The Gut Microbiota and Obesity

Written By David Piccinati

Much credit and appreciation to Davis et al for their excellent article from which I have pulled much from for this post [2].

I feel like everybody is talking about the gut microbiome these days. I have seen posts and non-scholarly articles touting the benefit of this or that probiotic, prebiotic, synbiotics, fecal transplants (it’s a real thing), etc etc etc. There are posts claiming taking the right probiotic can cure every malady out there from diarrhea to cancer to Alzheimer’s.

Unfortunately, most of these claims are based on very shaky data (animal data, small numbers, not randomized or controlled, high dropout rate, sketchy statistics) or, worse, no data at all. In this post I want to talk specifically about the quality data out there on the microbiome and obesity. Keep in mind, I am talking specifically about the gut microbiome and its relationship to obesity.

 SUPER BRIEF SUMMARY

Like many things in medicine there is a lot of “it depends” and “it’s complicated” when it comes to this topic. Unfortunately, the data is all over the place and it is difficult to do large systematic reviews and meta-analysis given the heterogeneity of the data. I would take any recommendation with a large grain of salt (figuratively of course) as most claims are likely exaggerated at best. I will not be routinely recommending probiotics to my patients aside from some specific cases.

THE WHOLE TALK

Did you know there are more microbes in and on your body than actual human cells? The microbes are definitely winning when it comes to sheer numbers. The human gut microbiota consists of up to 100 trillion microbes and possesses at least 100 times more genes (the microbiome) than are present in the entire human genome [1]. “These microbes serve a number of important functions including: producing additional energy otherwise inaccessible to the host by breaking down soluble fiber; producing vitamins such as biotin, folate and vitamin K; metabolizing xenobiotics such as the inactivation of heterocyclic amines formed in meat during cooking; preventing colonization by pathogens; and assisting in the development of a mature immune system” [2].

Now, it seems, the bulk of research is attempting to find causal links outside of the local effects of the micro-organism. Yes, a bacteria can digest a specific sugar so our gut can absorb it, BUT, does this bacteria’s sheer presence and function affect the rest of human physiology outside of the gut as well?

 

Some of the first data establishing a potential link between gut microbiota and obesity involved comparing germ free mice to normal mice. A mouse raised in a sterile environment with no gut bacteria will have 40% lower body fat compared to conventionally reared mice. If you then transplant the colonic bacteria from the conventional mouse to the germ-free mouse it will have a 60% increase in body fat. In both phases (pre and post transplant) the food intake was the same between both groups [3].

 

So, it would seem, having no gut bacteria is potentially protective against obesity.  However, that is not a realistic option as it is basically impossible to have no exposure to bacteria in our lives. Perhaps it is the relative amount of different bacterial classes that exert an effect. There are two families of bacteria that make up the bulk of our intestinal microbiota: Firmicutes and Bacteroidetes. There has been abundant research, in both animal and human models, that has demonstrated obese individuals and individuals fed a high fat / high sugar diet (read “Western diet”) have an increased ratio or Firmicutes to Bacteroidetes [6,7,8,9,10.11]. It would seem perhaps the goal could be to increase the Bacteroidetes / Firmicutes ratio.

However, now we start to run into a chicken / egg problem. Does our microbiota effect our risk of obesity or does an obesogenic diet change the microbiota. A 2015 study attempting to decipher if genetics or diet had a greater role in gut microbiota found that eating a high-fat, high-sugar diet consistently and significantly altered the ratio of Bacteroidetes to Firmicutes. This effect was found regardless of the mouse genotype [5]. Although we can’t change our genes, these studies would suggest we can exert an effect on the composition and our microbiota.

BUT…DOES IT MAKE A DIFFERENCE???

The real question is, does altering our microbiota actually have an effect on obesity and weight gain/loss? Or, as is often the case, are there other confounders that are the true driving influencer (such as socioeconomic status, variety of diet, quality of diet, smoking, alcohol consumption, etc.). Although interesting, does all of this research just demonstrate correlations without clinical, patient oriented, significance?

Let’s start with PREBIOTICS

In brief, a prebiotic is almost any non-digestible food product that can be fermented by bacteria and is believed to exert a positive effect on the host’s physiology. The majority of these are oligosaccharides (complex sugars). Some of the most common prebiotics you’ll find on the shelf are inulin, lactulose, resistant starches and other oligosaccharides [12]. It has been demonstrated that taking in prebiotics can alter the gut microflora [13,14]. Also, as stated above, altering the ratios of the gut microflora can have a significant correlation to obesity. This suggests a potential benefit of prebiotics if the desired microbes are encouraged to thrive compared to those less desirable groups. However, much more research is needed to assess if there is a clinically significant impact to these interventions.

Now let’s talk PROBIOTICS

 

Probiotics is defined by the World Health Organization as “live microoganisms which when administered in adequate amounts, confer a health benefit on the host.” Most probiotics on the market these days include the following (or some combination of): lactobacilli, streptococci, bifidobacterial, Saccharomyces boulardii. In my view, the first question is if the ingested probiotic actually sticks around in the gut. It seems that the probiotics we take do not actually colonize the gut and only seem to stick around while one is taking the supplement. [15] Furthermore, short term interventions do not have a prolonged effect and the gut microflora will regress to the pre-intervention state [21].

Regardless, there has been some pretty convincing animal data. Daily administration of Saccharomyces boulardii changed the gut microflora. Specifically there was an increase in Bacteroidetes and decrease in Firmicutes. Additionally, there was a reported decrease in mouse body fat and circulating inflammatory markers [16].

Unfortunately, the human data is not as consistent or reproducible. One study observed a decrease in body mass gain and fat accumulation in normal weight healthy men given Saccharomyces boulardii and a high fat hypercaloric diet compared to placebo [17]. Another trial demonstrated a significant reduction in abdominal visceral fat in humans given Lactobacillus gasseri over a 12 week period [18]. Unfortunately, it doesn’t seem like probiotics will be the holy grail to prevent obesity. A meta-analysis (combining the results of multiple studies) demonstrated the same Lactobacillus probiotic may promote weight gain in undernourished individuals but it may also reduce weight gain in the obese subject [19].

However, there does appear to be a significant increase in Firmicutes and decreased microbial diversity in obese individuals. Once again, it is difficult to say if these is a risk factor for obesity, or if an obesogenic diet leads to these observed differences in observed gut flora [22,24].

As an example, Wastyk et.al. demonstrated that a diet high in plant based fiber and fermented foods increased microbiome diversity and decreased some markers of inflammation [23]. There are a lot of limitations to this study, mostly there were only 18 participants per a study arm, but this supports that dietary modifications may be the driving factor in the microbiome and patient outcomes.

 DISCUSSION

At this time, this doesn’t mean prebiotics and/or probiotics are necessarily good or bad when it comes to obesity. Like many things in human research we just need more data. A larger and more recent meta analysis by López-Moreno et al came to a similar conclusion: “Net beneficial trends could be interpreted from the meta-analysis, beyond the difficulties faced in aligning the heterogeneous data. Microbiota positive modulation capacity by probiotics seemed to be correlated with BMI and lipid biomarkers. However, due to the small number of studies that investigated the effects of probiotics in relation to the microbiota, it was unclear if they correlate with all the other glycemic, inflammation, and gut hormone parameters.” [25]

So, be wary when a product makes big claims as they are likely not actually supported by solid data. A manufacturer can pick and choose what data they use to support their product while specifically withholding any contradictory data. A future direction might include analyzing a patient’s microbiota and using that data to tailor a diet plan. For example, knowing an individual’s microbiota may be able to predict dietary energy availability and help formulate a specific dietary program [20].

All this being said, am I going to recommend probiotics to my patients? Probably not as standard practice. Although there does seem to be some signal toward benefit in patients suffering from obesity, at the moment the data is very heterogeneous and there seems to be minimal (if any) patient oriented impact. I wouldn’t talk a patient out of using a probiotic, but I’m definitely not focusing their time/energy/money on this intervention when others have a demonstrably greater impact.

 

SOURCES

1.       Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010; 464:59–65. [PubMed: 20203603]

2.       Davis, “The Gut Microbiome and Its Role in Obesity.” NutrToday. 2016 ; 51(4): 167–174. doi:10.1097/NT.0000000000000167.

3.       Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci USA. 2004; 101:15718–15723. [PubMed: 15505215]

4.       Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444:1027–1031. [PubMed: 17183312]

5.       Carmody RN, Gerber GK, Luevano JM Jr. et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe. 2015; 17:72–84. [PubMed: 25532804]

6.       Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013; 34:124124.

7.       Jumpertz R, Le DS, Turnbaugh PJ, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am. J. Clin. Nutr. 2011; 94:58–65. [PubMed: 21543530]

8.       Duncan SH, Lobley GE, Holtrop G, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int. J. Obes. 2008; 32:1720–1724.

9.       Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008; 3:213–223. [PubMed: 18407065]

10.   Turnbaugh PJ, Ridaura VK, Faith JJ, et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 2009; 1:6ra14.

11.   Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011; 334:105–108. [PubMed: 21885731]

12.   Lim CC, Ferguson LR, Tannock GW. Dietary fibres as “prebiotics”: implications for colorectal cancer. Mol. Nutr. Food Res. 2005; 49:609–619. [PubMed: 15864790]

13.   Gostner A, Blaut M, Schaffer V, et al. Effect of isomalt consumption on faecal microflora and colonic metabolism in healthy volunteers. Br. J. Nutr. 2006; 95:40–50. [PubMed: 16441915]

14.   Ramirez-Farias C, Slezak K, Fuller Z, et al. Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzil. Br. J. Nutr. 2008; 1:1–10.

15.   Corthesy B, Gaskins HR, Mercenier A. Cross-talk between probiotic bacteria and the host immune system. J. Nutr. 2007; 137:781s–790s. [PubMed: 17311975]

16.   Osterberg KL, Boutagy NE, McMillan RP, et al. Probiotic supplementation attenuates increases in body mass and fat mass during high-fat diet in healthy young adults. Obesity. 2015; 23:23642370. /. [PubMed: 26466123]

17.   Everard A, Matamoros S, Geurts L, et al. Saccharomyces boulardii administration changes gut microbiota and reduces hepatic steatosis, low-grade inflammation, and fat mass in obese and type 2 diabetic db/db mice. MBio. 2014; 5:e01011–01014. [PubMed: 24917595]

18.   Kadooka Y, Sato M, Ogawa A, et al. Effect of Lactobacillus gasseri SBT2055 in fermented milk on abdominal adiposity in adults in a randomized controlled trial. Br. J. Nutr. 2013; 110:1696–1703. [PubMed: 23614897]

19.   Million M, Angelakis E, Paul M, et al. Comparative meta-analysis of the effect of Lactobacillus species on weight gain in humans and animals. Microb. Pathog. 2012; 53:100–108. [PubMed: 22634320]

20.   Zeevi D, Korem T, Zmora N, et al. Personalized nutrition by prediction of glycemic responses. Cell. 2015; 163:1079–1094. [PubMed: 26590418]

21.   Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–108. doi:10.1126/science.1208344.

22. Pinart, Mariona, Andreas Dötsch, Kristina Schlicht, Matthias Laudes, Jildau Bouwman, Sofia K. Forslund, Tobias Pischon, and Katharina Nimptsch. “Gut Microbiome Composition in Obese and Non-Obese Persons: A Systematic Review and Meta-Analysis.” Nutrients 14, no. 1 (January 2022): 12. https://doi.org/10.3390/nu14010012.

23. Wastyk, Hannah C., Gabriela K. Fragiadakis, Dalia Perelman, Dylan Dahan, Bryan D. Merrill, Feiqiao B. Yu, Madeline Topf, et al. “Gut-Microbiota-Targeted Diets Modulate Human Immune Status.” Cell 184, no. 16 (August 2021): 4137-4153.e14. https://doi.org/10.1016/j.cell.2021.06.019.

24. Le Chatelier, Emmanuelle, Trine Nielsen, Junjie Qin, Edi Prifti, Falk Hildebrand, Gwen Falony, Mathieu Almeida, et al. “Richness of Human Gut Microbiome Correlates with Metabolic Markers.” Nature 500, no. 7464 (August 2013): 541–46. https://doi.org/10.1038/nature12506.

25. López-Moreno, Ana, Antonio Suárez, Camila Avanzi, Mercedes Monteoliva-Sánchez, and Margarita Aguilera. “Probiotic Strains and Intervention Total Doses for Modulating Obesity-Related Microbiota Dysbiosis: A Systematic Review and Meta-Analysis.” Nutrients 12, no. 7 (June 29, 2020): 1921. https://doi.org/10.3390/nu12071921.

David Piccinati
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