Antibiotics and Obesity

[Lochdale]

According to this study:
http://commonhealth.wbur.org/2012/08/study-antibiotics-in-young-infants-may-set-stage-for-childhood-obesity

There may be a correlation between giving a child an antibiotic between birth and five months and an increased risk of obesity.

Sounds, er, awful. We gave our own child antibiotics for an ear infection when he was five and a half months.

Any thoughts on the study?

[DSeid]

Interesting.

On the one hand anything that further encourages serious thought before prescribing an antibiotic for conditions that may not really need them (or parents “demanding” them") is a good thing. (Truth be told antibiotic prescriptions have already come way down in the last several years.)

OTOH this is, as noted, a correlation only. Kids who are prone to infections more may also be more prone to “overweight”. Kids who are early in daycare may be more prone to overweight and more prone to infections. Other social or class or physiologic factors may predispose to both without the antibiotics being the cause. And while alterations in the microbiome provides a plausible explanation it is becoming such a trendy field that I am becoming a bit skeptical of what may be conclusions over-reaching the data as it stands.

Still - when an antibiotic is prescribed ask if it is really needed or if watchful waiting could be tried first. Much of what kids are treated with antibiotics for can sometimes resolve without them.

[Lochdale]

Interesting analysis. My son had an ear infection that was clearly upsetting him but I do tru and err on the side of not over prescribing. Hopefully this study will be followed up on.

[Red_Stilettos]

The connection between childhood antibiotics and obesity is the gut microbiome, which is the collection of bacteria inhabiting the gut. Each person has a unique microbiome, and it changes with age and environment. The role of the microbiome in a host of diseases is a very hot research topic.

Infants are thought to acquire their starter microbiome from their parents, mostly mom. The presence of these organisms plays a very important role in gut development. Animals raised in complete sterility, so they have no microbiome, do not develop the same level of gut functioning that non-sterile animals do. We can’t do that experiment on humans, but it has been replicated in flies, mice, and pigs, so it is expected to hold for humans as well.

When we take antibiotics, we completely disrupt our microbiome. In adults, it returns to its previous state (or a very close approximation) relatively quickly. In children, it takes longer to recover. If that disturbance occurs at the right time in development, it could mimic the impact of a microbiome-free development, resulting in poor gut function. When you consider the role of hormones in coordinating gut function, metabolism, and appetite, it’s not a big leap to see how this could lead to obesity.

This is the theory underlying the cited paper. Much of the links are conjecture at this point, but all of the biological parts are intact and the links are reasonable.

If you are interested in the role of the microbiome in obesity, here are a couple of interesting reads. Try not to get too bogged down in the sequencing details. The biology is more interesting than the technology.

Comparison of microbiomes of lean versus obese twins, role of genetics

Obesity-associated microbiome in adults

Both links go to the HTML version of the articles. PDFs are available from there.

[DSeid]

Well “completely disrupt” is a bit of hyperbole, but the hypothesis is plausible. I can see the possibility that frequent early antibiotic use could disrupt the developmental balance of the microbiome. But going from a correlation of slight increased BMI with moderate antibiotic use in certain time frames and not others in the middle, to causation, is a big conjecture.

The Economist just ran a pretty accessible, if a bit breathless, bit on the microbiome last week too.

So far it makes at least as much sense to conclude that the biome follows the weight rather than the other way around. When adults lose weight by any means the biome changes some, into the “lean” type. Yet the established biome type (the enterotype) seems to be pretty stable, reflectinglongterm feeding habits.

I am also confused because of conflicting concepts that are out there, both with good evidence to support them. As discussed in the Economist article and elsewhere, the concept is that some microbiomes do a better job breaking down fiber and relatively hard to digest starches into short chain fatty acids (SCFA) like butyrate, which get absorbed and provide extra calories which lead to weight gain. But those SCFAs are good things, sending satiety signals and causing less food intake.

Which microbiome should we be aiming for if we could aim??

[DSeid]

Attempting to educate myself further on this I found a pretty detailed review that you, Red Stilettos, and perhaps others, might be interested in. Confusing but detailed.

These are early days for untangling all of this. Some points harvested from the review -

The phylum level variations with obesity are not consistently found by all groups and perhaps the better way of parsing it is look at how the grouping of functional biomarkers vary, independent of which phylum those biomarkers come from, such as producing particular communication signals and the co-colonization of bacteria which ferment (producing H2 and substrate the body uses) and methanogenic archaea which utilize the H2 allowing for greater fermentation.

That first bit is gone into in some detail - the microbiota produce compounds that have complex interactions with the host at all levels from the intestinal lining to higher gut levels to liver storage and to skeletal muscle to brain centers that regulate satiety and behaviors to control of inflammation throughout the body. Increased energy harvest is only the very tip of the iceberg in how the microbiome impacts weight, fat levels, and the impact of fat on health outcomes.

Specific to SCFAs:

The gut microbiota synthesizes a broad spectrum of hydrolases (65) that digest complex dietary carbohydrates to monosaccharides and SCFAs such as acetate, propionate, and butyrate. As end products of bacterial fermentation, these SCFAs represent an important energy source. SCFAs not only diffuse passively into the circulation, but may also act in the gut as signaling molecules. Propionate and acetate are ligands for two G protein–coupled receptors (GPCRs), Gpr41 and Gpr43, mainly expressed by intestinal epithelial cells (66, 67). Conventionally raised Gpr41–/– mice and germ-free Gpr41–/– mice colonized with only Bacteroides thetaiotaomicron and Methanobrevibacter smithii are significantly leaner than wild-type littermates despite similar levels of chow consumption, while there are no differences between wild-type or Gpr41–/– germ-free mice (68). These studies showed that Gpr41 might be a regulator of host energy balance through effects that are dependent upon the gut microbiota and their metabolic capacity (ref. 68 and Figure ​Figure1).1). Upon activation of GPCRs, propionate and acetate induce the release of peptide YY (Pyy). Pyy, an enteroendocrine cell–derived hormone that normally inhibits gut motility and accelerates intestinal transit rate, might be involved in these Gpr41-mediated effects, as Gpr41–/– mice colonized with only Bacteroides thetaiotaomicron and Methanobrevibacter smithii demonstrated increased circulating Pyy levels, an increased transit time, and reduced calorie extraction from the diet (68). Gpr41 also mediates SCFA-induced synthesis of leptin, an adipocytokine with pleiotropic effects on appetite and energy metabolism (69).

SCFAs also act as ligands of Gpr43, and Gpr43–/– mice appear protected from high-fat diet–induced obesity and insulin resistance, at least partly due to Gpr43-regulated energy expenditure (70). Moreover, stimulation of Gpr43 by SCFAs limits inflammation in experimental models of colitis, arthritis, and asthma (71). Germ-free mice, devoid of SCFAs due to the absence of bacteria that would ferment dietary fiber, exhibited exacerbated inflammation in these models, similar to Gpr43–/– mice (71). Gpr43 might provide a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses (71) and could possibly also play some role in colon carcinogenesis (72).

In summary, the gut microbiota affects host energy expenditure and metabolic and immune/inflammatory functions via several pathways. The intestinal epithelium is at the interface between environment, microbiota, and host and plays a substantial and remarkable role in all of these processes…

… Besides immune and inflammatory mechanisms, other pathways may be involved in the link between gut microbiota and metabolic syndrome. Our microbiota produces enzymes that degrade ingested polysaccharides, thereby promoting the absorption of nutrients (especially carbohydrates), resulting in increased liver lipogenesis, hepatic insulin resistance, and hyperinsulinemia. It has been demonstrated that high intake of cereal fiber is associated with reduced risk for T2D. Various dietary components including wheat fiber, inulin, oat β-glucan, or starch with high amylase content affect glucose absorption, decrease insulin secretion, increase concentrations of the incretin Glp1, and increase SCFA production and absorption (84–86). …

Early days!

[Yllaria]

This blog entry refers to a mouse study. There’s no link to the study itself, though.

[DSeid]

It links to the abstract though. It would be nice to get the detail on how the microbiomes changed from the article though.

I apologize for yammering on in this thread but this is very interesting stuff and posting helps me work through my own understanding and open it up to anyone else’s …

The review article I linked to above cites this study which compared “the gut microbiota of children aged 1–6 y living in a village of rural Africa in an environment that still resembles that of Neolithic subsistence farmers with the gut microbiota of western European children of the same age, eating the diet and living in an environment typical of the developed world.” They matched children for concordant growth parameters.

The differences between those groups are of course many, including different genetic make-ups and a host of non-diet environmental factors, but it does not seem unreasonable to focus on the higher fiber, and lower antibiotic exposure of the African children compared to the Western ones. They can reasonably be held up as more representative of the state that our microbiomes and bodies have co-evolved into prior to the modern era including but not restricted to the several decades of the obesity epidemic. Examples of Paleolithic nutrition they are not; these kids eat little animal protein, much less than the European children studied, who “were eating a typical western diet high in animal protein, sugar, starch, and fat and low in fiber.” The EU children were also eating many more calories per day.

Firmicutes are twice as abundant in the EU children as evidenced by the different ratio between Firmicutes and Bacteroidetes (F/B ratio ± SD, 2.8 ± 0.06 in EU and 0.47 ± 0.05 in BF), suggesting a dramatically different bacterial colonization of the human gut in the two populations. Interestingly, Prevotella, Xylanibacter (Bacteroidetes) and Treponema (Spirochaetes) are present exclusively in BF children microbiota (Figs. 2 A and B, Fig. S2, and Table S5). We can hypothesize that among the environmental factors separating the two populations (diet, sanitation, hygiene, geography, and climate) the presence of these three genera could be a consequence of high fiber intake, maximizing metabolic energy extraction from ingested plant polysaccharides. … The ratio of Firmicutes to Bacteroidetes differs in obese and lean humans, and this proportion decreases with weight loss on low-calorie diet (9). …

… Whole grains are concentrated sources of dietary fiber, resistant starch, and oligosaccharides, as well as carbohydrates that escape digestion in the small intestine and are fermented in the gut, producing short-chain fatty acids (SCFAs). Xylanibacter, Prevotella, Butyrivibrio, and Treponema are exclusive to the BF children (Fig. S2) and indicate the presence of a bacterial community using xylane, xylose, and carboxymethylcellulose to produce high levels of SCFAs (18) whose protective role against gut inflammation has been well proven (19). These bacteria can ferment both xylan and cellulose through carbohydrate-active enzymes such as xylanase, carboxymethylcellulase, and endoglucanase (http://www.cazy.org).

Other SCFA-producing bacteria, such as Bacteroides and Faecalibacterium species, particularly F. prausnitzii (Table S5), found in both populations, could generally indicate the importance of maintaining a microflora with potentially anti-inflammatory capability (20). … in BF children we found a significantly higher amount of total SCFAs compared with EU children (one-tailed Student t test, P = 4.5 × 10−4; Fig. 3A). In particular, propionic and butyric acids are nearly four times more abundant in BF than in EU fecal samples … Previous analyses on the physiological significance of SCFA (24) showed how SCFA are rapidly absorbed from the colon. Therefore, an abundance of SCFA in the feces indicates production of SCFA from microflora at levels far above the absorption rate. …

… We can hypothesize that the reduction in richness we observe in EU compared with BF children, could indicate how the consumption of sugar, animal fat, and calorie-dense foods in industrialized countries is rapidly limiting the adaptive potential of the microbiota. This microbial simplification harbors the risk of depriving our microbial gene pool of potentially useful environmental gene reservoirs …

Put this together - we co-evolved with diverse microbiomes which could adapt to a wide variety of available nutritional patterns. They have throughout our evolutionary history thrived by helping us thrive, helping us harvest more energy from our food (which typically was much more high fiber than is the modern Western diet) with our bodies in turn co-evolving. The result was a non-linear interplay of satiety signals from SCFAs, signals that helps coordinate effective energy storage, and ones that decrease inflammation. Different genomes have likely different means to deal with these signals.

Our modern environment is however very different. Our diets trigger inflammation (peripherally and in brain). Our gut diversity is significantly less, both as a consequence of the modern diet, likely from the op posited antibiotic exposures altering microbiomes’ developmental trajectories, and those changes have the potential to amplify upon each other and even more so, intergenerationally.

Yeah, I buy it.