A new study by Wang and colleagues in the journal Obesity describes a link between obesity and the risk of sepsis.

This work is important because it provides another explanation for the increase in all-cause mortality that accompanies increases in waist circumference, and also because it points toward an explanation for why we get fat in the first place.

The classic understanding is that fat represents a means of storing excess energy. In this view, fat has an adaptive function to protect against starvation during nutritional scarcity.

The immunologic role of visceral fat challenges that simplistic view. Visceral fat is immunologically active and is a site of abundant resident macrophages. Adipocytes and fat-associated white blood cells are an important source of body-wide inflammation.

Because of its role in inflammation, visceral fat is linked to many of the complications of obesity, including hypertension, atherosclerosis and diabetes.

In a parallel development, recent work has identified the gut as a source of translocating bacteria and bacterial endotoxin. These immune agonists are an important cause of visceral fat accumulation, obesity, and subsequent chronic low grade inflammation. In addition, translocation of gut bacteria has been compared to low-grade septicemia, and is thought to be a precursor to gut derived sepsis. If gut bacteria are a root cause of both sepsis and visceral fatness, then a relationship between obesity and sepsis makes sense.

Many recent studies support the concept that gut bacteria are responsible for obesity. These findings raise the possibility that visceral adiposity might have an adaptive function aimed at gut bacteria. If so, visceral fat accumulation might be an adaptation with costs and benefits. While the costs include increased risk of cardiovascular and metabolic diseases, a potential benefit of visceral fat is the capacity to mobilize immune defenses against invasive gut bacteria.

Along these lines, Hegde and Dhurandar recently wrote a review on the infection-fat link and the antimicrobial effects of fat in Clinical Microbiology and Infection:

“In addition to the immune cells of adipose tissue, evidence is emerging that even pre-adipocytes and adipocytes are likely to interact with invading microbes.“

These lines of evidence imply that fat itself is not the cause of sepsis, but constitutes a defense against invasive gut bacteria. In the Wang et al. study, in fact, only the morbidly obese had a higher risk of sepsis. That result is in line with expectations of the hypothesis that visceral fat has a host defense function. Moderate obesity, in fact, might protect against certain infections, which may explain decreased mortality among the overweight, known as the obesity paradox,

If visceral fat has a host defense function, it makes sense that its removal would not improve inflammation and might in fact increase the risk of septic death.

It is worth pointing out that the concept of a host defense function of abdominal fat is not new. In 1906, Rutherford Morison termed visceral fat in the omentum “the abdominal policeman” for its role in preventing sepsis. Morison wrote:

“Abscesses in connexion with the vermiform appendix are locked up, and pus is generally prevented from escaping into the general peritoneal cavity by the omentum.“

This observation comports with the hypothesis that the main function of visceral fat is to contain and prevent the spread of gut bacteria into sterile sites. Not only does containment occur anatomically as described by Morison, but at a microscopic level as well. Visceral fat acts as an immunological organ that provides fuel for the immune system, generates pro-inflammatory cytokine mobilization, and houses phagocytic cells that mop up bacteria that escape the gut.

If further research substantiates a host defense function of fat, it will add an adaptive lens with which to view the complex web of metabolic and inflammatory changes in obesity. Appreciating the physiologic function of fat, and the selective pressure induced by gut microbes, will be critical to discovering new ways of treating obesity and related diseases.

A key sentence in Katherine Lemon et al.’s “Microbiota-Targeted Therapies: An Ecological Perspective” jumped out at me.

Lemon et al. write:

“The host may be indifferent to which species are present, but the community’s ability to liberate nutrients from the diet and resist pathogen invasion are vital.”

They write that which members of the gut microbiota are present might be less important than their function. Lemon et al. certainly hit the nail on the head by identifying the fitness effects of the microbiota: their ability to provide energy to the host and to prevent invasive infection.

A next step in pursuing an ecological approach to the gut microbiome might be to actually measure the fitness consequences of changed microbiota in the lab and in humans.

Joe Alcock MD

Dariush Mozaffarian, a Harvard epidemiologist, has published a study on the health benefits of omega-3 fatty acid found in fish.

Eating fish is protective against atherosclerosis and stroke.

There is no discussion of microbiota in this study, but it interesting to see how human epidemiology data are in sync with studies of the effects of omega-3 fats on gut microbiota.

There is less and less mystery about what constitutes a healthy diet. Red meat, in general, shortens life spans. Processed meat may be to blame for the majority of that effect. Wild marine fish high in omega 3 fatty acids, by contrast, protects against atherosclerosis. Diets high in fish are associated with longevity.

Other processed foods high in simple sugars, are likewise associated with obesity, diabetes and chronic inflammatory diseases. Complex carbohydrates, and food rich in polyphenols by contrast prevent those diseases. The microbiota are the key to understanding these varied effects.

It is important to understand that the Paleolithic diet, which is intuitively attractive, is insufficient to explain all the health effects of these foods. In particular, the divergent inflammatory effects of fatty acids argue for an alternative viewpoint, that our immune system has evolved to recognize commonly consumed nutrients and makes adjustments depending on how those foods influence microbiota. That is the basis for the nutrient signaling model of dietary inflammation.

Joe Alcock MD

I had an interesting conversation today with Lisa Hannam, the health editor of Glow magazine, based in Toronto Canada.

I explained the nutrient signaling hypothesis, a new model for the the inflammatory effects of food. The basic idea is that foods that encourage the growth of harmful microbes are recognized by the immune system and serve an early warning (pro-inflammatory) signaling function. On the flip side: foods that inhibit the growth of harmful microbes have evolved an anti-inflammatory immune signaling function.

Lisa Hannam asked me what the take home message would be for her readers. On reflection, I realized we should redefine what “empty calories” really means. Empty calories are, of course, the absence of nutritional value in junk food.  In light of the nutrient signaling model, “empty calories” are better recognized as nothing but fuel for the growth of harmful bacteria. These foods are bad for us because they result in harmful changes to the microbiota. Many saturated fats and simple sugars fall in this category.

Healthy diets, resulting in healthy microbiota and a healthy immune system require food that counteracts the growth of harmful bugs.  “Healthy” nutrients are generally foods with antimicrobial properties; these inihbit the growth of pathogens and pathobionts (opportunistic pathogens). Antimicrobial nutrients include omega-3 fatty acids, complex carbohydrates, and polyphenols in fruits and berries.

We need anti-microbial nutrients to discourage the overgrowth of harmful bacteria. Recent evidence suggests that nutrients with antimicrobial effects can also have prebiotic effects, stimulating beneficial bacterial growth. So, the best, healthiest, foods probably have both properties: inhibition of harmful microbes and (not coincidentally) fertilizer for the growth of beneficial bacteria. We might need a new term like antimicrobial prebiotic (AMP) or probiomic to describe this dualistic beneficial effect.

So eat with an eye towards both prebiotic and antimicrobial properties in your food! Luckily, many delicious foods have these properties including chocolate, red wine, broccoli, apples, citrus, and chile and curry spices!

Bon Appetit!

Joe Alcock

R. Straub published an article entitled Evolutionary medicine and chronic inflammatory state–known and new concepts in pathophysiology last year in which he argues that chronic inflammatory diseases – responsible for the bulk of cardiovascular disease in humans – are caused by re-directed energy stores to the activated immune system. Re-allocation of energetic resources to immunity is a central part of arguments we have explored previously on this blog: for example here,  here, and here.

I should note that my co-author Ed Legrand and I have criticized part of Straub’s arguments in our 2012 paper in the Quarterly Review of Biology, Turning Up The Heat, Immune Brinksmanship in the Acute Phase Response. I will elaborate more on that this afternoon.