The following is an early draft of a section written for a review paper
Inflammation has a well-characterized role in promoting cancer  and an inverse relationship with longevity . One prospective cohort study of 2,438 subjects aged 70-79 with an average follow-up of 5.5 years reported that elevated inflammatory markers IL-6, CRP, and TNF-α were strongly associated with both increased cancer incidence and cancer mortality after excluding cancer diagnoses within two years of baseline . Another study of 7178 patients with stable cardiovascular disease and CRP < 10 mg/L and a median follow-up of 8.3 years also reported strong association between cancer and CRP levels, with sensitivity analyses excluding patients within 1, 2, and 5 years all showing similar results . Another study with 7,017 participants aged 55 years or older with a mean follow-up of 10.2 years using CRP as a biomarker and excluding cancer diagnosis before 5 years follow-up reported similar results . A large literature, moreover, demonstrates the relationship between genetic variants that produce higher lifetime inflammatory exposure and risk from a variety of cancers, including breast [6,7], non-Hodgkin’s lymphoma , gastric cancer , prostate cancer , lung cancer , and others. The relationship, too, between chronic infection and tumorogenesis is well-known, with about 18% of cancer globally due to chronic infection and a large portion of that to the inflammatory component of such infections . Historical cohort data moreover suggest a link between childhood mortality from infectious disease (a proxy for cohort-wide inflammatory exposure or nutritional deficiency) and risk of death later, the latter of which may be mediated in part by increased cancer risk [13,14].
Accordingly, the ketogenic diet has been proposed to lower cancer risk by reducing inflammation .
Several studies have recently been published on the role of beta-hydroxybutyrate, the principal metabolite elevated during the ketogenic diet, on NLRP3 inflammasome-mediated inflammatory markers and disease [16–19]. NLRP3 is an innate immune sensor that is activated by toxins, ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals and may have an important etiological role in type 2 diabetes, atherosclerosis, multiple sclerosis, Alzheimer’s disease, age-related functional decline, bone loss, and gout . In 2015, investigators reported the results of a series of elegant experiments showing that beta-hydroxybutyrate inhibits activation of the NLRP3 inflammasome in response to LPS treatment in both rodents in vitro and in vivo and in human monocytes in vitro, via a potassium channel mediated mechanism . In contrast however, a recent paper has reported the opposite effect, namely an increase in LPS activation when human monocytes were exposed to betahydroxybutyrate . Marked methodological differences between the papers might account for these conflicting findings. In Youm et al., 2015, isolated monocytes were cultured in 11.1 mM glucose, then exposed to BHB and LPS for 1 hour and 4 hours, respectively. On the other hand, Neudorf et al., 2019 exposed for two hours to LPS human monocytes which were still in the original whole blood that had been drawn from subjects who consumed an exogenous ketone ester or ketone salt 2.5 hours earlier. Thus, the different findings might be accounted for by the differences in glucose in the media/blood, differences in LPS and BHB exposure time, differences in effects on the monocytes from non-monocyte cells in the whole blood versus lack of such effects in the media, and differences in exposure to other metabolites (such as fatty acids) and hormones (such as insulin) which may also be modulated in response to betahydroxybutyrate and may change the time-course of the phenotype in vivo compared to in vitro. Context may be a key determinant of the effect of betahydroxybutyrate on immune cell phenotypes; if so, this context-dependence needs to be adequately described before making strong claims about the impact of BHB on NLRP3 inflammasome activation.
Much preclinical data exists demonstrating the efficacy of the ketogenic diet in rodent models of inflammatory disease . In one rat model of pain, KD decreased swelling and plasma extravasation . However, as with previous studies discussed, this study is also confounded by profound protein restriction, with the ketogenic diet group having 5% of calories from protein, and the control group having 28% of calories from protein. Although some recent human studies suggest that higher protein intakes may be associated with lower inflammatory markers [23,24], some recent studies in rodents have shown the opposite [25,26], with one recent study in particular demonstrating particularly profound immunomodulatory effects of a protein-restricted diet in rodents . This calls into question whether the anti-inflammatory effects seen in this study are due to ketosis or to protein restriction.
Another study showed that the KD alleviates motor dysfunction induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin used to model Parkinson’s in rodents . For diet, this study cited another paper, which itself provided scant detail about the composition of the diet . In another rat model of fever, KD reduced inflammatory markers in the blood and lower fever . Yet this study too used a profoundly protein-restricted diet, with the KD group having approximately 1/3 of the protein as a proportion of total calories as the controls. Another study showed that motor, learning, and brain defects in a mouse model of multiple sclerosis were ameliorated by the KD . This study provided no information about the control diet, confounding interpretation. In a recent study using a mouse model of gout, no information was given about the control diet used .
Suffice to say, the lack of appropriate control diets for ketogenic diet rodent studies makes many or most of the studies conducted to date difficult to interpret.
The body of human study literature is equivocal. Although there are a number of relevant randomized controlled trials comparing low- and high-carbohydrate diets and inflammatory markers during weight loss, we could find no systematic reviews or meta-analyses on the topic, which has also been reported by a recent National Lipid Association report . We will therefore briefly review of a random sampling of eleven relevant randomized clinical trials comparing a low- to a high-carbohydrate diet.
Four studies showing reduced inflammatory markers
Among these, four showed that a low-carbohydrate diet improved blood inflammatory markers: two showed lower blood C-reactive protein [32,33], a risk factor highly associated with cardiovascular disease risk and activation of systemic inflammatory pathways , one showed for the low-carbohydrate group compared to the high-carbohydrate group lower levels of IL-8, TNF-alpha, MCP-1, I-CAM, and PAI-1, among a selection of 20 markers , and one showed for the low-carbohydrate group lower serum amyloid A levels (with null findings for other markers including CRP) . Three of these studies [32,33,35] were only of three months in duration and therefore predictably showed greater weight loss in the low-carbohydrate group, an effect that is lost in longer-term studies (see above section on weight loss). Because weight loss is one of the best-established means of reducing blood inflammatory markers in the general population , differential weight loss in the arms of the low- versus high-carb trials confounds interpretation of these studies. One of these three studies  found no difference after adjusting for weight loss, while the effect on inflammatory markers remained after adjusting for weight loss in the other two studies [33,35]. In one of these remaining two studies of these three, baseline characteristics were not appropriately matched in ways that might be relevant to CRP levels, particularly with respect to metabolic markers and possibly CRP itself . Nonetheless, the findings of Forsythe et al., 2008, the third of these studies, are suggestive. The study finding elevated serum amyloid A levels showed borderline statistical significance (p = 0.04) at a p=0.05 cutoff and did not adjust for multiple comparisons of inflammatory markers, of which there were nine reported, suggesting that this finding was not in fact statistically significant .
Four studies show no difference in inflammatory markers
Nonetheless, in three other studies in this sample, there was no difference in inflammatory markers between groups, despite significantly greater weight loss in the low-carbohydrate group [38–40], suggesting the opposite of the above studies: that a low-carbohydrate diet might mitigate some of the positive effects on inflammatory markers of weight loss. And in yet another study that showed no difference in weight loss, there was also no difference in C-reactive protein between groups .
Three studies show a worsening of inflammatory markers
Finally, in the three remaining studies in this sample, higher CRP was observed in the low-carbohydrate group compared to the high-carbohydrate group [42–44]. Importantly, unlike the previous studies, two of these three studies were in subjects that lost similar amounts of weight [43,44]. However, while weight loss was tightly controlled, with equal weight loss during the baseline diet and ketogenic diet phases, Rosenbaum et al., 2019 was conducted in crossover fashion, with 4 weeks on the baseline diet followed by 4 weeks on the ketogenic diet, with roughly 2 kg lost per 4-week phase and no washout period. The lack of randomization of diet order (or alternatively, the lack of a second crossover phase back to baseline diet) confounds interpretation of causality of C-reactive protein changes during the ketogenic diet period in this trial . The results however of Ebbeling et al., 2012 are suggestive, and the impact on C-reactive protein on inflammatory markers remains to be reported from a new study by the same group (NCT02068885; see Ebbeling et al., 2018).
In summary, the evidence for changes in inflammatory markers is mixed, with studies with equivalent weight loss between groups showing worsening of these inflammatory markers [43,44]; one study with higher weight loss in the low-carbohydrate group also showing worsening ; other studies with higher weight loss in the low-carbohydrate group showing either neutral effects [38–40] or benefits to inflammatory markers [32,33,35], some of which remain after controlling for weight loss [33,35], and others of which that do not .
Subtle differences in dietary composition, adherence, or other aspects of study design could account for the heterogeneity of these study findings. Likewise, although only blood inflammatory markers were reported in these studies, it is conceivable that inflammatory markers in the organs or tissues (e.g. liver, muscle biopsy) could be markedly differentially expressed compared to blood, thereby causing blood-only inflammatory marker studies to overlook real effects. However, we are not aware of human randomized controlled trials assessing low-carbohydrate versus high-carbohydrate diets that have looked at inflammatory markers other than in the blood. Moreover, given that low-carbohydrate diets have not shown more weight loss at 12 months than high-carbohydrate diets (Churuangsuk et al., 2018; see section on weight loss), weight equivalence is an important experimental variable to control for in such studies. But even this approach poses a critical problem: weight loss at twelve months or more is not different between diets probably because of non-adherence to a low energy intake and perhaps to the diet itself , not necessarily because the diets equilibrate in their theoretical biological capacity to induce weight loss despite strict adherence. Thus, studies that evaluate differences in inflammatory markers between low- and high-carbohydrate diets with weight equivalence and strict adherence in the period of less than 6-12 months of duration are not necessarily representative of real-world differences between low- and high-carbohydrate diets at twelve months or longer, the latter of which will likely be substantially deviated from the original diet prescribed and thus may have a different inflammatory marker profile than a more strictly adhered-to version of the low-carbohydrate diet.
Therefore, as with weight loss, the crucial problem with the carbohydrate-restricted or ketogenic diet in modulating inflammatory markers, assuming it does so in humans, is adherence. If adherence is not possible in the long-term, then short-term nutrition studies looking at inflammatory markers may be evaluating a phenomenon that does not occur in the real world over a long enough period of time to be practically applicable. Thus, interventions that are expected to exert their effects in the long-term (such as through inflammatory signaling), should be validated as an adherable intervention by the population being studied under the conditions of the RCT in question, in order to make the results of that RCT of practical utility to recommendations, guidelines, or clinical practice.
On the basis of currently existing evidence, it cannot be concluded that carbohydrate-restricted or ketogenic diets reduce inflammatory markers in humans and thus cannot exert their effect on cancer prevention or treatment through an anti-inflammatory mode of action. It is possible that the ketogenic diet has tissue-specific anti-inflammatory action, but this can only be shown for a minority of tissues via biopsy. The majority of tissues for which this effect might be demonstrated will require a randomized clinical trial for a specific inflammatory disease state.
An early draft of a table that summarizes the above randomized controlled trials
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