Anti-Inflammatory Nutrition Summary

Introduction

Inflammation can be a double-edged sword. It allows us to defend ourselves against microbial invasion and allows our injuries to heal. Yet, on the other hand, if the inflammatory response is not sufficiently resolved, the resulting chronic low-level inflammation can attack our organs, accelerating the early development of chronic disease [1]. Maintaining inflammation in a zone that is not too low, but not too high is one of the key factors for successful aging due to the reduction of early onset chronic disease. However, in addition to microbial invasion or physical injuries, we now understand that our diet can also activate as well as resolve our internal inflammatory responses.

Diets can be either pro-inflammatory or anti-inflammatory depending on the hormonal responses they generate. This is because these hormonal responses as well as specific nutrients in the diet are intimately connected with the most primitive part of our inflammatory responses: the innate immune system. This part of our immune system has been evolutionarily conserved for hundreds of millions of years and can be considered our first line of defense in the generation of inflammation. What is important to realize is that the innate immune system is under considerable dietary control.

INFLAMMATION AT THE MOLECULAR LEVEL

The central hub of the innate immune system is the gene transcription factor nuclear factor kappaB (NF-κB).  This is the master switch that turns on the expression of various inflammatory gene products such as cyclo-oxygenase-2, tumor necrosis factor-α, interleukin IL-1β, IL-6, etc. which amplify the initial inflammatory response by signaling to nearby cells to ramp up their inflammatory responses [2].

There are a number of dietary factors that can activate NF-κB.  These factors include oxidative stress from consumption of excess dietary calories and an overproduction of pro-inflammatory hormones derived from arachidonic acid [3,4].  Additional dietary factors include saturated fatty acids, and advanced glycosylated end products (AGE) acting through specific receptors at the cell surface to activate NF-κB [5].

However, inflammation is not like a burning log whose fire eventually dies out. The inflammatory response consists of two distinct phases [5]. The first phase is the initiation of the inflammatory response. The second phase is the resolution of that same inflammatory response. The resolution phase is controlled by a unique groups of hormones (resolvins, protectins, and maresins) derived from omega-3 fatty acids [6]. As long as the initiation and resolution phases of inflammation are balanced, then inflammatory homeostasis can occur. On the other hand, if the initiation phase is too strong or the resolution phase is too weak, the end result is chronic low-level cellular inflammation that is below the perception of pain.  It is this chronic cellular inflammation, which is the driving force in the development of obesity, metabolic syndrome, and diabetes and their associated co-morbidities [7].

MEASURING CELLULAR INFLAMMATION

Because cellular inflammation is below the perception of pain, the process of describing it and as well as measuring it has posed a challenge. The earliest marker of cellular inflammation was high-sensitivity C-reactive protein (hs-CRP) [8]. This protein is synthesized in the liver in response to elevated levels of IL-6 in the blood [9]. Unlike inflammatory cytokines that either have short half-lives or only enter the blood in very low concentrations [10], hs-CRP is a relatively long-lived protein in the blood and therefore is more easily measured [11]. The major clinical drawback of hs-CRP is that even slight bacterial infections can rapidly elevate its levels and, consequently, it is not very reliable marker [12]. Furthermore, it is a late downstream marker of cellular inflammation as opposed to an early warning of the buildup of chronic cellular inflammation.

Inflammatory cytokines expressed by the activation of NF-κB (such as tumor necrosis factor (TNF), IL-1β, and IL-6) are better potential markers of cellular inflammation, yet their levels in the blood are very low and they have very short half-lives, making their use as analytical markers of cellular inflammation less feasible [9,10].

Perhaps the best marker of the extent of cellular inflammation is the ratio of two fatty acids in the blood, the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid eicosapentaenoic acid (EPA).  AA is the building block of pro-inflammatory eicosanoids that stimulate inflammation. On the other hand, EPA is not only a competitive inhibitor of AA for the enzymes necessary for the production of inflammatory eicosanoids, but also the building block for very powerful pro-resolution mediators such as resolvin E1 (RvE1) and resolvin E2 (RvE2).  Thus, the AA/EPA ratio in the blood provides a surrogate marker into the potential balance of inflammation and resolution in every cell in the body.  The first use of this marker as an indication of changes in inflammatory cytokines was demonstrated in 1989 (13).  Furthermore, unlike hs-CRP, the AA/EPA ratio is a stable and reliable marker and often becomes elevated years ahead of the elevation of hs-CRP [5, 7, 14].

MANAGEMENT OF CHRONIC CONDITIONS BY ANTI-INFLAMMATORY NUTRITION

Although virtually every chronic disease can be connected with increasing cellular inflammation, the three that are most germane are obesity, metabolic syndrome, and diabetes.  There are also a wide number of other conditions such heart disease, autoimmune conditions, and neurological conditions that are also associated with increased cellular inflammation.

Obesity

Obesity can be defined as excess fat accumulation. However, it is only when that excess fat in the adipose tissue becomes inflamed that it leads to the development of insulin resistance and eventual development of lipotoxicity in the liver and skeletal muscle (15).  Under normal conditions, the adipose tissue operates like a typical bank: taking in excess energy from the diet and storing it in the form of triglycerides in the fat cells and then releasing that energy throughout the day when insulin levels begin to drop.  Normally, this process works very well unless disrupted by increased cellular inflammation that leads to elevated insulin levels due to insulin resistance [5,14-16).

One molecular consequence of increased insulin resistance in the adipose tissue is the inhibition of hormone-sensitive lipoprotein lipase in the fat cell.  This prevents the release of stored fat into the blood for energy production by the mitochondria.  As a result, fat accumulation begins in the adipose tissue cutting off the primary source of stored energy for the rest of the body generating fatigue.  At the same time, cellular inflammation also disturbs the intricate satiety mechanisms in the hypothalamus, leading to increased hunger.

Metabolic Syndrome

Metabolic syndrome can be considered the first stage of the metastasis of cellular inflammation from the adipose tissue to other organs, in particular to the liver and the muscles. Metabolic syndrome is not a defined condition, but a cluster of associated

clinical markers such as elevated waist measurement, high triglycerides, low high-density lipoprotein (HDL) cholesterol, and hyperinsulinemia. All of these symptoms can be linked to insulin resistance [15-17]. Metabolic syndrome can be considered pre-diabetes because if left untreated the conversion rate to type 2 diabetes is 5% to 10% per year [18].

Diabetes

Type 2 diabetes occurs with the destruction of beta cells in the pancreas, leading to the inability to secrete sufficient amounts of insulin to control blood sugar levels. With this comes a rapid increase in blood glucose levels with a potential corresponding increase in AGE products that can bind to receptors known as RAGE, which also activate NF-κB [19].  The hydroxylated fatty acid 12-HETE, derived from arachidonic acid, appears to be a major player in the destruction of beta cells in the pancreas [20].

Macronutrients and Inflammation

To understand the basic principles of anti-inflammatory nutrition, it is best to describe how various macronutrients in any diet can become either pro-inflammatory or anti-inflammatory [21].  Among the most important to consider is the flow of dietary omega-6 and omega-3 fatty acids into the precursors of pro-inflammatory eicosanoids and anti-inflammatory resolvins.

Omega-6 and omega-3 fatty acids are essential fatty acids meaning they must be supplied by the diet.   The omega-6 fatty acids are the basic building blocks for a wide variety of pro-inflammatory eicosanoids. Although the real molecular foundation for pro-inflammatory eicosanoids is arachidonic acid, the vast bulk of dietary omega-6 fatty acids in the diet consist of linoleic acid.

The metabolic conversion of linoleic acid into arachidonic acid goes through several steps as shown in Fig. 1.

Figure 1.  Conversion of linoleic acid into arachidonic acid

anti-inflammatory-nutrition-figure-1

The enzymes delta-6 and delta-5 desaturase are rate-limiting enzymes that normally control the flux of linoleic acid into arachidonic acid. Both of these enzymes are under hormonal and dietary control [22]. The hormone insulin (controlled by the amount of carbohydrate at a meal) activates these enzymes, whereas the hormone glucagon (controlled by the amount of protein at meal) inhibits their activity.  Furthermore, the amount of insulin released in a meal depends on the glycemic load of the carbohydrates consumed. Refined carbohydrates such as those found in bread, pasta, and processed foods are rapidly broken down to glucose. The more rapidly the glucose enters the bloodstream, the more rapidly insulin is released from the pancreas to remove excess glucose from the bloodstream. On the other hand, carbohydrates such as fruits and vegetables have a much lower glycemic load, meaning that they have a more limited impact (especially non-starchy vegetables) on the rise of blood glucose levels. As a result, insulin secretion is significantly reduced, and this reduces the potential activation of both delta-6 and delta-5 desaturase.

Long-chain omega-3 fatty acids such as EPA and docosahexaenoic acid (DHA) are weak feedback inhibitors of the rate-limiting delta-6 and delta-5 desaturase enzymes necessary for the production of arachidonic acid.  Therefore, as the levels of linoleic acid increase without a corresponding rise in the levels of EPA and DHA, there is constant pressure to generate more arachidonic acid. This effect is accelerated by the high levels of insulin generated by a high-glycemic-load diet that results in the more rapid conversion of excess linoleic acid into arachidonic acid. With the increased levels of arachidonic acid in cells, the likelihood of producing more pro-inflammatory eicosanoids is significantly enhanced.

The role of saturated fats in the generation of inflammation is more indirect compared to omega-6 fatty acids. Toll-like receptor 4 (TLR-4) interacts with the saturated fatty acid component of lipopolysaccharide (LPS) from gram-negative bacteria. Saturated fats can also activate TLR-4, thus activating NF-κB although at a lower intensity than LPS itself [23,24].

Palmitic acid (the predominant saturated fatty acid in the diet) can also directly cause inflammation in the hypothalamus thus disturbing the energy-balance system that control calorie intake (16).

Whereas omega-6 and saturated fatty acids are pro-inflammatory, omega-3 fatty acids have anti-inflammatory effects. As mentioned above, omega-3 fatty acids are weak inhibitors of the rate-limiting enzymes required for the generation of AA. They also can compete with AA for the enzymes required to generate eicosanoids.  However, the 3-dimensional structures of EPA and DHA are quite different, therefore imparting different effects. In particular, EPA and AA are very similar in 3-dimensional structure, thus making EPA a better competitive inhibitor than DHA of the cyclooxygenase (COX) enzyme required to convert AA into pro-inflammatory eicosanoids, especially into prostaglandins and thromboxanes. As a result, the higher the level of EPA in the cell membrane relative to AA, the less likely it is that pro-inflammatory eicosanoids can be synthesized.

The real anti-inflammatory power of omega-3 fatty acids, however, lies in their ability to function as substrates to a wide range of pro-resolution mediators that include resolvins, protectins, and maresins [5,6]. These pro-resolution mediators are the key to reducing the levels of chronic cellular inflammation to bring any initial pro-inflammatory response back to homeostasis.

Monounsaturated fats such as oleic acid are virtually neutral in terms of eicosanoid actions. As a result, monounsaturated fats should be considered to be non-inflammatory.

Finally, there is the role of polyphenols in inflammation [25,26]. Polyphenols are the chemicals that give fruits and vegetables their color. At high enough levels, they have anti-inflammatory actions by activating the gene transcription factor PPAR-gamma that inhibits the activation of NF-κB [5,25]

Developing A Practical Diet Based On the Principles of Anti-Inflammatory Nutrition

Because obesity, metabolic syndrome, and diabetes all ultimately arise from diet-induced inflammation, the logical approach to minimize the impact of these inflammation-related conditions is to develop a practical anti-inflammatory diet that can be easily maintained for a lifetime. The overall goal of such a diet is to reduce systemic low-level chronic inflammation.

A major problem in developing any diet is that if one macronutrient nutrient goes up, then another must come down. This also means that the hormonal responses caused by a particular macronutrient nutrient will also rise and fall accordingly with the changes in the balance of macronutrients.  The challenge is to find the right macronutrient combination to maintain the appropriate synergy of hormonal responses consistent with the least number of calories that can provide continuous control of cellular inflammation.

Finding the appropriate balance of macronutrients follows a bell-shaped curve based on the protein-to–glycemic load ratio as shown in Fig. 2.

Figure 2.  Ratio of protein-glycemic load for improved insulin control

anti-inflammatory-nutrition-figure-2

If dietary carbohydrate content in the diet is too high, this will generate excess insulin production. If this is coupled with high levels of omega-6 fatty acids, this can lead to increased cellular inflammation. At the other extreme, when the carbohydrate content is too low, this can generate ketosis with a corresponding rise in cortisol [27].

Between these two hormonal extremes exists a zone in which insulin levels are stabilized.  This leads to improved stabilization of blood sugar levels, resulting in greater satiety and less fatigue.

Another important question that has to be addressed is the level of calories required for an anti-inflammatory diet to be successful. This is important because it has been shown that the consumption of excess calories also creates inflammation in the hypothalamus, leading to increased appetite [28].  Therefore the ideal anti-inflammatory diet must also be calorie-restricted, yet generate the necessary hormonal responses that lead to a lack of hunger or fatigue.

History of Anti-Inflammatory Diets

The first anti-inflammatory diet was proposed in the book, The Zone [21]. The central focus of this anti-inflammatory diet was based on the dietary principles previously discussed.  In addition, there was a strong emphasis in that proposed diet on reducing the levels of omega-6 and saturated fats in such a diet with most of the fats coming from non-inflammatory monounsaturated fats.

From a practical viewpoint such an anti-inflammatory diet had a slight excess of low-glycemic load carbohydrates to low-fat protein. When the overall fat content was factored in, the diet would provide approximately 40% low-glycemic-load carbohydrates, 30% low-fat protein, and 30% fat high in monounsaturated fats and be low in omega-6 and saturated fatty acids at each meal in order maintain consistent hormonal responses throughout the day.   Such as diet might be considered a 40-30-30 diet.  However, this proposed anti-inflammatory diet was also a calorie-restricted one to prevent the inflammatory effect of the consumption of excess calories.  Thus a calorie-restricted 40-30-30 diet is considered to be a Zone diet. Thus, the absolute levels of the various macronutrients of the proposed calorie-restricted anti-inflammatory diet are shown in Table 1 at various total caloric intakes. The usual recommendation for females would be 1,200 calories per day and for males it would be 1,500 calories per day.

Table 1.  Levels of macronutrients on a calorie-restricted anti-inflammatory diet.

Macronutrient1,200 calories/day1,500 calories/day
Carbohydrate120 g/day150 g/day
Protein90 g/day112 g/day
Fat40 g/day50 g/day

It can be seen from Table 1 that at these caloric intakes, the absolute levels of protein are adequate, the absolute levels of low-glycemic-load carbohydrates are moderate (although the volume of those low-glycemic carbohydrates on the plate would be significant), and the absolute levels of fats would be considered low.

For ease of calculation, each meal would maintain a balance of one gram of fat (primarily monounsaturated fats) for every two grams of low-fat protein and three grams of low-glycemic load carbohydrates (primarily non-starchy vegetables and limited amounts of fruits) and a maximum of 400-500 calories per meal.

CLINICAL SUPPORT FOR AN ANTI-INFLAMMATORY DIET

The first clinical trial to support such a macronutrient ratio in treating diabetics was reported in 1998 [29]. In this study, it was demonstrated that insulin resistance was significantly reduced within four days and well before any weight loss was observed.

Carefully controlled clinical trials at Harvard Medical School in 1999 gave further support to the rapid hormonal changes and improvement in satiety using such the same macronutrient ratio in overweight children [30]. Follow-up research at Harvard Medical School confirmed these findings of increased satiety in overweight adults [31]. More recent studies at Harvard Medical School have demonstrated that this macronutrient ratio compared to iso-caloric high-carbohydrate diets resulted in superior reductions in cellular inflammation, even though the weight loss in both groups were identical [32].

In 2007, the Joslin Diabetes Center at Harvard Medical School announced their new dietary guidelines for treating obesity, metabolic syndrome, and diabetes [33]. These guidelines in terms of macronutrient composition and calorie content were virtually identical to those proposed more than a decade earlier [21]. Subsequent studies and other publications from the Joslin Diabetes Research Foundation has supported this anti-inflammatory diet concept [34,35].

Numerous other clinical studies of this anti-inflammatory diet having 40% of calories as carbohydrates, 30% of calories as protein, and 30% of calories as fat have demonstrated superior weight loss, improved insulin levels, increased fat loss, increased satiety, and, most important, reduced cellular inflammation compared to iso-caloric diets higher in carbohydrate, but lower in protein [36-42].

From a visual standpoint, the composition of the plate for each meal is shown in Fig. 3.

Figure 3.  Configuration of a typical plate for improved hormonal control

anti-inflammatory-nutrition-figure-3

At every meal, the plate should be divided into 3 equal sections.  One section should contain low-fat protein approximately the size and thickness of the palm of the hand. Appropriate low-fat protein choices would be chicken, fish, or protein-rich vegetarian sources. The other two thirds of the plate should be filled with low-glycemic load carbohydrates (primarily non-starchy vegetables and limited amounts of fruits). This will simultaneously maintain a low glycemic load and provide adequate levels of polyphenols.

Finally, the ideal added fat would be a small amount of extra virgin olive oil (approximately 5 ml). The hormonal success of this dietary balance will be indicated by

the lack of hunger and maintenance of mental acuity for the next 5 hours as demonstrated by Harvard researchers in 1999 (30).

Clinical Markers of Inflammatory Risk and Their Ideal Ranges

There are three clinical markers that are important to be achieved and maintained for an anti-inflammatory diet to be considered successful. Each of these markers relates to a different component of the inflammatory response and all three markers should be within appropriate ranges to ensure that cellular inflammation is successfully being managed.

AA/EPA Ratio

The first of these markers is the AA/EPA ratio. As discussed earlier, this marker represents the balance of the initiation and resolution responses to inflammation.  AA is the dietary building block of pro-inflammatory eicosanoids that drive the initiation phase of inflammation.  Ideally the AA levels in the blood should be between 7 and 9% of the total fatty acids.  The resolution of inflammation is driven by resolvins derived from both EPA and DHA.  For methodological reasons, better precision is achieved measuring the AA/EPA ratio as opposed to the AA/EPA +DHA ratio. In addition, the levels of DHA will always be greater than EPA due to the ongoing metabolism of omega-3 fatty acids.  Therefore, if there are adequate levels of EPA in the blood, then there will be more than adequate levels of both EPA and DHA to make the full range of resolvins required for resolution.  Ideally the levels of EPA should be 4% of the total fatty acids in the blood.  This ensures the summation of EPA and DHA will always be greater than 8% as it is in the blood of the Japanese population.    The higher the AA/EPA ratio, the higher are the levels of cellular inflammation. The ideal AA/EPA ratio should be between 1.5 and 3. The average AA/EPA ratio in the Japanese population is 1.5 [43], whereas the AA/EPA ratio is 18 in the average American population [44]. If the AA/EPA is less than 1, then the potential for bleeding increases, although there is a significant reduction in cardiovascular events compared to the use of statins [45]. As long as the AA/EPA ratio remains above 1, there is no indication of any increased bleeding [46].

Modulation of the AA/EPA is easily achieved by the diet.  If the AA levels in the blood are greater than 9% of the total fatty acids, then a more restrictive anti-inflammatory diet is required to lower insulin and a greater restriction of omega-6 fatty intake is also required.  If the EPA levels are less than 4% of the total fatty acids, then greater consumption of fatty fish or omega-3 fatty concentrates is required.   The AA/EPA ratio reflects the previous 30 days of dietary intake.  Thus within 60 days of dietary changes, significant changes in the AA/EPA can be observed (13).

Triglyceride/HDL Ratio

The triglycerides/ HDL ratio is a surrogate marker for insulin resistance in the liver and indicates the beginning of the development of metabolic syndrome [47,48]. The ideal ratio should be less than 1 (using mg/dl) or less than 0.4 (using mmol/ml).

If the TG/HDL ratio is greater than the ideal range, this would indicate that insulin resistance is beginning to appear in the liver and that a more strict anti-inflammatory diet is required to reduce the cellular inflammation that causes such insulin resistance.   It will take approximately 60 days of a strict anti-inflammatory diet to begin to reduce the TG/HDL ratio.

HbA1c

AGE proteins are glycosylated proteins generated by either excess glucose in the blood or a lack of polyphenols in the diet to generate the synthesis of anti-oxidant enzymes to reduce oxidative stress that promotes the glycosylation process. Glycosylated hemoglobin (HbA1c) is a marker of long-term blood glucose control and is an indicator of the development of type 2 diabetes.  It is also a good marker of the levels of AGE in the blood.  It is generally accepted that HbA1c levels of greater 6.5% are indicative of diabetes and increasing mortality [49].  However, the optimal level of HbA1c should be 5.0%.  This is because levels of HbA1c are associated with increased mortality [50].  Since the red blood cell has a four-month lifetime in the blood, changes in the levels of this marker will be apparent within 120 days of adding adequate levels polyphenols to the diet in addition to following a more strict anti-inflammatory diet.

These optimal ranges of the markers of cellular inflammation are summarized in Table 2.

Table 2.  Optimal ranges of markers of cellular inflammation

Marker Optimal Range
AA/EPA ratio1.5-3
TG/HDL ratioLess than 0.4 if measured in mmoles/l
Less than 1 if measured in mg/dl
HbA1c4.9-5.1%

All three clinical parameters should be within their optimal ranges to ensure that low-level cellular inflammation is being controlled.

Anti-Inflammatory Supplements

Often even a strict anti-inflammatory diet will not be sufficient to reach the desired ranges of the clinical markers described above. Under these circumstances, there are two additional anti-inflammatory supplements to consider adding to an anti-inflammatory diet.

Omega-3 Fatty Acid Concentrates

The most important of these anti-inflammatory supplements is highly refined omega-3 fatty acids, which will help reduce the AA/EPA ratio and thus increase the pro-resolution potential of the diet. The definition of a highly refined omega-3 fatty acid concentrate would be one that has very low polychlorinated biphenyls or PCBs.  The PCBs levels should be 5 ppb or lower.  This is because all fish are contaminated by PCBs and the higher the omega-3 fatty acid contents of the fish, the higher the contamination because PCBs are fat soluble.  Thus all fish oils derived from fatty acids (sardines, anchovies, salmon, etc.) contain PCBs, which are known endocrine disruptors [51,52] and their elevated intake is associated with increased risk of cardiovascular disease (52).

A suggested intake of supplemental omega-3 fatty acids would be a minimum of 2.5 grams of EPA and DHA per day. However, the ideal dosage will be determined by titrating the blood to an appropriate AA/EPA ratio between 1.5 and 3.

Polyphenol Extracts

As mentioned earlier, fruits and vegetables contain polyphenols although at very low concentrations (0.1 to 0.2 per cent by weight). To have any benefits in activation of gene transcription factors, polyphenol intake should be at therapeutic levels.  In particular, low concentrations (500 mg/day) can activate the gene transcription factor Nrf2 to promote the synthesis of anti-oxidative enzymes (23,53).  Higher concentrations (1,000 mg/day) are required to activate another gene transcription factor (PPARϒ) necessary induce anti-inflammatory effects.  Still higher levels (1,500 mg /day) are required to active the SIRT-1 gene that promotes the synthesis of AMP kinase (54).  AMP kinase functions as the central control hub for metabolism just as NF-κB does for orchestrating the innate immune response.

Reaching polyphenol intakes of 500 mg per day is achievable by consuming a diet rich in fruits and vegetables.  Higher levels of polyphenol intake may require supplementation with refined polyphenol extracts.

Microbiota-induced inflammation

One of the least understood components of anti-inflammatory nutrition is its role modulating the inflammatory impact of the microbiota in the gut.  In particular, this includes the role of fermentable fiber in the diet as well as the levels of polyphenols and omega-3 fatty acids that are key components to reduce this potential source of inflammation.  Only about 10-15% of dietary fiber is fermentable by the microbes in the colon.  Therefore an anti-inflammatory diet must also be rich in fiber yet low in calorie.  This is why most of the carbohydrates of an anti-inflammatory diet have to come from non-starchy vegetables to fulfill this requirement.  The fermentable fiber contained with the total fiber intake is their primary source of energy for the microbiota in the colon to maintain its diversity as well as promote gut integrity necessary to limit inflammatory insults on our human cells.

How anti-inflammatory nutrition can control microbiota-induced inflammation is a complex story that starts with an understanding of how the integrity of the lining of the intestinal tract is paramount to prevent any significant penetration of microbial fragments into the blood.  The primary initial barrier between human cells and microbes is the mucus barrier.  The mucus barrier is essentially a “no-man’s land” that not only keep microbes and microbial fragments, but also large protein or fragments of proteins from coming into direct contact with the epithelial cells and the immune cells directly behind them.  Mucus is composed of complex polysaccharides that are continually being produced by the goblet cells in the intestinal wall.

The next barrier after the mucus barrier is the tight junction of the epithelial cells that line the mucosa of the gut.  The integrity of this barrier requires the constant generation of adequate levels of specialized proteins (occuldins, zonlins, etc.) that maintain the tight junctions of the epithelial cells. However, these barriers in the gut can be disrupted very easily by pro-inflammatory eicosanoids (particularly leukotrienes) that are derived from arachidonic acid (AA).  The disruption of the tight junction in the gut is foundation of what is termed “leaky gut syndrome”.  If microbial fragments breach both barriers (the mucus barrier and the gut mucosa), then microbes or their fragments can interact with the TLR system to generate inflammatory responses.

The TLR sentry system on the surface of human cells is set up to detect microbial fragments.  Once any microbial fragment is detected, there is a rapid activation of NF-κB to increase the production of pro-inflammatory protein products include inflammatory cytokines and the COX-2 enzyme required for the production of pro-inflammatory eicosanoids.  Therefore any leakage of the microbes or microbial fragments into the blood from the gut can represent a significant source of potential systematic inflammation.  The most widely studied microbial fragment capable of inducing a powerful inflammatory response is lipopolysaccharide (LPS) which part of the outer cell wall of gram-negative bacteria.  LPS is a specific ligand for TLR-4.   As the levels of LPS rise in the blood, a low-level chronic inflammatory condition known as metabolic endotoxemia occurs (55). This added inflammatory burden could be a significant contributing factor to the development of obesity, metabolic syndrome, and diabetes.  It should be noted that the levels of microbial fragments in blood needed to induce metabolic endotoxemia are perhaps two orders of magnitude lower than the levels associated with the more severe inflammatory condition of sepsis.

Thus a dietary program to minimize metabolic endotoxemia becomes a significant component of an anti-inflammatory nutrition.  Ensuring that the microbes in the gut are well nourished is a necessary first step.  Since their only sources of nutrition are fermentable fibers, this has to be a component of any successful anti-inflammatory diet.  Human DNA only has the capacity to synthesize the enzymes that can breakdown starch (a polymer of glucose molecules with defined chemical linkage between the glucose moieties) into monosaccharides for absorption.  Microbes in the colon can only undertake the metabolism of other polysaccharide-based fibers into carbohydrate monomers that can be used for energy for the gut microbiota.

Besides supplying nourishment to the microbiota and epithelial cells in the colon, there are two types of end products of the fermentation process of the carbohydrates derived from the fermentable fiber by the microbes in the colon.  The first include the various gases that cause flatulence.  The other fermentation end products are short chain fatty acids (SCFA).  The SCFA are not only the primary energy source for the epithelial cells in the colon, but they can also have significant anti-inflammatory actions.

One of the primary microbes in maintaining the mucus barrier is recently discovered microbe known as A. muciniphila (56).  This particular microbe appears to be a central player in controlling microbe-induced inflammation.  Without adequate fermentable fiber in the diet, all microbes will seek alternative sources of energy for survival.  In the case of A. muciniphila, its primary alternative food source is the carbohydrate polymers that make up the mucus barrier.  This will reduce the size of the mucus barrier and therefore increase the likelihood of metabolic endotoxemia.  On the other hand, if this microbe is getting adequate nutrition from fermentable fiber, it will leave the mucus polysaccharides intact thus decreasing gut permeability. This is why increased levels of A. muciniphila are strongly associated with decreased cellular inflammation (57).

A high saturated fat diet can also speed up metabolic endotoxemia.  The entry rate of LPS into the blood can be accelerated by piggybacking onto fats, especially trans and saturated fats (58).  It has also been demonstrated in transgenetic fat-1 mice, that the conversion of omega-6 into omega-3 fatty acids will increase A. muciniphila production (59).  The same effect can be achieved by the use of high-dose fish oil rich in omega-3 fatty acids.  Finally, polyphenols also increase the production of A. muciniphila (60-62).  With the increase in A. muciniphila levels in the microbiota, both gut permeability and cellular inflammation within the gut membrane decreases.  This is another reason why a high intake of supplemental omega-3 fatty acids and polyphenols are critical for anti-inflammatory nutrition both for both our human cells and the microbiota in the gut.

Summary

Anti-inflammatory nutrition is ultimately based on new breakthroughs in molecular biology to understand the role of diet for reducing chronic low-level cellular inflammation.  This is important since cellular inflammation is the underlying cause of many chronic disease conditions.  The cause of this low-level cellular inflammation can either be directly induced by the diet or indirectly induced by dietary disturbances of gut microbiota.  Both causes can be modified by anti-inflammatory nutrition.

In particular there are four key components that must be addressed by an anti-inflammatory diet:

  1. Maintaining a constant hormonal balance in the blood allowing calorie restriction without hunger or fatigue.
  2. Achieving an adequate balance of the precursors of the hormones necessary to balance initiation and resolution of inflammation.
  3. Maintain appropriate gene activation by adequate levels of polyphenols.
  4. Modulation of the gut microbiota-induced inflammation.

The success of anti-inflammatory nutrition can be determined by maintaining specific clinical markers related to cellular inflammation within certain ranges.  If any of these markers are outside their appropriate ranges, then appropriate dietary interventions can realign them in a relatively short period of time (30-120 days).  The use of such anti-inflammatory diets can potentially reduce the likelihood of development of chronic low-level inflammation as well as attenuate the severity of many existing chronic disease conditions associated with increased cellular inflammation.

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