I want to continue my series on weight dysregulation by examining the role endotoxemia may play. As you may have noticed, nowhere in the title does the word obesity appear. While I will talk about how gram-negative pathogens can promote weight gain, it’s equally clear that lipopolysaccharides (LPSs) derived from these same organisms can also cause weight loss. Inflammatory states as seen in sepsis or cancer are well-known for causing body wasting or cachexia. This phenomenon seems partly mediated by increases in the cytokine tumor necrosis factor alpha (TNF-α), also known by its nickname cachexin. Interleukin 1 and 6 also appear to be necessary players in this process.
Therefore, I want to emphasize that under no circumstance should being overweight be interpreted as having metabolic endotoxemia. In the absence of signs indicating ill-health, being heavy may signal nothing more than excess caloric intake relative to energy expenditure. Weight is, after all, a very poor indicator of health status.
This is illustrated by the fact that there are plenty of thin people with serious medical conditions. Many normal or underweight people have heart attacks, suffer strokes, get cancer, develop diabetes, live with debilitating depression or anxiety, have thinning bones, very high blood pressure, experience gastrointestinal disorders, are incapable of getting a good night’s sleep, have an autoimmune disease, develop Parkinson’s or Alzheimer’s, etc. Many of these people pride themselves on being able to fit into the same clothes they wore during high school or college. But by no objective criteria can we classify these people as healthy.
The following fictional dialog illustrates my point:
A restaurant in Anytown, USA:
Amber: Heather, did you see that fat cow that just walked by?
Heather: See her? I felt my chair shake!
Amber (giggling): Heather, you always make me laugh!
Heather: Jesus, you would think someone like that would get a clue. I mean, how out-of-control and lazy do you have to be to let yourself get that way? Can you imagine how unhealthy that must be?
Amber: Tell me about it. And when I think about how they raise my medical insurance rates or drain the taxpayer with their medical bills, it really pisses me off.
Heather: Plus they’re so gross to look at with their fat asses jiggling all over the damn place.
Amber: (laughing): There you go again! Almost spit out my Diet Coke. Hey, so was the doctor able to do anything about your chronic fatigue?
Heather: Well, he upped my thyroid medication, but that didn’t stop me from spending most of yesterday in bed.
Heather: Yeah. I couldn’t work out at the gym which really sucked as I want to rock my new size 0 dress at Bob’s office party. So how you doing?
Amber: Same old same old. I’m still having trouble with my digestion and I’m wondering how healthy it is to go three days without a bowel movement. I’m about to set a new record.
Heather: Oh, that doesn’t sound good.
Amber: And it doesn’t feel good either. I wonder if colon cleansing would help?
Heather: My brother-in-law’s cousin’s sister’s housekeeper said it did wonders for her!
Amber: Then maybe I should try it. That herbal-colon-fasting cleanse that set me back a couple hundred dollars didn’t work for me at all. Hey, did your brother Mark and his wife get home safe after their visit with you guys?
Heather: Oh yeah. But you remember that cough he had?
Amber: How could I forget. It was pretty bad the day we all went to the movies.
Heather: Well, after they got home, he went to see the doctor who discovered it was pneumonia and checked him into the hospital
Amber: Is he OK?
Heather: Oh, he’s fine. Just spent two nights there and was released. You know how trim he is and how he won’t eat anything that isn’t low-fat or whole grain so I’m surprised it even happened. Good news though. His doctor was happy with his very low cholesterol levels.
Amber: Oh, that’s good. At least he doesn’t have to worry about a heart attack.
Heather: Yeah, that is good news. How’s your mom doing?
Amber: Still overweight I’m afraid. I keep telling her she needs to lose weight, but in one ear out the other.
Heather: How old is she now?
Amber: 76 and healthy as a horse. She and the new boyfriend are going out ballroom dancing tonight.
Heather: Wow, that’s amazing. I barely have enough energy to get dressed most days. Your mom’s been overweight for as long as I’ve known you.
Amber: I know right? But she’s active, always out doing things and never gets sick.
Heather: Well, that probably means you’ve got good genes.
Amber: Maybe. Anyway hon, I’m going to be late for my appointment with my psychiatrist. My anxiety has been really terrible lately and he wants to adjust my meds.
Heather: That’s OK, I have to get going too. I have a Pilates class I need to get to. A friend told me it might help with my osteopenia.
Amber: Aint’ growing old hell?
Heather: At least we’re thin!
Amber: Amen to that!
(Hugs and kisses all around)
Yes indeed, “at least we’re thin!” The mantra of the unhealthy non-overweight everywhere!
There is precious little evidence that being overweight is much of a problem in the absence of other disease markers. What evidence does exist implicates morbid obesity and being underweight:
In these charts, we see the results of mortality in three separate National Health and Nutrition Examination Survey (NHANES) studies conducted since the 1970s. (1) The square solid box tracks all-cause mortality from all three NHANES surveys. People with BMIs that are currently classified as overweight (25 to 29) have the lowest mortality rates of all age groups studied. I can’t think of a better illustration for the absurdity of considering BMIs in this range as unhealthy, but I’m not an “expert” so what do I know?
Even BMIs between 30 and 34, what would normally be termed obese, experienced mortality rates not much different from normal-weight or overweight people. Not until you exceed a BMI of 35 are mortality rates elevated, and mainly in those younger than 70 years of age.
Now look at the left side of the chart. BMI’s under 18.5 showed consistently higher deaths from all causes with rates highest in the 60-69 age group. This relationship holds true even in the normal-weight unwell.
Normal-weight diabetics are more likely to die sooner than overweight or obese diabetics. (2) In fact, this holds true for those on dialysis, those who’ve had a heart attack, have high blood pressure, have kidney disease or have suffered a stroke. Known as the obesity paradox, it throws a bit of cold water on those warning about the dire consequences of the obesity epidemic. For a nice article on this paradox click here.
So to those of you reading this who have been ridiculed for being overweight by an Amber, Heather or Mark in your life, rest assured that your statistical chances of outliving them are higher. You’re welcome.
The focus on obesity is driven partly by monetary considerations rather than scientific findings. Pointing out that being underweight may be hazardous to health doesn’t sell diet books, gym memberships, fashion magazines, employ personal trainers, increase revenue for Weight Watchers® or Jenny Craig®, increase funding for obesity researchers, the CDC or NIH, fatten the bank accounts of bariatric surgeons or sell diet pills.
There’s also an unpalatable class bias to obesity alarmism as well:
“Women’s concerns about weight are as much or more about class as about health. Achieving and maintaining thinness is an important way in which the contemporary elite in rich nations, and especially elite women, signal their status. This has been well documented in France, where elite French women both are thinner and strive toward an even thinner ideal than do poorer French women, and has also been shown to be true for American elites as well. The pursuit of (female) thinness is an integral part of elite and middle-class (but not working-class) habitus, or a largely unconscious, taken-for-granted, and embodied worldview. The reframing of fatness as unhealthy lends medical authority to this century-old dislike for fatness among the elite and white middle classes. At the same time, it casts as irresponsible cultural preferences for heft among the working classes and, in the American context, some ethnic minorities. The idea that “obesity kills” thus can and is used as a justification for imposing elite white preferences of thinness onto working classes and people of color, in an instance of what French sociologist Pierre Bourdieu calls symbolic violence. At the same time, the framing of obesity as illness brought on by bad personal choices can and is used to blame the poor, rather than poverty or inequality, for negative health outcomes.”
What’s Wrong with Fat? – Abigail C. Saguy
It’s far more important for your health to be fit than trim. Trying to starve yourself into a body you were not meant to have is probably hazardous to your health and will likely hasten your exit from this planet.
With that as prologue, what evidence exists for implicating endotoxemia in weight dysregulation in those cases where the person, regardless of weight, also suffers from diabetes or other indicators of disease?
In rodents and humans, lipopolysaccharides have been shown to increase levels of circulating inflammatory cytokines that reduce eating behavior and lead to weight loss. (3) (4) (5) This shouldn’t shock any of you who have had food poisoning or other bacterial infections. Apart from the symptoms that such illnesses produce, in many instances appetite disappears. If the infection lasts long enough, it’s not unusual to experience dramatic weight loss.
Inflammatory responses increase circulating cortisol. Chronically elevated cortisol leads to catabolism. As I wrote here:
“…when cortisol production is increased, glucose output in the liver goes up and glucose uptake by muscle, fat and other tissue goes down resulting in a rise in blood-glucose levels. In order to increase glucose production in the liver, it breaks down protein and fat in muscle, fat, connective and lymphoid tissue so the liver can produce glucose from these building blocks. Doing so mobilizes energy for the brain and the heart which makes sense in an emergency, but is harmful to health if cortisol production is chronically raised over long periods of time.”
So in a bad case of small intestinal bacterial overgrowth (SIBO) or colon-based dysbiosis leading to endotoxin translocation, it is quite conceivable that weight loss through suppression of appetite and increased cortisol production can result. But what of translocating gut pathogens and weight gain? Do gut pathogens have the potential to increase weight through these same inflammatory pathways? The evidence suggests yes.
In a ground breaking paper published in 2007, researchers were able to induce obesity in mice by infusing them with lipopolysaccharides even in the absence of excess energy intake. (6) These mice developed many of the same markers as mice fed a purified high-fat, corn-oil and lard diet. Mice became insulin resistant, had elevated levels of fasting glucose, high systemic inflammation, and raised triglyceride levels, all markers indicative of metabolic syndrome in humans.
The authors of this study theorized that the differences seen in studies showing an anorexic effect of LPSs and their own study was due primarily to the difference between an acute and chronic response to gram-negative bacterial infection. As I wrote here, this is also the best explanation for the wide variability in unhealthy total cholesterol levels in people.
In another recent paper from China inoculating the gram-negative pathogen Enterobacter cloacae, derived from the feces of a morbidly obese patient, into both germ-free and conventional mice, was sufficient to initiate obesity and insulin resistance when combined with high-fat feeding. (7) The pathogen came from a 26-year-old Chinese man who weighed 385 pounds (174.8 kg) and had a BMI of 58.78. He also had hypertension, triglycerides of 237, diabetes and impaired liver function.
To see what effect Enterobacter and a bacterial medium known as Lysogeny broth (LB medium) would have on the weight of germ-free mice, these pathogens were inoculated into rodents every day for a week. It isn’t entirely clear from this paper what bacterium was in the LB medium. I assume it was E. coli as that is what it typically contains.
By the way, this was only possible because the mice had sterile guts devoid of beneficial bacteria that would otherwise resist such colonization. As the researchers made clear in their supplementary material:
“…we have found that B29 [Enterobacter] couldn’t colonize conventional mice gut in our previous study (B29 failed to be detected one week after inoculatin)…”
To overcome this resistance to colonization, Enterobacter and LB medium were both given to the conventional mice throughout the duration of the feeding study.
Both germ-free and conventional mice were divided into four groups. Two groups of mice in both the germ-free and conventional cohort were fed a low-fat chow diet. Two other groups in both the germ-free and conventional cohort were fed a high-fat rodent chow.
This high-fat formula contained 34.9 grams of fat compromising 60% of calories. Fat composition consisted of 245 grams of lard and 25 grams of polyunsaturated omega-6 soybean oil. According to the Diet Research website, manufacturer of this formula, the last fatty acid analysis of lard used in their formulation reveals 34.3% saturated fat, 38.9% monounsaturated fat, and 26.8% polyunsaturated fat. Of the total 270 grams of fat, (assuming soybean oil is 15% saturated, 24% monounsaturated and 61% polyunsaturated) 87.785 (32.51%) total grams were saturated fat, 101.305 (37.52%) total grams were monounsaturated fat, and 80.91 (29.96%) total grams were polyunsaturated fat. Of the three types of fat, omega-6 polyunsaturates would be the most prone to causing increased intestinal permeability, endotoxemia and liver inflammation. (8)
During the first week of study, some groups showed decreases in weight testifying to the anorexic effect of LPSs. By week two, all groups had regained their lost weight or gained weight. Noticeable increases in weight gain were seen in the germ-free rodents colonized by Enterobacter and fed the high-fat diet, and to a lesser extent those fed a high-fat diet after inoculation with LB medium:
NCD+LB and NCD+B29 represents the normal chow diets with Lysogeny broth and Enterobacter respectively. HFD+LB and HFD+B29 are the high-fat diets with the same respective constituents. As you can see, in both germ-free (first chart) and conventional mice, high-fat feeding with Enterobacter consistently led to weight gain in both groups. In the conventional mice, LB medium also resulted in similar weight gain.
Here is a chart of caloric intake for the germ-free mice. Unfortunately, the authors of this paper did not include a food intake chart for the conventional mice. As you can see here, caloric intake between the normal chow LB medium group and the high-fat Enterobacter group were quite similar. Nevertheless, weight gain in the high-fat Enterobacter group was much higher suggesting that Enterobacter acted by reducing metabolic rate in these germ-free rodents.
I wish the authors of this study had examined how metabolism in these animals was affected. Were they less active in their cages than the low-fat chow group? Were their body temperatures lower? I would suspect so. And I imagine the obese human who donated this gut pathogen was similarly lethargic and sensitive to cold.
While there are no conclusive studies I could find in the literature that explain the exact mechanism for lowered metabolic rate in chronic endotoxemia, I would imagine it’s mediated by the same pathways responsible for Euthyroid Sick Syndrome. This syndrome is characterized by low levels of the active form of thyroid hormone, T3. T4 thyroid hormone is produced by the thyroid gland, but must be partly converted into the more active form of T3 which occurs mainly in the liver.
Approximately 30% to 40% of all circulating T4 is converted to T3 in a healthy human and accounts for 80% to 90% of circulating T3. Liver disease and infection will affect this conversion for the worse:
“The liver is perhaps the most important site of T4 to T3 conversion and decreases in T3 generation may reflect a direct effect of liver disease on the deiodinative process [removal of iodine] rather than an indirect effect of systemic illness. Similarly, thyroid hormone transport in blood will be affected in a major way by liver disease since this organ is responsible for synthesis of all three binding proteins (TBG, TBPA, and albumin) and since binding protein production also varies with specific liver disorders. Finally, the liver serves to take up T4 and release both T4 and T3 into blood, and liver injury, particularly when acute, can contribute significantly to the circulating hormone pool. (page 195)
Shortly after the onset of clinical infection in man, there occurs a fall in serum T4 and T3 levels reflecting decreased TSH [thyroid stimulating hormone] stimulation of the thyroid, decreased thyroidal secretion, accelerated T4 disappearance, and the effect of inhibition of hormone binding to transport proteins. Therapy of the infection and recovery is associated with resumption of TSH release and thyroidal secretion and a progressive rise in serum T4 and T3 levels. The depression in serum T3 also reflects decreased T4 to T3 conversion and increases in serum rT3 [reverse T3] have also been noted in some infections in which it was measured, presumably on the basis of a decreased clearance.”
Alterations in Thyroid Function in Patients with Systemic Illness: The “Euthyoid Sick Syndrome”
Translation: both liver dysfunction and infection (which is precisely what metabolic endotoxemia results in) will affect metabolic regulation in a negative manner. Cortisol also inhibits secretion of thyroid hormone and T3 generation from T4, thereby implicating stress, including stress from bacterial translocation from the gut, for impaired metabolic rate. (9)
As all fat, including polyunsaturated omega-6 fatty acids, increases translocation of gut pathogens, especially in the presence of gut dysbiosis, the results seen in this Chinese study are not surprising. Insulin resistance was highest in the high-fat group with Enterobacter as were levels of serum lipopolysaccharide binding protein and blood-glucose levels. This group also had the lowest adiponectin levels mirroring what was seen in the obese donor. Adiponectin is an anti-inflammatory hormone secreted by fat cells and important for proper glucose and fatty acid metabolism. Typically, the higher the rate of obesity, the lower the level of adiponectin.
Another curious finding in this study was the higher colonization of Enterobacter in the guts of the previously germ-free mice fed the low-fat diet:
Here we see consistently higher levels of pathogens in the guts of the normal-chow, Enterobacter group represented by the blue bar. This may have been due to the higher translocation of Enterobacter to systemic circulation in the high-fat fed mice. Or perhaps, this is due to the differences in bile secretion. Bile not only helps digest fat, it also keeps the intestinal tract free of colonizing pathogens through its antibacterial properties. (10) Since less bile would have been produced in the low-fat group, this would account for the discrepancy. This also probably accounts for the emails I get from people following low-fat, gluten-rich diets who suffer from SIBO and gallbladder dysfunction.
Here we see a comparison between mice fed a high-fat, purified diet and germ-free mice fed the same high-fat diet but with guts full of Enterobacter. The MRI image in the upper-right corner reveals the differences in fat tissue accumulation (represented by light areas) between both mice. Lower graphs show worse glucose parameters in the high-fat fed, Enterobacter mice.
Finally, when some of these germ-free mice were inoculated with bifidobacteria, they did not experience the same levels of obesity when fed high-fat rodent chow:
The green line represents high-fat feeding with a gut that was colonized by a strain of bifidobacteria. As you can see, the addition of bifidobacteria protected against many of the effects of this chow. Of the three high-fat groups charted, this group experienced the least weight gain. The authors noted:
“Inoculating 6- to 10-week-old germfree mice…with a strain of Bifidobacterium animals via alternation of NCD and HFD feeding did not induce the same obese phenotype, suggesting that obesity cannot be induced by introducing any bacteria in the germfree mice under HFD feeding.”
As I’ve noted before, a byproduct of bifidobacteria fermentation is butyrate, a short-chain saturated fatty acid important in preserving gut barrier function and preventing translocation of gut pathogens to systemic circulation. Healthy bifidobacteria colonies in the colon also prevent colonization of this part of the gastrointestinal tract with pathogens, both bacterial and fungal. Had these researchers supplemented with lactobacillus, they would have also noted a decline in endotoxemia from the small intestine where lactobacillus works to prevent pathogen attachment to the small intestinal gut wall.
And what became of the obese bacterial donor?
He was placed on a calorie-restricted, low-fat diet consisting of a whole-grain, canned gruel with prebiotics. What type of whole grain this diet formula contained is not mentioned in the study, nor have the researchers responded to my email inquiry. Each can contained 100 grams of dry material consisting of 59 g of carbohydrates, 15 g of protein, 5 g of fat and 6 g of fiber. He was also treated with Chinese medicine (again not sure what that entailed). I imagine the prebiotics were included to increase his levels of bifidobacteria. As I’ve mentioned before, low bifidobacteria levels are a common finding in the morbidly obese as well as those afflicted with various forms of gut dysbiosis.
A total of four cans of gruel at 336 kcal or 1,344 kcal a day were eaten for 23 days. He lost a little over 66 pounds (30.1 kg) after nine weeks, and a little over 113 pounds (51.4 kg) after 23 weeks leaving him at a weight of about 272 pounds (123.4 kg) and with a BMI of 41.5. After nine weeks, his detectable population of Enterobacter was reduced from 35% of fecal bacterial content to 1.8%, becoming undetectable by the end of week 23. Levels of serum endotoxin dropped during his weight loss along with interleukin-6 cytokine levels. His levels of C-reactive protein, a marker of systemic inflammation, decreased. Levels of adiponectin increased. While not measured, I imagine cytokine levels of tumor necrosis factor alpha also went down. (11)
By week 9, the patient experienced a complete resolution of his diabetes as well as normalization of his hypertension. His liver tests also showed improvement. Resolution of diabetes and high blood pressure is no small achievement, nor is losing 113 pounds. His triglycerides fell to 152.
One concern I have with this very low-fat diet is possible future bacterial colonization of his small intestine. Insufficient bile secretion, caused either by gallbladder disease or a very low-fat diet, can encourage the growth of small gut pathogens in the presence of impaired gastric barrier function. That said, although still obese, he’s far healthier than he was when he started. I wish him continued success.
So what can we take from this? Endotoxemia caused by gut dysbiosis is not a desirable state in either the obese, the very thin or in the normal weight. How it affects weight is dependent on the unique genetic makeup of the person experiencing it, the translocating pathogen(s) responsible for it, whether the infection is chronic or acute, the composition of the diet, the state of the person’s gut flora, how appetite and behavior is impacted and the severity of lowered resting metabolic rate.
In a situation where depressed metabolic rate is overcompensated by increased food intake, weight gain will result. In a situation where appetite is suppressed, as in acute endotoxemia, a very thin, yet unhealthy, body type is the consequence. Of the two states, the research clearly indicates that the former is more conducive to survival than the latter.
That said, the best course is to concentrate on eating a whole-food, non-toxic diet that sustains a healthy gastrointestinal tract and beneficial gut flora populations, while engaging in enough exercise to maintain fitness. If you do that, who cares if your waistline matches that of an Amber, Heather or Mark? The thin may look fetching dressed in their finest whilst lying in their coffins, but given the choice, I’d bet they’d rather take part in the funeral procession then be the object of its attention.
In the next and concluding post in this series, I look at the role of stress in weight regulation.
Saguy, A. (2012). What’s Wrong with Fat?. New York: Oxford University Press
Wartofsky, L. and Burman K.D. (1982) Alterations in Thyroid Function in Patients with Systemic Illness: The “Euthyroid Sick Syndrome” Endocrine Reviews, 3(2): 164-217.