2011, pp. 2126-32., doi: 10.1172/JCI58109.
18. Turnbaugh, P.J., et al. “A core gut microbiome in obese and lean twins.” Nature, vol 457, no. 7228, 2009, pp. 480-84., doi: 10.1038/nature07540.
19. Turnbaugh, P.J., et al. “An obesity-associated gut microbiome with increased capacity for energy harvest.” Nature, vol 444, no. 7122, 2006, pp. 1027-31., doi: 10.1038/nature05414.
20. Vrieze, A., et al. “Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.” Gastroenterology, vol 143, no. 4, 2012, pp. 913-6.e917., doi: 10.1053/j.gastro.2012.06.031.
21. World Health Organization. “Obesity and Overweight.” http://www.who.int/mediacentre/factsheets/fs311/en/


Copyright © 2019 Skylar Steinberg