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Reframing Nutritional Microbiota Studies To Reflect an Inherent Metabolic Flexibility of the Human Gut: a Narrative Review Focusing on High-Fat Diets


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There is a broad consensus in nutritional-microbiota research that high-fat (HF) diets are harmful to human health, at least in part through their modulation of the gut microbiota. However, various studies also support the inherent flexibility of the human gut and our microbiota's ability to adapt to a variety of food sources, suggesting a more nuanced picture. In this article, we first discuss some problems facing basic translational research and provide a different framework for thinking about diet and gut health in terms of metabolic flexibility. We then offer evidence that well-formulated HF diets, such as ketogenic diets, may provide healthful alternative fuel sources for the human gut. We place this in the context of cancer research, where this concern over HF diets is also expressed, and consider various potential objections concerning the effects of lipopolysaccharides, trimethylamine-N-oxide, and secondary bile acids on human gut health. We end by providing some general suggestions for how to improve research and clinical practice with respect to the gut microbiota when considering the framework of metabolic flexibility.
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Reframing Nutritional Microbiota Studies To Reect an Inherent
Metabolic Flexibility of the Human Gut: a Narrative Review
Focusing on High-Fat Diets
Jonathan Sholl,
Lucy J. Mailing,
Thomas R. Wood
Université Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
Independent Researcher, Milwaukee, Wisconsin, USA
Institute for Human and Machine Cognition, Pensacola, Florida, USA
Center on Human Development and Disability, University of Washington, Seattle, Washington, USA
Department of Pediatrics, University of Washington, Seattle, Washington, USA
Jonathan Sholl and Lucy J. Mailing contributed equally. Author order was based on relative contributions to drafting and editing the manuscript.
ABSTRACT There is a broad consensus in nutritional-microbiota research that high-
fat (HF) diets are harmful to human health, at least in part through their modulation
of the gut microbiota. However, various studies also support the inherent exibility
of the human gut and our microbiotas ability to adapt to a variety of food sources,
suggesting a more nuanced picture. In this article, we rst discuss some problems fac-
ing basic translational research and provide a different framework for thinking about
diet and gut health in terms of metabolic exibility. We then offer evidence that well-
formulated HF diets, such as ketogenic diets, may provide healthful alternative
fuel sources for the human gut. We place this in the context of cancer research,
where this concern over HF diets is also expressed, and consider various potential
objections concerning the effects of lipopolysaccharides, trimethylamine-N-oxide,
and secondary bile acids on human gut health. We end by providing some gen-
eral suggestions for how to improve research and clinical practice with respect to
the gut microbiota when considering the framework of metabolic exibility.
KEYWORDS cancer, gut health, high-fat diets, metabolic exibility, microbiota
It is generally accepted that diet is a major factor shaping both the composition and
the function of the human gut microbiota. However, much debate focuses on the
health effects of dietary components, with ber generally being seen as not only bene-
cial but necessary and animal fat (and sometimes protein) from high-fat (HF) diets
being singled out as detrimental to the gut microbiota (19). As a result, concerns over
HF diets feature heavily in the framing of studies on the microbiota and health. For
instance, HF or even high-protein, low-carbohydratediets are often suggested to play a
causal role in various forms of cancer, cardiovascular disease, immunological dysregulation,
and diabetes, through a variety of mechanisms (1014). This concern is expressed by inter-
national authorities on gut health, e.g., the European Society of Neurogastroenterology
and Motility (15), and in consensus statements by groups like the International Cancer
Microbiome Consortium (16).
It seems safe to say that the consensus is that HF diets are harmful to human health,
at least in part through their modulation of our gut microbiota. Put differently, the pri-
mary substance that feeds benecialgut microbes is microbiota-accessible carbohy-
drates(17), and in the absence of these, protein and fat will deteriorate our gut health.
One of the most cited studies used to support this consensus is that of David et al.
(18). While this study demonstrates how quickly the human gut microbiota adapts to
Citation Sholl J, Mailing LJ, Wood TR. 2021.
Reframing nutritional microbiota studies to
reect an inherent metabolic exibility of the
human gut: a narrative review focusing on
high-fat diets. mBio 12:e00579-21. https://doi
Editor Danielle A. Garsin, University of Texas
Health Science Center at Houston
Copyright © 2021 Sholl et al. This is an open-
access article distributed under the terms of
the Creative Commons Attribution 4.0
International license.
Address correspondence to Jonathan Sholl,, or Thomas R.
Published 13 April 2021
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on April 13, 2021 by guest from
dietary changes, what is less clear is how this should be interpreted (9). As we will dis-
cuss, this study highlights the need to consider the metabolic exibility of the gut
(19, 20). We are still far from being able to precisely dene a healthygut microbiota
(2125), and it is quite likely that the human gut and its microbial symbionts evolved
to adapt to a variety of macronutrient patterns. Acknowledging this exibility will
help to expand research and guide clinical interventions.
Here, we suggest one way in which translational research on nutrition and the
microbiota can be misleading (1st section) and provide a way to reframe this research
in terms of metabolic exibility (2nd section). We then offer evidence supporting the
potential healthfulness of alternative fuel sources derived from HF ketogenic diets
(KDs) (3rd section) and question the harmful role of these diets in diseases such as can-
cer (4th section). After addressing some likely objections (5th section), we end by rais-
ing the concern that the consensus on dietary fat may reect a research bias more
than physiological reality and provide suggestions for future research.
We are not the rst to point out the limitations of preclinical nutritional microbiota
research or the ubiquitous problem of HF diets in animal models. These diets are typi-
cally composed of soybean oil, lard, rened sugar, and little to no ber (26, 27), which
Craig Warden called the mouse equivalent of pork rinds, ribs, and coke(28). The clas-
sic animal HF diet is therefore much more reective of the standard American diet
than nutritionally replete high-fat diets, such as therapeutic KDs (29, 30). Evidence for
the role of simple sugars in harmfully disrupting the gut microbiota is growing (31),
and this alone should provide ample reason not to draw conclusions based solely on
fat content without considering other macronutrients or dietary quality.
While human metabolism can adapt to diets higher in either fats or carbohydrates,
the natural diet of a mouse is low in fat and high in carbohydrates. It is therefore unsur-
prising that mice develop issues when eating a species-inappropriate diet. The strain
of mice commonly used for such studies, C57BL/6, has also been genetically selected
for its ability to gain weight in response to a HF diet. While humans are capable of
weight loss or gain on a variety of dietary patterns (3234), C57BL/6 mice have greater
weight gain and metabolic disruptions on low-carbohydrate diets (35). Consequently,
...rodent models of obesity may be most valuable in the understanding of how meta-
bolic mechanisms can work in ways different from the effect in humans(35). Broadly
translating ndings from inbred mice fed a highly rened HF diet to humans is there-
fore fraught with potential for misunderstanding.
Similar problems exist in the clinical literature examining effects of the diet on the
gut microbiota and associated disease risk. For instance, in the Malmö Offspring Study,
Ericson et al. identied health-consciousand sugar and high-fat dairydietary pat-
terns associated with decreased and increased risk of having prediabetes, respectively
(36). The latter pattern was characterized by high intakes of pastry/desserts, high-fat
milk/cream, low-ber bread, potatoes, and processed/red meat, with the overarching
assumption that these components all equally and signicantly contribute to the
potential negative effects of this dietary pattern. Though these foods may cluster to-
gether frequently on the population level, we cannot assume that they contribute equally
ferent effects on both the gut microbiota and on general health. As highlighted in the com-
mentary accompanying reference 36, the association between the health-conscious dietary
pattern and prediabetes was lost after adjusting for body mass index (BMI) (2), suggesting
that a primary driver of differences between dietary patterns may be caloric intake. Any
attempt to assess the effects of dietary components on health must consider food process-
ing and energy density, both of which appear to contribute to increased caloric intake
beyond the effect of individual macronutrients (37, 38). One must also consider whether it
is the presence or absence of certain foods that drives downstream effects (2). Without a
nuanced approach examining dietary quality and individual dietary components, we are
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left making assumptions about fat in human diets similar to those made when we attrib-
ute the effects of HF diets in rodents purely to fat content.
We largely agree that the Westerndiet full of processed food causes problems for
both the mouse and the human gut microbiota. However, there are a variety of ways
to construct an HF diet, with data from humans suggesting that well-formulated thera-
peutic KDs, which in some clinical trials contain between 3 and 5 servings of non-
starchy vegetables per day (39, 40), may be more benecial for our gut and overall health
than some animal studies suggest (30, 41, 42). What is needed, then, is a way to reframe
the debate to better reect the overall evidence.
New technologies and greater interest in gut health in recent years have dramati-
cally increased our understanding of gut microbes. Nevertheless, we are still unable to
dene a healthygut microbiota (22, 25). On average, any two individuals share only
about a third of their gut microbiota, with the other two-thirds varying depending on
genetics, geographical location, history of antibiotic and medication use, mode of
delivery at birth, diet, and other undetermined factors (43, 44). It is even possible that
two otherwise-healthy individuals can show no overlap in microbiota composition
(44). Thus, outside clear instances of dysbiosis, we have insufcient information to say
that one individualstwo-thirdsis any better than anothers.
While it is generally believed that diversity and community stability are key compo-
nents of a healthy gut ecosystem, even these can sometimes be associated with dis-
eased states (45, 46). Some of the keystone microbes commonly considered crucial for
gut health, such as Bidobacterium, are completely absent from the guts of traditional
cultures, like the Hadza, who are otherwise virtually free of chronic disease (47). Gut
health and dysbiosis thus remain vague and sometimes contested concepts (25, 48,
49); if there is a healthy coremicrobiota, it may be at the level of microbial functions,
not species (23, 43). Part of this relative lack of insight may result from technologies
such as 16S rRNA sequencing, which do not provide accurate information beyond the
genus level and provide little insight into microbial functions (50). While there is hope
that higher-resolution technologies (e.g., metagenomics, metabolomics), larger data
sets, and advanced computing techniques will bring us closer to dening a healthy micro-
biota, many researchers call for moving away from cataloguing species and toward an
approach that considers the intricate nature of microbiota-host interactions (22, 51).
While technological advances are eagerly awaited, some initial clarity might come
from placing the human microbiota in its evolutionary context. Our relationship with
our gut microbes is the product of thousands of generations of close coevolution (52,
53). The environments in which we evolved also required regular adaptation to chang-
ing conditions. Our ancestors may not always have had steady access to food and
would likely have undergone occasional bouts of signicant deprivation when food
was scarce (54, 55). Similarly, diets changed seasonally and geographically, as is
reected by the seasonal changes in the guts of traditional populations, like the Hadza
(56), or in the specic adaptations in cultures known to eat relatively few plant foods,
such as the Inuit (57, 58). This variability can be explained in terms of metabolic exibil-
ity (19), which is the evolved ability to shift our metabolism to changes in dietary intake:
to burn and use carbohydrates when they are plentiful and to turn dietary fat or stored
body fat into ketones for energy when food or carbohydrates are scarce. Consequently,
it seems likely that our guts also exhibit the exibility to adapt to changing food sources
rather than suffer signicant gut dysfunction whenever ber is absent.
In line with this evolutionary perspective on the compositional and functional
adaptability of our gut and its microbiota, David et al. write (18),
Our ndings that the human gut microbiome can rapidly switch between
herbivorous and carnivorous functional proles may reect past selective pressures
during human evolution. Consumption of animal foods by our ancestors was likely
volatile, depending on season and stochastic foraging success, with readily available
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plant foods offering a fallback source of calories and nutrients. Microbial communities
that could quickly, and appropriately, shift their functional repertoire in response to
diet change would have subsequently enhanced human dietary exibility.
In other words, a healthygut microbiota adapts to a wide range of food sources
and does not necessarily become more or less pathogenic depending on the amount
of carbohydrate or fat in the diet. Moreover, while short-term dietary changes tend to
produce signicant changes in the gut microbiota (18), long-term studies suggest a rel-
ative resilience of the microbiota to shifts in diet (59). Due to the aforementioned fac-
tors shaping gut microbiota (43, 44), we should consider whether a dietary change
must produce signicant physiological changes in the host before a new microbial sta-
bility is achieved, with diet-induced uctuations merely an expression of the guts abil-
ity to adapt to ensure optimal function. If human guts are inherently metabolically ex-
ible, short-term diet-induced changes in microbiota composition could be considered
a potential hallmark of gut health (60). We should thus determine whether the short-
and long-term taxonomic changes resulting from this metabolic exibility are predic-
tive of overall health outcomes and how/whether the microbiota drives those out-
comes (6163).
Gut bacteria metabolize complex carbohydrates to produce short-chain fatty acids
(SCFAs), like acetate, propionate, and butyrate, with the last being the preferred fuel
source for gut epithelial cells. Published estimates suggest that butyrate provides
about 70% of colonic epithelial cell energy requirements (64), with a regular supply of
butyrate required to maintain gut barrier function. What remains to be seen is how dif-
ferent diets modulate SCFA production and whether this results in different down-
stream health effects.
Animal-based diets. The work of David et al. (18) has been instrumental in high-
lighting how quickly and reliably the human gut microbiota adapts to dietary changes.
What is unclear is whether this study should be used to support the avoidance of diets
high in fat or protein. Ten healthy human volunteers were placed on a short-term
plant-based diet (PBD) consisting of 300 g of carbohydrate per day from cereal, vegeta-
bles, rice, lentils, and fruit or on an animal-based diet (ABD) consisting of less than 3 g
of carbohydrates per day, with 30% of calories from protein and 70% of calories from
fat from eggs, meat, and cheese. Subjects on the ABD group were conrmed to be in
ketosis by day 2 of the diet, with distinct gut microbial communities emerging in both
diet groups within 3 days.
The most interesting and perhaps contentious nding was that there was no signi-
cant change in alpha-diversity in either group (18). Those on the ABD saw an increase
in the relative abundance of bile-tolerant microorganisms, like Bilophila,Alistipes,and
Bacteroides spp., and a decrease in the relative abundance of microbes known to metab-
olize complex dietary plant bers, such as Roseburia,Eubacterium,andRuminococcus
spp. While often cited as evidence that an ABD is harmful, this is far from conclusive. The
PBD, despite being supposedly uniquely capable of producing butyrate from micro-
biota-accessible carbohydrate metabolism, produced only slightly more butyrate than
did the ABD, with the ABD also resulting in signicantly greater production of isovalerate
and isobutyrate (Fig. 1) (18). Isobutyrate has been shown to activate many of the same
receptors as butyrate (see Considering alternative pathwaysbelow), weakening the
notion that PBDs are signicantly betterfor the gut due to butyrate/SCFA production.
Mucus barrier. Another recent study by Ang et al. conrmed that a ketogenic diet
(KD) can alter the structure and function of the gut microbiota (65). In humans, among
the most signicant changes of the fecal microbiota following a KD was a dramatic
reduction in the abundance of several Bidobacterium species. In controlled-feeding
studies of mice, the researchers found that KDs had a unique impact on the gut micro-
biota relative to conventional HF diets, with the abundance of Bidobacterium organ-
isms decreasing with increasing carbohydrate restriction. Further experiments found
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that both a KD or ketone ester supplementation increased beta-hydroxybutyrate
HB) in the lumen of the gut and in colon tissue (65), with ketone bodies directly in-
hibiting the growth of Bidobacterium. Ketosis was also associated with a reduction in
small intestinal Th17 cells, which help maintain the gut mucosal barrier and contribute
to pathogen clearance at mucosal surfaces. However, Th17 cells have also been impli-
cated in autoimmune and inammatory disorders (66).
Next, Ang et al. (65) sought to determine whether the change in Th17 cells was de-
pendent on the ketone-induced changes in the microbiota. Mice that received a fecal
transplant of the ketone-fed microbiota from human donors had signicantly fewer in-
testinal Th17 cells. Contrary to previous ndings that mice fed ber-free diets had a sig-
nicant breakdown of the colonic mucus layer (67, 68), Ang et al. write, A ketogenic
diet maintains a robust mucus layer despite the lack of fermentable carbohydrates
(65). The KD maintained not only the thickness of the mucus layer but also the expres-
sion of Muc2, the primary constituent of gut mucus. Nutritional ketosis might actually
support the gut mucus layer.
Multiple sclerosis and epilepsy. There are various levels of support for therapeutic
KDs on the gut and overall health in longer-term studies, for instance, the long-term
effects of a KD on the fecal microbiota in 25 patients with multiple sclerosis (MS) (69).
Like many autoimmune diseases, MS is associated with gut pathologies, with gut dys-
biosis and intestinal permeability potentially preceding the development of autoim-
munity (70). Swidsinski et al. (69) found that patients with MS tended to have reduced
numbers of Roseburia,Bacteroides, and Faecalibacterium prausnitzii organisms at base-
line than healthy individuals. The effects of a 6-month therapeutic KD were biphasic:
In the short term, bacterial concentrations and diversity were further reduced. They
FIG 1 Short-chain fatty acid (SCFA) production in humans eating low-fat, plant-based and high-fat,
animal-based diets. (a) Plant-based diets result in roughly twice the production of acetate and butyrate.
(b) Animal-based diets result in roughly twice the production of isovalerate and isobutyrate, which
have metabolic functions overlapping those of the traditional SCFAs acetate and butyrate. (Republished
from reference 18 with the permission of the publisher.)
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started to recover at week 12 and exceeded signicantly the baseline values after 23 to
24 weeks on the ketogenic diet(69). Such studies are inconclusive since they are rela-
tively uncontrolled, but they nevertheless further support the need to consider the
time course of dietary adaptation before determining whether a diet is benecial or
detrimental for the gut microbiota.
In another context, researchers investigated whether the benecial effects of a ther-
apeutic KD on epilepsy are mediated through the gut microbiota (71). The KD reduced
microbial diversity but increased the abundance of Akkermansia muciniphila and
Parabacteroides spp. By treating mice fed a normal high-carbohydrate diet with these
specic microbes, the researchers demonstrated that these taxa were at least partly re-
sponsible for the antiepileptic effects of the KD. Similar microbial changes, as well as
increases in butyrate and propionate, have been observed when using a modied
Mediterranean ketogenic diet in Alzheimers patients (72).
Together with the David et al. study (18), these ndings suggest that, while short-
term dietary changes can rapidly shift the composition of the gut microbiota, these
changes may not be detrimental and may provide benet. They also underline the
need to look at long-term dietary changes and collect samples at multiple time points
to determine the true effect of an intervention like a therapeutic KD, including whether
the benets or any risks are mediated through changes in the microbiota.
Considering alternative pathways. Multiple strands of evidence question an
assumption about normalmetabolic pathways in the gut. Alongside the SCFAs men-
tioned above, there are several other molecules that can serve as sources of fuel for
gut epithelial cells. The very idea of a preferredfuel source may be skewed from
studying people (and rodents) who eat a large amount of microbiota-accessible carbo-
hydrates. In other words, while butyrate production may be reduced on a KD, other
molecules can potentially take butyrates place to help maintain gut barrier function.
This shift to an alternative pathway is what we might expect from the perspective
of metabolic exibility, where we see a potential analogy between the butyrate-gut
connection and glucose-brain connection. While glucose is a necessary fuel for the
brain, we have known for some time that in the (relative) absence of carbohydrates,
the body will shift its metabolism from glucose to fatty acids, producing ketone bodies,
FIG 2 The many substrates and pathways that contribute to energy production in the intestinal epithelium. TCA, tricarboxylic
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such as
HB, to support brain metabolism (73). This kind of fatty acid-based metabo-
lism appears to have numerous neurological benets and may be a preferredfuel for
the brain during both development (74) and aging (75). Similarly, while researchers
repeatedly stress that gut epithelial cells are uniquely fueled by the butyrate produced
by our resident microbiota after consuming microbiota-accessible carbohydrates
(17), here too the body is exible, with
HB also being capable of supporting energy
requirements in the gut.
In fact, there are at least four molecules that can replace butyrate: isobutyrate, ace-
HB, and bile-derived acylcarnitines (Fig. 2). Isobutyrate is a metabolite of
protein fermentation that is typically produced at lower levels than butyrate. When bu-
tyrate is less abundant, isobutyrate can be absorbed from the gut lumen by gut epithe-
lial cells and metabolized for energy (76). Fecal isobutyrate was found to be elevated
in humans consuming a KD (18). Moreover, isobutyrate can stimulate the same recep-
tors as butyrate in the gut (GPR41, GPR43, and GPR109a) to inuence mucus secretion,
antimicrobial peptide release, and immune regulation (77), and while isobutyrate may
be produced at lower levels on a moderately high-protein diet than butyrate would be
produced on a high-carbohydrate diet (18), isobutyrate appears to be a more potent
stimulator of butyrate receptor GPR41 (FFAR3) than butyrate itself (78). In other words,
what isobutyrate lacks in concentration relative to butyrate, it may make up for in po-
tency. Relatedly, this may provide a reason not to confuse high-protein and rened HF
diets, since the most abundant end products of protein fermentation or catabolism are
SCFAs, such as isobutyrate (79). As suggested by David et al., it might be the overall
context in which protein fermentation occurs that is important to downstream health
outcomes rather than the protein fermentation itself.
Like butyrate,
HB can also stimulate GPR109a, reducing intestinal inammation (80,
81). Most notably, however, both
HB and its related ketone body acetoacetate are inter-
mediates in the pathway for butyrate metabolism; when butyrate is taken up by gut epithe-
lial cells, it is converted into
HB rst and then acetoacetate before being broken down fur-
ther for energy (Fig. 2) (82). Gut epithelial cells express the monocarboxylate transporter
MCT1, a primary ketone body transporter on the basolateral surface (83), and several papers
suggest that gut epithelial cells are capable of utilizing ketone bodies from the vascular bed
(84, 85). As gastrointestinal inammation and mucosal damage can impair butyrate uptake
from the intestinal lumen (86, 87), circulating ketones may provide a potential therapeutic
option in certain patients with gastrointestinal disease.
To our knowledge, no studies have assessed the effects of ketones or a KD on gut
barrier function. However, a recent study found that ketone body signaling regulates
the normal function of intestinal stem cells (ISC) and their ability to respond to injury
(88). In this study,
-methylbutyryl-coenzyme A (HMG-CoA) synthase 2
(HMGCS2), a rate-limiting step in ketone production, was enriched in small intestinal
stem cells. Ablating the Hmgcs2 gene in mice diminished
HB levels in the crypts,
compromising ISC function and regeneration of the gut epithelium after injury.
HB rescued ISC function and partially restored intestinal regeneration. A
KD also increased HMGCS2 expression and ISC number, function, and postinjury
regeneration. In contrast, a glucose-supplemented diet suppressed ISC ketogenesis
and skewed the differentiation of ISC toward goblet and Paneth cells. Notably, once
stem cells had differentiated into mature epithelial cells and migrated out of the
crypt, they expressed very little HMGCS2. This suggests that mature epithelial cells
do not possess the ability to generate large amounts of ketones through the classical
ketogenic pathway (via condensation of two molecules of acetyl-CoA), though we
know that they have the ability to utilize ketones.
Thus, it follows that if (i) a KD produces high levels of ketones in mature intestinal
epithelial cells (as Ang et al. [65] found) and (ii) these are not being generated in
mature epithelial cells (as is suggested by the lack of HMGCS2 in the work of Chen et
al. [88]), then the ketones are almost certainly coming from circulation. Along these
lines, the authors write, Because exogenous ketones rectify Hmgcs2 loss in vitro and in
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vivo, liver or other nonintestinal sources of ketones may substitute or supplement ISC-
generated ketones in KTD-mediated regeneration, where circulating ketone levels are
highly elevated(88).
Lastly, it has recently been shown that not only can colonic epithelial cells oxidize
both short- and long-chain fatty acids but also, through mitochondrial metabolism,
these cells can oxidize medium- and long-chain acyl-carnitines that are delivered from
biliary secretions (89). This has clinical relevance in that a reduction in these metabo-
lites may contribute to colonic inammation. Importantly, this provides yet another
host-derived energy source for the epithelium during low-carbohydrate diets to com-
plement the three discussed above. We will return to this below since bile acid secre-
tion is a common concern with HF diets.
To conclude, we suggest that a more nuanced picture of how HF diets impact gut
and overall health is required, with particular attention being paid to therapeutic KDs.
By considering the alternative pathways by which ketones and KDs can inuence gut
function, we can move toward a more evolutionarily consistent picture of human gut
variability. Nevertheless, research needs to clarify whether the benets of lower carbo-
hydrate or KDs come directly from increasing
HB, reducing inammation, modifying
insulin and glucose metabolism, reducing caloric intake, altering the gut microbiota, or
other undetermined factors.
We now briey discuss colorectal cancer (CRC), where the HF diet-microbiota link is
commonly highlighted. While the 2019 consensus statement by the International
Cancer Microbiome Consortium acknowledges the need for better human studies
into how the microbiota inuences carcinogenesis (16), it nevertheless implicates a
high-fat, low-ber Western-style diet in changes in mucosal biomarkers of cancer risk
(90). This follows the WHOs 2015 classication of redandprocessedmeatas a
(class 2A) probable carcinogen, which relies heavily on preclinical and mechanistic
data due to our current inability to isolate the effects of individual foods in clinical
epidemiological studies (91, 92). A recent review in Nature echoes the WHOs position
on processed and red meat and cancer, aiming to establish an oncogenicCRC-asso-
ciated microbiota (93).
In their Nature review, Janney et al. rely on the nding that CRC etiology is largely
environmental, potentially accounting for 70 to 90% of the disease risk (93). Here,
dietis strongly implicated, and the authors stress those diets that are low in ber and
high in fat and red meat.However, in the two references used to support this claim,
only one mentions red meat(94) and only in the context of epidemiological associa-
tions, which are often plagued by healthy-user bias and signicant reporting error (95,
96). Moreover, Janney et al. (93) vacillate between the terms high-fatand Westernized
high-fat,which introduces confounders. Some mechanistic studies in mice do appear to
support this HF diet-cancer link (97100), but this might be tumor type specic (101,
102). As the HF dietsstudied are admixtures of rened sugars and/or hydrogenated
oils, as mentioned above, this conates a junk food-mimicking diet with any diet high in
fat. Such results thus remain inconclusive (103), as we discuss below. Some of the sug-
gested mechanisms connecting diet and CRC are protein fermentation, secondary bile
acids, and increased levels of reactive oxygen species and reactive nitrogen species due to
increased bile acid, heme iron, decreases in SCFAs, and specicmicrobialchanges,e.g.,an
increased Bilophila abundance.Asdiscussedaboveandexploredinmoredetailbelow,the
rst three mechanisms are not clearly pathogenic, the putative antitumorigenic properties
of butyrate (104) can also be obtained through alternative mechanisms, the relevance of
heme iron remains to be seen (105, 106), and the signicance of microbial changes
depends on the broader physiological context and the relative abundances of microbes.
Since various conditions, such as irritable bowel syndrome (IBS), ulcerative colitis, and
Crohns disease, appear to increase ones risk for developing CRC (107109), further
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research might consider the role of KDs in these contexts (110). Unfortunately, few such
studies have been performed, and we are often left with case studies (111, 112).
We can, however, piece together various strands of evidence suggesting a more
nuanced picture on animal fats as CRC risk factors. First, some mouse models and pre-
clinical studies show KDs or ketones to be cancer suppressive (113, 114), perhaps pri-
marily through glucose restriction (103) and by increasing intratumoral oxidative stress,
leading to tumor cell apoptosis (115). Variations of therapeutic KDs might provide ben-
ets for breast cancer by decreasing tumor necrosis factor alpha (TNF-
) and insulin
while increasing interleukin 10 (IL-10) (116) and may be a promising adjuvant therapy
for various cancers (117121). However, as many of these studies are in animal models,
caution is warranted (122, 123). At the least, these studies and recent reviews suggest
a variety of mechanisms by which animal-food-based KDs may have benecial effects
on colorectal and other cancers.
This evidence converges with studies suggesting that reducing red meat and total
fat consumption, while increasing fruit and grain consumption, does not reduce the
risk for polyp reoccurrence even after 8 to 16 years (124126) and has unclear risk ben-
ets for CRC or any kind of cancer (127129). Animal models suggesting that beef
consumption does not promote cancer, that bacon may be protective, and that un-
saturated fat may have carcinogenic effects (130, 131) all increase the likelihood that
strong statements on animal foods and cancer are premature. Similarly, a growing
number of reviews and meta-analyses weaken the links between meat consumption
and cancer (132136) and possibly overall health (137, 138), with some showing
inverse correlations between meat intake and overall mortality in speciccohorts
(139) and lower rates of CRC in meat eaters than in vegetarians (140). Studies that
correlate meat intake with CRC also suggest a complex etiology due to contributing
factors, such as obesity and hyperinsulinemia (141). As most of these studies have
limitations, more research will be needed (142, 143), with the overall balance of evi-
dence not currently appearing to support an independent effect of animal-based
foods on the incidence of CRC. Given meats long-term presence in the hominid diet
(144147), it is more likely that modern dietary components and cooking techniques
are driving cancer risk factors through their effects on our guts and general
We acknowledge that there are likely to be various objections concerning the
effects of fat and protein on our gut microbiota. We will address three of these, lipo-
polysaccharides, trimethylamine-N-oxide (TMAO), and secondary bile acids, and end
with a cautionary note concerning KDs and hydrogen sulde (H
LPS. High-fat diets are commonly said to increase intestinal absorption of lipopoly-
saccharides (LPS), which are a group of endotoxins found in the cell walls of Gram-neg-
ative bacteria. If LPS gets into circulation, it can cause low-grade systemic inammation
(148), with the type and extent of the response dependent on the microbial source
and LPS subtype (149). When we consume more long-chain fatty acids, our body
makes more chylomicrons, which can carry LPS (150). Indeed, fat-enriched meals have
been shown to moderately increase serum levels of LPS in both mice and humans
(151, 152). While worth considering, we believe that, for several reasons, this is unlikely
to contribute signicantly to systemic inammation in those consuming KDs.
First, several studies suggest that the transport of LPS by chylomicrons may confer
an advantage because it favors the clearance of LPS by the liver, reducing LPS toxicity
(153, 154). Moreover, chylomicrons have an innate ability to inactivate LPS (155), and
the increased absorption of LPS appears to reduce inammation in the gut mucosa
(156). Similar benecial adaptations can be seen with exercise, which increases LPS
translocation but also LPS clearance, for instance via upregulation of anti-LPS immuno-
globulins (157). This is important since the primary mode of systemic exposure to LPS
is not through fat absorption but through reduced gut barrier function (158). When
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the gut is permeable, large amounts of LPS can leak into the submucosa and blood-
stream, causing localized gut immune responses and systemic inammation (159). This
is likely to be a consequence, rather than a cause, of the metabolic endotoxemia asso-
ciated with metabolic syndrome and cardiovascular disease, with poor systemic health
subsequently impairing gut barrier function (160). Certain LPS subtypes have also been
suggested to have benecial immunomodulating roles (161). In other words, com-
pared to the intestinal permeability associated with inammatory gastrointestinal con-
ditions, chylomicron-induced LPS absorption is likely minimal. One hypothesis emerg-
ing from these various studies that can be tested in humans is whether, for patients
dealing with severe intestinal permeability, chylomicron-induced detoxication of LPS
reduces inammation enough to facilitate healing of the gut epithelium.
Importantly, many of the above-described studies are preclinical, but they neverthe-
less point to promising mechanisms that are being pursued in human studies to better
contextualize the various roles of LPS. If fat-induced LPS absorption were an issue, we
would expect to see increased systemic inammation in those fed a KD. In contrast,
humans consuming therapeutic KDs generally experience a reduction in systemic inam-
mation (162), with possible anti-inammatory mechanisms, including NLRP3 inamma-
some inactivation (163), modulation of TNF-
, IL-6, IL-8, MCP1, E-selectin, I-CAM, and
PAI-1 (all studied in a registered clinical trial [164]), and an improved cytosolic NADH/
ratio (165). Taken together, these studies should assuage some concerns of LPS
absorption following fat intake.
TMAO. Conventional nutrition science has long considered diets rich in animal-
based foods a risk factor for cardiovascular disease. A recent mechanism of interest is
TMAO (61). Increased concentrations of TMAO in circulation have been shown to con-
tribute to atherosclerosis in animal models and correlate with cardiovascular disease
risk in human studies (166). Certain gut bacteria convert choline and carnitine, both
prominent in animal foods, to trimethylamine (TMA), which is then absorbed and oxi-
dized in the liver to TMAO. However, some in vitro and animal evidence points to an
altered small intestinal microbiota characterized by an overabundance of choline-con-
suming, TMA-producing Escherichia coli as the culprit for high TMAO, rather than
excess consumption of animal products (167).
More importantly, a recent study suggests that gut microbiota composition can
inuence the amount of TMAO produced with an animal-based diet. Bacteria in the
genus Bilophila,whichtendtoincreaseinsubjectsonananimal-baseddiet,maybe
able to help circumvent TMAO production by degrading TMA to dimethylamine
(DMA) (168). Further analysis revealed that in a human cohort, Bilophila was signi-
cantly more abundant in the microbiotas of healthy individuals than in those with
cardiovascular disease. As such, Bilophilas pathogenicity may be context dependent,
and it may even be benecial for mitigating cardiovascular disease. Additionally,
recent Mendelian randomization studies have suggested that increased TMAO in
those at risk of cardiovascular disease may be a consequence of metabolic dysfunc-
tion, rather than an independent risk factor for disease risk (169). For multiple rea-
sons, we thus believe that TMAO may not be a signicant independent contribution
to cardiovascular disease, with gut and overall health more likely to be the critical
drivers of any associations.
Bile acids. It is commonly argued that an HF diet might be detrimental to the gut
microbiota and gut barrier because it stimulates increased secretion of secondary bile
acids (170). While some studies have shown that sustained exposure of the gut barrier
to high concentrations of bile acids (above 400
M) results in intestinal permeability
(171), physiologic doses of bile acids (which may be nontoxic up to 50 to 100
[172]) have several potential benets. For instance, bile acids have been shown to sup-
port barrier function by inducing the secretion of mucus from goblet cells, promoting
epithelial cell migration, and boosting gut innate immune defenses (173). They can
have antimicrobial properties, helping to regulate the gut microbiota, and may protect
against small intestinal dysbiosis (174, 175). Several studies even suggest that bile acids
activate enteroendocrine cells to release serotonin, which helps promote gut motility
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(176). Evidence for the physiological role of biliary secretions in producing an alterna-
tive fuel (acyl-carnitines) for gut epithelial cells was discussed above (89).
Exploring the complexities of every type of conjugated and deconjugated bile acid
is beyond the scope of this article (177), but this should be sufcient to question the
assumption that bile acid secretion resulting from the consumption of animal foods is
inherently pathogenic.
S. There is one important caveat concerning KDs and individuals with H
ated bacterial overgrowth. H
S is normally produced in the body and acts as an impor-
tant signaling molecule. Certain gut bacteria can also produce H
S, which at low con-
centrations has been shown to protect the gut against injury, stimulate gut motility,
and support ulcer healing (178). However, an overabundance of these bacteria can
lead to excess H
S, which has been linked to diarrhea, gut hypersensitivity, IBS, irritable
bowel disease (IBD), and colorectal cancer (179), thereby suggesting pleotropic and
dose-dependent effects (178). Some of the common H
S producers in the human gut,
Desulfovibrio spp., Bilophila wadsworthia, and Fusobacterium nucleatum, tend to thrive
on a diet that is high in animal protein and fat (180, 181). Thus, in patients with an
overabundance of these microbes, it is probably best to avoid a ketogenic or high-fat
diet until they can address this issue. Adding ber to the diet (e.g., Brassica vegetables)
may reduce the abundance of sulfate-reducing bacteria (182), further suggesting that
the dietary context accompanying protein and fat consumption be considered.
Overall, we do not believe that there is sufcient evidence to suggest that the pro-
duction of TMAO or LPS following animal protein/fat consumption or the physiologic
increase of bile acids seen on a KD is harmful to the gut microbiota or gut barrier func-
tion. These metabolites might exacerbate ongoing pathological conditions of dysbio-
sis, but there are reasons to believe that they are not harmful under physiological
We conclude by suggesting how nutritional microbiota research might proceed in
terms of what questions need to be asked or answered and how studies could be car-
ried out.
1. Researchers should be more explicit about the kind of HF diets used. A diet
mimicking a Western diet is not nutritionally equivalent to all HF diets, which vary
in terms of fat sources and overall diet quality. Even changing the language in
articles from high-fatto high-fat, high-sugarwould better reect the diet
studied and could alter perceptions. From there, it will be helpful to study levels
of ber in HF or animal-based diets, which represent variations on the theme of
nutritionally replete low-carbohydrate or therapeutic KDs.
2. While studies are starting to focus on different fat sources (4, 183, 184), still more
are needed with as few confounders as possible. Some of the most problematic
for mechanistic studies include the use of rened/hydrogenated fats and seed
oils, which likely have rather different metabolic effects than fats from whole
plant and animal foods, especially when these oils are mixed with rened sugars.
Nutritional epidemiology should not only account for fat sources and dietary
patterns/context but should explicitly address (un)healthy-user biases. The
problem is not that such biases exist, as some may be unavoidable. The problem
is that they remain under-discussed.
3. We should clearly acknowledge the limitations of animal research to inform
human health/nutrition and our limited knowledge of what constitutes a
healthygut microbiota. Since it is likely that gut health encompasses more
variability than is often acknowledged, we need to further test the evidence that
humans evolved to tolerate, adapt to, and perhaps thrive on a variety of dietary
patterns, with varying proportions of ber, protein, and fat. An interdisciplinary
approach may better elucidate the health effects of diet-gut interactions.
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4. Researchers should explicitly state whether their interpretation considers the
physiological context or makes claims based solely on isolated mechanisms and
nutritional epidemiology. Properly labeling evidence and placing observations in the
broader context of research can help prevent potentially biased interpretations.
5. Similarly, researchers might carefully consider the differences in host and
microbial metabolism. For instance, studies relying on fecal samples might skew
towards microbes found in the large intestine or colon, where carbohydrates are
digested and metabolized. This may obscure the role of microbial and host
responses in the small intestine (9, 185), thereby underrepresenting the microbes
that are more involved in fatty acid catabolism or the production of lipase
coenzymes in the jejunum. Similarly, by focusing largely on microbial metabolism
of carbohydrates and ber, we might be overlooking host-specic metabolism,
which appears to be highly adaptable to relative levels of dietary fat and protein.
6. Clinicians can also remain open-minded to alternative dietary approaches. One
implication of considering alternative energy sources is that in the presence of a
healthymicrobiota and gut mucosa, butyrate is probably sufcient to fuel the
gut. However, if patients (i) have ulcerative colitis or other mucosal damage, with
impaired butyrate uptake, (ii) have gut dysbiosis characterized by a lack of butyrate
producers, or (iii) are on a restrictive diet, such as a low-FODMAP (fermentable
oligosaccharides, disaccharides, monosaccharides, and polyols) diet or the specic
carbohydrate diet (SCD), resulting in reduced butyrate production, it may be wise
for clinicians to consider nontraditionaltherapeutic options, such as KDs, to
support gut epithelial metabolism, at least until treating the underlying gut
pathologies and healing the gut mucosa.
7. Finally, it will be important to objectively weigh the evidence concerning plants,
animal fats, and proteins. Conventional wisdom holds the belief that plants are
denitively healthful and animal products are at least potentially harmful. The
effects of this belief can lead to conicts of interest in nutrition studies more
generally (186) and may inuence the decision-making leading to dietary
guideline statements that provide strong recommendations despite abundant
evidence supporting the idea that humans can thrive on a diverse range of
diets (187).
In the end, we hope that more time and research will help to uncover these biases
and lead to a more accurate depiction of the responsiveness of the human gut and its
microbes to nutritional variations.
Jonathan Sholl received funding from the European Research Council (ERC) under
the European Unions Horizon 2020 research and innovation program (grant agreement
637647), IDEM. Once this grant was completed, he received funding from the Université
de Bordeaux, Région Nouvelle-Aquitaine, and SIRIC BRIO.
1. Redondo-Useros N, Nova E, González-Zancada N, Díaz LE, Gómez-
Martínez S, Marcos A. 2020. Microbiota and lifestyle: a special focus on
diet. Nutrients 12:1776.
2. Maskarinec G, Hullar MAJ. 2020. Understanding the interaction of diet
quality with the gut microbiome and their effect on disease. J Nutr
3. Kolodziejczyk AA, Zheng D, Elinav E. 2019. Diet-microbiota interactions
and personalized nutrition. Nat Rev Microbiol 17:742753. https://doi
4. Wolters M, Ahrens J, Romaní-Pérez M, Watkins C, Sanz Y, Benítez-Páez A,
Stanton C, Günther K. 2019. Dietary fat, the gut microbiota, and meta-
bolic healtha systematic review conducted within the MyNewGut pro-
ject. Clin Nutr 38:25042520.
5. Rinninella E, Cintoni M, Raoul P, Lopetuso LR, Scaldaferri F, Pulcini G,
Miggiano GAD, Gasbarrini A, Mele MC. 2019. Food components and
dietary habits: keys for a healthy gut microbiota composition. Nutrients
6. Valdes AM, Walter J, Segal E, Spector TD. 2018. Role of the gut micro-
biota in nutrition and health. BMJ 361:k2179.
7. Gentile CL, Weir TL. 2018. The gut microbiota at the intersection of diet
and human health. Science 362:776780.
8. Singh RK, Chang H-W, Yan D, Lee KM, Ucmak D, Wong K, Abrouk M,
Farahnik B, Nakamura M, Zhu TH, Bhutani T, Liao W. 2017. Inuence of
diet on the gut microbiome and implications for human health. J Transl
Med 15:73.
9. Sonnenburg JL, Bäckhed F. 2016. Diet-microbiota interactions as moder-
ators of human metabolism. Nature 535:5664.
Minireview ®
March/April 2021 Volume 12 Issue 2 e00579-21 12
on April 13, 2021 by guest from
10. Dzutsev A, Badger JH, Perez-Chanona E, Roy S, Salcedo R, Smith CK,
Trinchieri G. 2017. Microbes and cancer. Annu Rev Immunol 35:199228.
11. Schwabe RF, Jobin C. 2013. The microbiome and cancer. Nat Rev Cancer
12. Barrett M, Hand CK, Shanahan F, Murphy T, O'Toole PW. 2020. Mutagene-
sis by microbe: the role of the microbiota in shaping the cancer genome.
Trends Cancer 6:277287.
13. Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, Nicholson JK.
2012. Therapeutic modulation of microbiota-host metabolic interactions.
Sci Transl Med 4:137rv6.
14. Xavier JB, Young VB, Skufca J, Ginty F, Testerman T, Pearson AT, Macklin P,
Mitchell A, Shmulevich I, Xie L, Caporaso JG, Crandall KA, Simone NL,
Godoy-Vitorino F, Grifn TJ, Whiteson KL, Gustafson HH, Slade DJ, Schmidt
TM, Walther-Antonio MRS, Korem T, Webb-Robertson B-JM, Styczynski MP,
Johnson WE, Jobin C, Ridlon JM, Koh AY, Yu M, Kelly L, Wargo JA. 2020. The
cancer microbiome: distinguishing direct and indirect effects requires a sys-
temic view. Trends Cancer 6:192204.
15. European Society of Neurogastroenterology and Motility. The inuence
of diet on gut microbiota. European Society of Neurogastroenterology
and Motility, Vienna, Austria.
16. Scott AJ, Alexander JL, Merrield CA, Cunningham D, Jobin C, Brown R,
Alverdy J, O'Keefe SJ, Gaskins HR, Teare J, Yu J, Hughes DJ, Verstraelen H,
Burton J, O'Toole PW, Rosenberg DW, Marchesi JR, Kinross JM. 2019.
International Cancer Microbiome Consortium consensus statement on
the role of the human microbiome in carcinogenesis. Gut 68:16241632.
17. Sonnenburg ED, Sonnenburg JL. 2014. Starving our microbial self: the
deleterious consequences of a diet decient in microbiota-accessible
carbohydrates. Cell Metab 20:779786.
18. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE,
Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ,
Turnbaugh PJ. 2014. Diet rapidly and reproducibly alters the human gut
microbiome. Nature 505:559563.
19. Smith RL, Soeters MR, Wüst RCI, Houtkooper RH. 2018. Metabolic exibil-
ity as an adaptation to energy resources and requirements in health and
disease. Endocr Rev 39:489517.
20. Storlien L, Oakes ND, Kelley DE. 2004. Metabolic exibility. Proc Nutr Soc
21. Berg G, Rybakova D, Fischer D, Cernava T, Vergès M-CC, Charles T, Chen
X, Cocolin L, Eversole K, Corral GH, Kazou M, Kinkel L, Lange L, Lima N,
Loy A, Macklin JA, Maguin E, Mauchline T, McClure R, Mitter B, Ryan M,
Sarand I, Smidt H, Schelkle B, Roume H, Kiran GS, Selvin J, de Souza RSC,
van Overbeek L, Singh BK, Wagner M, Walsh A, Sessitsch A, Schloter M.
2020. Microbiome denition re-visited: old concepts and new chal-
lenges. Microbiome 8:103.
22. Proctor L. 2019. Priorities for the next 10 years of human microbiome
research. Nature 569:623625.
23. Bäckhed F, Fraser CM, Ringel Y, Sanders ME, Sartor RB, Sherman PM,
Versalovic J, Young V, Finlay BB. 2012. Dening a healthy human gut
microbiome: current concepts, future directions, and clinical applica-
tions. Cell Host Microbe 12:611622.
24. McBurney MI, Davis C, Fraser CM, Schneeman BO, Huttenhower C,
Verbeke K, Walter J, Latulippe ME. 2019. Establishing what constitutes a
healthy human gut microbiome: state of the science, regulatory consid-
erations, and future directions. J Nutr 149:18821895.
25. Shanahan F, Ghosh TS, O'Toole PW. 2021. The healthy microbiome
what is the denition of a healthy gut microbiome? Gastroenterology
26. Warden CH, Fisler JS. 2008. Comparisons of diets used in animal models
of high-fat feeding. Cell Metab 7:277.
27. Pellizzon MA, Ricci MR. 2018. Effects of rodent diet choice and ber type
on data interpretation of gut microbiome and metabolic disease
research. Curr Protoc Toxicol 77:e55.
28. Jones D. 2008. In research: mice diet studies faulted. UC Davis, Davis,
29. Paoli A, Rubini A, Volek JS, Grimaldi KA. 2013. Beyond weight loss: a
review of the therapeutic uses of very-low-carbohydrate (ketogenic)
diets. Eur J Clin Nutr 67:789796.
30. Ludwig DS. 2020. The ketogenic diet: evidence for optimism but high-
quality research needed. J Nutr 150:13541359.
31. Khan S, Waliullah S, Godfrey V, Khan MAW, Ramachandran RA, Cantarel
BL, Behrendt C, Peng L, Hooper LV, Zaki H. 2020. Dietary simple sugars al-
ter microbial ecology in the gut and promote colitis in mice. Sci Transl
Med 12:eaay6218.
32. Gardner CD, Kiazand A, Alhassan S, Kim S, Stafford RS, Balise RR, Kraemer
HC, King AC. 2007. Comparison of the Atkins, Zone, Ornish, and LEARN
diets for change in weight and related risk factors among overweight
premenopausal women: the A to Z Weight Loss Study: a randomized
trial. JAMA 297:969.
33. Gardner CD, Trepanowski JF, Del Gobbo LC, Hauser ME, Rigdon J,
Ioannidis JPA, Desai M, King AC. 2018. Effect of low-fat vs low-carbohy-
drate diet on 12-month weight loss in overweight adults and the associ-
ation with genotype pattern or insulin secretion: the DIETFITS random-
ized clinical trial. JAMA 319:667679.
34. Wright N, Wilson L, Smith M, Duncan B, McHugh P. 2017. The BROAD
Study: a randomised controlled trial using a whole food plant-based diet
in the community for obesity, ischaemic heart disease or diabetes. Nutr
Diabetes 7:e256.
35. Borghjid S, Feinman R. 2012. Response of C57Bl/6 mice to a carbohy-
drate-free diet. Nutr Metab (Lond) 9:69.
36. Ericson U, Brunkwall L, Hellstrand S, Nilsson PM, Orho-Melander M. 2020.
Ahealth-conscious food pattern is associated with prediabetes and gut
microbiota in the Malmö Offspring Study. J Nutr 150:861872. https://
37. Brunstrom JM, Drake ACL, Forde CG, Rogers PJ. 2018. Undervalued and
ignored: are humans poorly adapted to energy-dense foods? Appetite
38. Hall KD, Ayuketah A, Brychta R, Cai H, Cassimatis T, Chen KY, Chung ST,
Costa E, Courville A, Darcey V, Fletcher LA, Forde CG, Gharib AM, Guo J,
Howard R, Joseph PV, McGehee S, Ouwerkerk R, Raisinger K, Rozga I,
Stagliano M, Walter M, Walter PJ, Yang S, Zhou M. 2019. Ultra-processed
diets cause excess calorie intake and weight gain: an inpatient random-
ized controlled trial of ad libitum food intake. Cell Metab 30:6777.e3.
39. Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, Campbell
WW, Hazbun TL, Volk BM, McCarter JP, Phinney SD, Volek JS. 2018. Effec-
tiveness and safety of a novel care model for the management of type 2
diabetes at 1 year: an open-label, non-randomized, controlled study. Di-
abetes Ther 9:583612.
40. Phinney S, Bailey B, Volek J. 2018. The ten dening characteristics of a
well-formulated ketogenic diet. Virta Health Corp, San Francisco, CA.
41. Ludwig DS, Willett WC, Volek JS, Neuhouser ML. 2018. Dietary fat: from foe
to friend? Science 362:764770.
42. Athinarayanan SJ, Hallberg SJ, McKenzie AL, Lechner K, King S, McCarter
JP, Volek JS, Phinney SD, Krauss RM. 2020. Impact of a 2-year trial of nutri-
tional ketosis on indices of cardiovascular disease risk in patients with
type 2 diabetes. Cardiovasc Diabetol 19:208.
43. Clemente JC, Ursell LK, Parfrey LW, Knight R. 2012. The impact of the gut
microbiota on human health: an integrative view. Cell 148:12581270.
44. Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. 2018.
Current understanding of the human microbiome. Nat Med 24:392400.
45. Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, Wang W, Tang W, Tan Z, Shi
J, Li L, Ruan B. 2015. Altered fecal microbiota composition in patients
with major depressive disorder. Brain Behav Immun 48:186194. https://
46. Johnson KV-A, Burnet PWJ. 2016. Microbiome: should we diversify from
diversity? Gut Microbes 7:455458.
47. Schnorr SL, Candela M, Rampelli S, Centanni M, Consolandi C, Basaglia G,
Turroni S, Biagi E, Peano C, Severgnini M, Fiori J, Gotti R, Bellis GD, Luiselli
D, Brigidi P, Mabulla A, Marlowe F, Henry AG, Crittenden AN. 2014. Gut
Minireview ®
March/April 2021 Volume 12 Issue 2 e00579-21 13
on April 13, 2021 by guest from
microbiome of the Hadza hunter-gatherers. Nat Commun 5:3654.
48. Petersen C, Round JL. 2014. Dening dysbiosis and its inuence on host
immunity and disease. Cell Microbiol 16:10241033.
49. Hooks KB, OMalley MA. 2017. Dysbiosis and its discontents. mBio 8:
50. Laudadio I, Fulci V, Palone F, Stronati L, Cucchiara S, Carissimi C. 2018.
Quantitative assessment of shotgun metagenomics and 16S rDNA
amplicon sequencing in the study of human gut microbiome. OMICS
51. Litvak Y, Bäumler AJ. 2019. Microbiota-nourishing immunity: a guide to
understanding our microbial self. Immunity 51:214224.
52. Foster KR, Schluter J, Coyte KZ, Rakoff-Nahoum S. 2017. The evolution of
the host microbiome as an ecosystem on a leash. Nature 548:4351.
53. McFall-Ngai M, Hadeld MG, Bosch TCG, Carey HV, Domazet-LošoT,
Douglas AE, Dubilier N, Eberl G, Fukami T, Gilbert SF, Hentschel U, King
N, Kjelleberg S, Knoll AH, Kremer N, Mazmanian SK, Metcalf JL, Nealson
K, Pierce NE, Rawls JF, Reid A, Ruby EG, Rumpho M, Sanders JG, Tautz D,
Wernegreen JJ. 2013. Animals in a bacterial world, a new imperative for
the life sciences. Proc Natl Acad Sci U S A 110:32293236. https://doi
54. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ,
Mosley M, Notterpek L, Ravussin E, Scheer FAJL, Seyfried TN, Varady KA,
Panda S. 2014. Meal frequency and timing in health and disease. Proc
Natl Acad Sci U S A 111:1664716653.
55. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. 2018. Intermit-
tent metabolic switching, neuroplasticity and brain health. Nat Rev Neu-
rosci 19:8194.
56. Smits SA, Leach J, Sonnenburg ED, Gonzalez CG, Lichtman JS, Reid G,
Knight R, Manjurano A, Changalucha J, Elias JE, Dominguez-Bello MG,
Sonnenburg JL. 2017. Seasonal cycling in the gut microbiome of the
Hadza hunter-gatherers of Tanzania. Science 357:802806. https://doi
57. Fumagalli M, Moltke I, Grarup N, Racimo F, Bjerregaard P, Jorgensen ME,
Korneliussen TS, Gerbault P, Skotte L, Linneberg A, Christensen C,
Brandslund I, Jorgensen T, Huerta-Sanchez E, Schmidt EB, Pedersen O,
Hansen T, Albrechtsen A, Nielsen R. 2015. Greenlandic Inuit show genetic
signatures of diet and climate adaptation. Science 349:13431347.
58. Girard C, Tromas N, Amyot M, Shapiro BJ. 2017. Gut microbiome of the
Canadian Arctic Inuit. mSphere 2:e00297-16.
59. Fragiadakis GK, Wastyk HC, Robinson JL, Sonnenburg ED, Sonnenburg
JL, Gardner CD. 2020. Long-term dietary intervention reveals resilience
of the gut microbiota despite changes in diet and weight. Am J Clin Nutr
60. López-Otín C, Kroemer G. 2021. Hallmarks of health. Cell 184:3363.
61. Frame LA, Costa E, Jackson SA. 2020. Current explorations of nutrition
and the gut microbiome: a comprehensive evaluation of the review liter-
ature. Nutr Rev 78:798812.
62. Krajmalnik-Brown R, Ilhan Z-E, Kang D-W, DiBaise JK. 2012. Effects of gut
microbes on nutrient absorption and energy regulation. Nutr Clin Pract
63. Walker AW, Ince J, Duncan SH, Webster LM, Holtrop G, Ze X, Brown D,
Stares MD, Scott P, Bergerat A, Louis P, McIntosh F, Johnstone AM,
Lobley GE, Parkhill J, Flint HJ. 2011. Dominant and diet-responsive
groups of bacteria within the human colonic microbiota. ISME J
64. Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, Bunger MK,
Bultman SJ. 2011. The microbiome and butyrate regulate energy metab-
olism and autophagy in the mammalian colon. Cell Metab 13:517526.
65. Ang QY, Alexander M, Newman JC, Tian Y, Cai J, Upadhyay V, Turnbaugh
JA, Verdin E, Hall KD, Leibel RL, Ravussin E, Rosenbaum M, Patterson AD,
Turnbaugh PJ. 2020. Ketogenic diets alter the gut microbiome resulting
in decreased intestinal Th17 cells. Cell 181:12631275.e16. https://doi
66. Zambrano-Zaragoza JF, Romo-Martínez EJ, de Jesús Durán-Avelar M,
García-Magallanes N, Vibanco-Pérez N. 2014. Th17 cells in autoimmune
and infectious diseases. Int J Inamm 2014:651503.
67. Schroeder BO, Birchenough GMH, Ståhlman M, Arike L, Johansson MEV,
Hansson GC, Bäckhed F. 2018. Bidobacteria or ber protects against
diet-induced microbiota-mediated colonic mucus deterioration. Cell
Host Microbe 23:2740.e7.
68. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M,
Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B,
Wilmes P, Stappenbeck TS, Núñez G, Martens EC. 2016. A dietary ber-
deprived gut microbiota degrades the colonic mucus barrier and enhan-
ces pathogen susceptibility. Cell 167:13391353.e21.
69. Swidsinski A, Dörffel Y, Loening-Baucke V, Gille C, Göktas Ö, Reißhauer A,
Neuhaus J, Weylandt K-H, Guschin A, Bock M. 2017. Reduced mass and
diversity of the colonic microbiome in patients with multiple sclerosis
and their improvement with ketogenic diet. Front Microbiol 8:1141.
70. Fasano A, Shea-Donohue T. 2005. Mechanisms of disease: the role of in-
testinal barrier function in the pathogenesis of gastrointestinal autoim-
mune diseases. Nat Clin Pract Gastroenterol Hepatol 2:416422. https://
71. Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. 2018.
The gut microbiota mediates the anti-seizure effects of the ketogenic
diet. Cell 173:17281741.e13.
72. Nagpal R, Neth BJ, Wang S, Craft S, Yadav H. 2019. Modied Mediterra-
nean-ketogenic diet modulates gut microbiome and short-chain fatty
acids in association with Alzheimers disease markers in subjects with
mild cognitive impairment. EBioMedicine 47:529542.
73. Cahill GF. 1976. Starvation in man. Clin Endocrinol Metab 5:397415.
74. Wood TR, Stubbs BJ, Juul SE. 2018. Exogenous ketone bodies as promis-
ing neuroprotective agents for developmental brain injury. Dev Neurosci
75. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier
M, Hennebelle M, Croteau E, Bocti C, Fulop T, Castellano C-A. 2016. Can
ketones help rescue brain fuel supply in later life? Implications for cogni-
tive health during aging and the treatment of Alzheimers disease. Front
Mol Neurosci 9:53.
76. Jaskiewicz J, Zhao Y, Hawes JW, Shimomura Y, Crabb DW, Harris RA.
1996. Catabolism of isobutyrate by colonocytes. Arch Biochem Biophys
77. Brown AJ, Jupe S, Briscoe CP. 2005. A family of fatty acid binding recep-
tors. DNA Cell Biol 24:5461.
78. Le Poul E, Loison C, Struyf S, Springael J-Y, Lannoy V, Decobecq M-E,
Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux
M. 2003. Functional characterization of human receptors for short chain
fatty acids and their role in polymorphonuclear cell activation. J Biol
Chem 278:2548125489.
79. Oliphant K, Allen-Vercoe E. 2019. Macronutrient metabolism by the
human gut microbiome: major fermentation by-products and their
impact on host health. Microbiome 7:91.
80. Graff EC, Fang H, Wanders D, Judd RL. 2016. Anti-inammatory effects of
the hydroxycarboxylic acid receptor 2. Metabolism 65:102113. https://
81. Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning
DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD,
Ganapathy V. 2009. GPR109A is a G-protein-coupled receptor for the
bacterial fermentation product butyrate and functions as a tumor sup-
pressor in colon. Cancer Res 69:28262832.
82. Henning SJ, Hird FJ. 1972. Ketogenesis from butyrate and acetate by the
caecum and the colon of rabbits. Biochem J 130:785790. https://doi
83. Iwanaga T, Kishimoto A. 2015. Cellular distributions of monocarboxylate
transporters: a review. Biomed Res 36:279301.
84. Roediger WEW. 1982. Utilization of nutrients by isolated epithelial cells
of the rat colon. Gastroenterology 83:424429.
85. Hanson PJ, Parsons DS. 1978. Factors affecting the utilization of ketone
bodies and other substrates by rat jejunum: effects of fasting and of diabe-
tes. J Physiol 278:5567.
Minireview ®
March/April 2021 Volume 12 Issue 2 e00579-21 14
on April 13, 2021 by guest from
86. Ferrer-Picón E, Dotti I, Corraliza AM, Mayorgas A, Esteller M, Perales JC,
Ricart E, Masamunt MC, Carrasco A, Tristán E, Esteve M, Salas A. 2020. In-
testinal inammation modulates the epithelial response to butyrate in
patients with inammatory bowel disease. Inamm Bowel Dis 26:4355.
87. Thibault R, De Coppet P, Daly K, Bourreille A, Cuff M, Bonnet C, Mosnier J,
Galmiche J, ShiraziBeechey S, Segain J. 2007. Down-regulation of the
monocarboxylate transporter 1 is involved in butyrate deciency during
intestinal inammation. Gastroenterology 133:19161927. https://doi
88. Cheng C-W, Biton M, Haber AL, Gunduz N, Eng G, Gaynor LT, Tripathi S,
Calibasi-Kocal G, Rickelt S, Butty VL, Moreno-Serrano M, Iqbal AM, Bauer-
Rowe KE, Imada S, Ulutas MS, Mylonas C, Whary MT, Levine SS, Basbinar
Y, Hynes RO, Mino-Kenudson M, Deshpande V, Boyer LA, Fox JG,
Terranova C, Rai K, Piwnica-Worms H, Mihaylova MM, Regev A, Yilmaz
ÖH. 2019. Ketone body signaling mediates intestinal stem cell homeo-
stasis and adaptation to diet. Cell 178:11151131.e15.
89. Smith SA, Ogawa SA, Chau L, Whelan KA, Hamilton KE, Chen J, Tan L,
Chen EZ, Keilbaugh S, Fogt F, Bewtra M, Braun J, Xavier RJ, Clish CB, Slaff
B, Weljie AM, Bushman FD, Lewis JD, Li H, Master SR, Bennett MJ,
Nakagawa H, Wu GD. 2020. Mitochondrial dysfunction in inammatory
bowel disease alters intestinal epithelial metabolism of hepatic acylcar-
nitines. J Clin Invest 131:e133371.
90. OKeefe SJD, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, Posma JM,
Kinross J, Wahl E, Ruder E, Vipperla K, Naidoo V, Mtshali L, Tims S,
Puylaert PGB, DeLany J, Krasinskas A, Beneel AC, Kaseb HO, Newton K,
Nicholson JK, de Vos WM, Gaskins HR, Zoetendal EG. 2015. Fat, bre and
cancer risk in African Americans and rural Africans. Nat Commun 6:6342.
91. Domingo JL, Nadal M. 2016. Carcinogenicity of consumption of red and
processed meat: what about environmental contaminants? Environ Res
92. IARC. 2015. IARC Monographs evaluate consumption of red meat and
processed meat. Press release 240. World Health Organization, Interna-
tional Agency for Research on Cancer, Geneva, Switzerland.
93. Janney A, Powrie F, Mann EH. 2020. Host-microbiota maladaptation in
colorectal cancer. Nature 585:509517.
94. Sari S, Sepanlou SG, Ikuta KS, Bisignano C, Salimzadeh H, Delavari A,
Ansari R, Roshandel G, Merat S, Fitzmaurice C, Force LM, Nixon MR,
Abbastabar H, Abegaz KH, Afarideh M, Ahmadi A, Ahmed MB,
Akinyemiju T, Alahdab F, Ali R, Alikhani M, Alipour V, Aljunid SM, Almadi
MAH, Almasi-Hashiani A, Al-Raddadi RM, Alvis-Guzman N, Amini S,
Anber NH, Ansari-Moghaddam A, Arabloo J, AreZ, Asghari Jafarabadi
M, Azadmehr A, Badawi A, Baheiraei N, Bärnighausen TW, Basaleem H,
Behzadifar M, Behzadifar M, Belayneh YM, Berhe K, Bhattacharyya K,
Biadgo B, Bijani A, Biondi A, Bjørge T, Borzì AM, Bosetti C, Bou-Orm IR,
Brenner H, Briko AN, et al. 2019. The global, regional, and national bur-
den of colorectal cancer and its attributable risk factors in 195 countries
and territories, 19902017: a systematic analysis for the Global Burden of
Disease Study 2017. Lancet Gastroenterol Hepatol 4:913933. https://doi
95. Shrank WH, Patrick AR, Alan Brookhart M. 2011. Healthy user and related
biases in observational studies of preventive interventions: a primer for
physicians. J Gen Intern Med 26:546550.
96. Archer E, Pavela G, Lavie CJ. 2015. The inadmissibility of what we eat in
America and NHANES dietary data in nutrition and obesity research and
the scientic formulation of national dietary guidelines. Mayo Clin Proc
97. Beyaz S, Mana MD, Roper J, Kedrin D, Saadatpour A, Hong S-J, Bauer-Rowe
KE, Xifaras ME, Akkad A, Arias E, Pinello L, Katz Y, Shinagare S, Abu-Remaileh
M, Mihaylova MM, Lamming DW, Dogum R, Guo G, Bell GW, Selig M,
Nielsen GP, Gupta N, Ferrone CR, Deshpande V, Yuan G-C, Orkin SH,
Sabatini DM, Yilmaz ÖH. 2016. High-fat diet enhances stemness and tumori-
genicity of intestinal progenitors. Nature 531:5358.
98. Luo C, Puigserver P. 2016. Dietary fat promotes intestinal dysregulation.
Nature 531:4243.
99. Schulz MD, Atay Ç, Heringer J, Romrig FK, Schwitalla S, Aydin B, Ziegler PK,
Varga J, Reindl W, Pommerenke C, Salinas-Riester G, Böck A, Alpert C, Blaut
High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis
independently of obesity. Nature 514:508512.
100. Doerner SK, Reis ES, Leung ES, Ko JS, Heaney JD, Berger NA, Lambris JD,
Nadeau JH. 2016. High-fat diet-induced complement activation mediates
intestinal inammation and neoplasia, independent of obesity. Mol Cancer
Res 14:953965.
101. Carracedo A, Cantley LC, PandolPP. 2013. Cancer metabolism: fatty
acid oxidation in the limelight. Nat Rev Cancer 13:227232. https://doi
102. Currie E, Schulze A, Zechner R, Walther TC, Farese RV. 2013. Cellular fatty
acid metabolism and cancer. Cell Metab 18:153161.
103. Kanarek N, Petrova B, Sabatini DM. 2020. Dietary modications for
enhanced cancer therapy. Nature 579:507517.
104. Louis P, Hold GL, Flint HJ. 2014. The gut microbiota, bacterial metabo-
lites and colorectal cancer. Nat Rev Microbiol 12:661672. https://doi
105. Bastide NM, Pierre FHF, Corpet DE. 2011. Heme iron from meat and risk
of colorectal cancer: a meta-analysis and a review of the mechanisms
involved. Cancer Prev Res (Phila) 4:177184.
106. Kruger C, Zhou Y. 2018. Red meat and colon cancer: a review of mecha-
nistic evidence for heme in the context of risk assessment methodology.
Food Chem Toxicol 118:131153.
107. Hu L-Y, Ku F-C, Lu T, Shen C-C, Hu Y-W, Yeh C-M, Tzeng C-H, Chen T-J,
Chen P-M, Liu C-J. 2015. Risk of cancer in patients with irritable bowel
syndrome: a nationwide population-based study. Ann Epidemiol
108. Jess T, Gamborg M, Matzen P, Munkholm P, Sorensen TIA. 2005. Increased
risk of intestinal cancer in Crohnsdisease:ameta-analysisofpopulation-
based cohort studies. Am J Gastroenterol 100:27242729.
109. Nørgaard M, Farkas DK, Pedersen L, Erichsen R, de la Cour ZD, Gregersen
H, Sørensen HT. 2011. Irritable bowel syndrome and risk of colorectal
cancer: a Danish nationwide cohort study. Br J Cancer 104:12021206.
110. Austin GL, Dalton CB, Hu Y, Morris CB, Hankins J, Weinland SR, Westman
EC, Yancy WS, Drossman DA. 2009. A very low-carbohydrate diet
improves symptoms and quality of life in diarrhea-predominant irritable
bowel syndrome. Clin Gastroenterol Hepatol 7:706708.e1. https://doi
111. Tóth C, Dabóczi A, Howard M, J Miller N, Clemens Z. 2016. Crohnsdis-
ease successfully treated with the paleolithic ketogenic diet. Int J Case
Rep Imag 7:570.
112. Lowery RP, Wilson JM, Sharp MH, Wilson GJ, Wagner R. 2017. The effects
of exogenous ketones on biomarkers of Crohns disease: a case report. J
Gastroenterol Dig Dis 2:811.
113. Poff AM, Ari C, Arnold P, Seyfried TN, D'Agostino DP. 2014. Ketone sup-
plementation decreases tumor cell viability and prolongs survival of
mice with metastatic cancer. Int J Cancer 135:17111720. https://doi
114. Weber DD, Aminazdeh-Gohari S, Koer B. 2018. Ketogenic diet in cancer
therapy. Aging (Albany NY) 10:164165.
115. Zhang N, Liu C, Jin L, Zhang R, Wang T, Wang Q, Chen J, Yang F, Siebert
H-C, Zheng X. 2020. Ketogenic diet elicits antitumor properties through
inducing oxidative stress, inhibiting MMP-9 expression, and rebalancing
M1/M2 tumor-associated macrophage phenotype in a mouse model of
colon cancer. J Agric Food Chem 68:1118211196.
116. Khodabakhshi A, Akbari ME, Mirzaei HR, Seyfried TN, Kalamian M,
Davoodi SH. 2020. Effects of ketogenic metabolic therapy on patients
with breast cancer: a randomized controlled clinical trial. Clin Nutr
117. Martin-McGill KJ, Marson AG, Tudur Smith C, Young B, Mills SJ, Cherry
MG, Jenkinson MD. 2020. Ketogenic diets as an adjuvant therapy for
glioblastoma (KEATING): a randomized, mixed methods, feasibility
study. J Neurooncol 147:213227.
118. Branco AF, Ferreira A, Simões RF, Magalhães-Novais S, Zehowski C, Cope
E, Silva AM, Pereira D, Sardão VA, Cunha-Oliveira T. 2016. Ketogenic
Minireview ®
March/April 2021 Volume 12 Issue 2 e00579-21 15
on April 13, 2021 by guest from
diets: from cancer to mitochondrial diseases and beyond. Eur J Clin
Invest 46:285298.
119. Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG,
Koer B. 2020. Ketogenic diet in the treatment of cancerwhere do we
stand? Mol Metab 33:102121.
120. Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller
ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. 2014.
Ketogenic diets as an adjuvant cancer therapy: history and potential
mechanism. Redox Biol 2:963970.
121. Martuscello RT, Vedam-Mai V, McCarthy DJ, Schmoll ME, Jundi MA,
Louviere CD, Grifth BG, Skinner CL, Suslov O, Deleyrolle LP, Reynolds
BA. 2016. A supplemented high-fat low-carbohydrate diet for the treat-
ment of glioblastoma. Clin Cancer Res 22:24822495.
122. Minzer S. 2020. Effectiveness of ketogenic diets on the survival of adult
oncological patients. Nutr Cancer 2020:111.
123. Erickson N, Boscheri A, Linke B, Huebner J. 2017. Systematic review: iso-
caloric ketogenic dietary regimes for cancer patients. Med Oncol 34:72.
124. Schatzkin A, Lanza E, Corle D, Lance P, Iber F, Caan B, Shike M, Weissfeld
J, Burt R, Cooper MR, Kikendall JW, Cahill J, Freedman L, Marshall J,
Schoen RE, Slattery M. 2000. Lack of effect of a low-fat, high-ber diet on
the recurrence of colorectal adenomas. N Engl J Med 342:11491155.
125. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Stampfer MJ, Rosner B,
Speizer FE, Willett WC. 1999. Dietary ber and the risk of colorectal can-
cer and adenoma in women. N Engl J Med 340:169176.
126. Lanza E, Yu B, Murphy G, Albert PS, Caan B, Marshall JR, Lance P, Paskett
ED, Weissfeld J, Slattery M, Burt R, Iber F, Shike M, Kikendall JW, Brewer
BK, Schatzkin A. 2007. The polyp prevention trialcontinued follow-up
study: no effect of a low-fat, high-ber, high-fruit, and -vegetable diet
on adenoma recurrence eight years after randomization. Cancer Epide-
miol Biomarkers Prev 16:17451752.
127. Beresford SAA, Johnson KC, Ritenbaugh C, Lasser NL, Snetselaar LG,
Black HR, Anderson GL, Assaf AR, Bassford T, Bowen D, Brunner RL,
Brzyski RG, Caan B, Chlebowski RT, Gass M, Harrigan RC, Hays J, Heber D,
Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Jackson RD, Kotchen
JM, Kuller LH, LaCroix AZ, Lane DS, Langer RD, Lewis CE, Manson JE,
Margolis KL, Mossavar-Rahmani Y, Ockene JK, Parker LM, Perri MG,
Phillips L, Prentice RL, Robbins J, Rossouw JE, Sarto GE, Stefanick ML,
Van Horn L, Vitolins MZ, Wactawski-Wende J, Wallace RB, Whitlock E.
2006. Low-fat dietary pattern and risk of colorectal cancer: the Womens
Health Initiative Randomized Controlled Dietary Modication Trial.
JAMA 295:643654.
128. Prentice RL, Thomson CA, Caan B, Hubbell FA, Anderson GL, Beresford
SAA, Pettinger M, Lane DS, Lessin L, Yasmeen S, Singh B, Khandekar J,
Shikany JM, Sattereld S, Chlebowski RT. 2007. Low-fat dietary pattern
and cancer incidence in the Womens Health Initiative Dietary Modica-
tion Randomized Controlled Trial. J Natl Cancer Inst 99:15341543.
129. Prentice RL, Caan B, Chlebowski RT, Patterson R, Kuller LH, Ockene JK,
Margolis KL, Limacher MC, Manson JE, Parker LM, Paskett E, Phillips L,
Robbins J, Rossouw JE, Sarto GE, Shikany JM, Stefanick ML, Thomson CA,
Van Horn L, Vitolins MZ, Wactawski-Wende J, Wallace RB, Wassertheil-
Smoller S, Whitlock E, Yano K, Adams-Campbell L, Anderson GL, Assaf
AR, Beresford SAA, Black HR, Brunner RL, Brzyski RG, Ford L, Gass M, Hays
J, Heber D, Heiss G, Hendrix SL, Hsia J, Hubbell FA, Jackson RD, Johnson
KC, Kotchen JM, LaCroix AZ, Lane DS, Langer RD, Lasser NL, Henderson
MM. 2006. Low-fat dietary pattern and risk of invasive breast cancer: the
Womens Health Initiative Randomized Controlled Dietary Modication
Trial. JAMA 295:629642.
130. Parnaud G, Peiffer G, Taché S, Corpet DE. 1998.Effect of meat (beef, chicken,
and bacon) on rat colon carcinogenesis. Nutr Cancer 32:165173. https://
131. Sakaguchi M, Hiramatsu Y, Takada H, Yamamura M, Hioki K, Saito K,
Yamamoto M. 1984. Effect of dietary unsaturated and saturated fats on
azoxymethane-induced colon carcinogenesis in rats. Cancer Res
132. Johnston BC, Zeraatkar D, Han MA, Vernooij RWM, Valli C, El Dib R,
Marshall C, Stover PJ, Fairweather-Taitt S, Wójcik G, Bhatia F, de Souza R,
Brotons C, Meerpohl JJ, Patel CJ, Djulbegovic B, Alonso-Coello P, Bala
MM, Guyatt GH. 2019. Unprocessed red meat and processed meat con-
sumption: dietary guideline recommendations from the Nutritional Rec-
ommendations (NutriRECS) Consortium. Ann Intern Med 171:756764.
133. Alexander DD, Cushing CA, Lowe KA, Sceurman B, Roberts MA. 2009. Meta-
analysis of animal fat or animal protein intake and colorectal cancer. Am J
Clin Nutr 89:14021409.
134. Mejborn H, Møller SP, Thygesen LC, Biltoft-Jensen A. 2020. Dietary intake
of red meat, processed meat, and poultry and risk of colorectal cancer
and all-cause mortality in the context of dietary guideline compliance.
Nutrients 13:32.
135. Turner ND, Lloyd SK. 2017. Association between red meat consumption
and colon cancer: a systematic review of experimental results. Exp Biol Med
(Maywood) 242:813839.
136. Han MA, Zeraatkar D, Guyatt GH, Vernooij RWM, El Dib R, Zhang Y,
Algarni A, Leung G, Storman D, Valli C, Rabassa M, Rehman N, Parvizian
MK, Zworth M, Bartoszko JJ, Lopes LC, Sit D, Bala MM, Alonso-Coello P,
Johnston BC. 2019. Reduction of red and processed meat intake and
cancer mortality and incidence: a systematic review and meta-analysis
of cohort studies. Ann Intern Med 171:711720.
137. Astrup A, Magkos F, Bier DM, Brenna JT, de Oliveira Otto MC, Hill JO,
King JC, Mente A, Ordovas JM, Volek JS, Yusuf S, Krauss RM. 2020. Satu-
rated fats and health: a reassessment and proposal for food-based rec-
ommendations. J Am Coll Cardiol 76:844857.
138. Dehghan M, Mente A, Zhang X, Swaminathan S, Li W, Mohan V, Iqbal R,
Kumar R, Wentzel-Viljoen E, Rosengren A, Amma LI, Avezum A, Chifamba J,
Diaz R, Khatib R, Lear S, Lopez-Jaramillo P, Liu X, Gupta R, Mohammadifard
A, Yusuf R, Hussein Yusufali A, Teo KK, Rangarajan S, Dagenais G,
Bangdiwala SI, Islam S, Anand SS, Yusuf S, Diaz R, Orlandini A, Linetsky
B, Toscanelli S, Casaccia G, Cuneo JM, Rahman O, Yusuf R, Azad A,
Rabbani K, Cherry H, Mannan A, Hassan I, et al. 2017. Associations offats
and carbohydrate intake with cardiovascular disease and mortality in 18
countries from ve continents (PURE): a prospective cohort study. Lancet
139. Lee JE, McLerran DF, Rolland B, Chen Y, Grant EJ, Vedanthan R, Inoue M,
Tsugane S, Gao Y-T, Tsuji I, Kakizaki M, Ahsan H, Ahn Y-O, Pan W-H,
Ozasa K, Yoo K-Y, Sasazuki S, Yang G, Watanabe T, Sugawara Y, Parvez F,
Kim D-H, Chuang S-Y, Ohishi W, Park SK, Feng Z, Thornquist M, Boffetta
P, Zheng W, Kang D, Potter J, Sinha R. 2013. Meat intake and cause-spe-
cic mortality: a pooled analysis of Asian prospective cohort studies. Am
J Clin Nutr 98:10321041.
140. Key TJ, Appleby PN, Spencer EA, Travis RC, Roddam AW, Allen NE. 2009.
Cancer incidence in vegetarians: results from the European Prospective
Investigation into Cancer and Nutrition (EPIC-Oxford). Am J Clin Nutr
141. Singh PN, Fraser GE. 1998. Dietary risk factors for colon cancer in a low-
risk population. Am J Epidemiol 148:761774.
142. Qian F, Riddle MC, Wylie-Rosett J, Hu FB. 2020. Red and processed meats
and health risks: how strong is the evidence? Diabetes Care 43:265271.
143. West-Denning J, Prochazka AV. 2020. NutriRECS Consortium provides
weak recommendations for continuing current red meat and processed
meat consumption. Ann Intern Med 172:JC15.
144. Ferraro JV, Plummer TW, Pobiner BL, Oliver JS, Bishop LC, Braun DR,
Ditcheld PW, Seaman JW, Binetti KM, Seaman JW, Hertel F, Potts R.
2013. Earliest archaeological evidence of persistent hominin carnivory.
PLoS One 8:e62174.
145. Cordain L, Eaton S, Miller JB, Mann N, Hill K. 2002. The paradoxical nature
of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin
Nutr 56:S42S52.
146. Mann N. 2007. Meat in the human diet: an anthropological perspective.
Nutr Diet 64:S102S107.
147. Milton K. 2003. The critical role played by animal source foods in human
(Homo) evolution. J Nutr 133:3886S3892S.
Minireview ®
March/April 2021 Volume 12 Issue 2 e00579-21 16
on April 13, 2021 by guest from
148. Creely SJ, McTernan PG, Kusminski CM, Fisher Ff M, Da Silva NF, Khanolkar
M, Evans M, Harte AL, Kumar S. 2007. Lipopolysaccharide activates an
innate immune system response in human adipose tissue in obesity and
type 2 diabetes. Am J Physiol-Endocrinol Metab 292:E740E747. https://doi
149. Vatanen T, Kostic AD, d'Hennezel E, Siljander H, Franzosa EA, Yassour M,
Kolde R, Vlamakis H, Arthur TD, Hämäläinen A-M, Peet A, Tillmann V, Uibo
R, Mokurov S, Dorshakova N, Ilonen J, Virtanen SM, Szabo SJ, Porter JA,
Lähdesmäki H, Huttenhower C, Gevers D, Cullen TW, Knip M, Xavier RJ, DIA-
BIMMUNE Study Group. 2016. Variation in microbiome LPS immunogenic-
ity contributes to autoimmunity in humans. Cell 165:842853. https://doi
150. Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E. 2009. Chylomicrons
promote intestinal absorption of lipopolysaccharides. J Lipid Res
151. Erridge C, Attina T, Spickett CM, Webb DJ. 2007. A high-fat meal induces
low-grade endotoxemia: evidence of a novel mechanism of postpran-
dial inammation. Am J Clin Nutr 86:12861292.
152. Laugerette F, Vors C, Géloën A, Chauvin M-A, Soulage C, Lambert-
Porcheron S, Peretti N, Alligier M, Burcelin R, Laville M, Vidal H, Michalski
M-C. 2011. Emulsied lipids increase endotoxemia: possible role in early
postprandial low-grade inammation. J Nutr Biochem 22:5359. https://
153. Harris HW, Grunfeld C, Feingold KR, Read TE, Kane JP, Jones AL,
Eichbaum EB, Bland GF, Rapp JH. 1993. Chylomicrons alter the fate of en-
dotoxin, decreasing tumor necrosis factor release and preventing death.
J Clin Invest 91:10281034.
154. Manco M, Putignani L, Bottazzo GF. 2010. Gut microbiota, lipopolysac-
charides, and innate immunity in the pathogenesis of obesity and cardi-
ovascular risk. Endocr Rev 31:817844.
155. Vreugdenhil ACE, Rousseau CH, Hartung T, Greve JWM, van 't Veer C,
Buurman WA. 2003. Lipopolysaccharide (LPS)-binding protein mediates
LPS detoxication by chylomicrons. J Immunol 170:13991405. https://
156. Parlesak A, Schaeckeler S, Moser L, Bode C. 2007. Conjugated primary
bile salts reduce permeability of endotoxin through intestinal epithelial
cells and synergize with phosphatidylcholine in suppression of inam-
matory cytokine production. Crit Care Med 35:23672374. https://doi
157. Lim CL, Pyne D, Horn P, Kalz A, Saunders P, Peake J, Suzuki K, Wilson G,
Mackinnon LT. 2009. The effects of increased endurance training load
on biomarkers of heat intolerance during intense exercise in the heat.
Appl Physiol Nutr Metab 34:616624.
158. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM,
Burcelin R. 2008. Changes in gut microbiota control metabolic endotox-
emia-induced inammation in high-fat diet-induced obesity and diabe-
tes in mice. Diabetes 57:14701481.
159. Yue C, Ma B, Zhao Y, Li Q, Li J. 2012. Lipopolysaccharide-induced bacte-
rial translocation is intestine site-specic and associates with intestinal
mucosal inammation. Inammation 35:18801888.
160. Thaiss CA, Levy M, Grosheva I, Zheng D, Soffer E, Blacher E, Braverman S,
Tengeler AC, Barak O, Elazar M, Ben-Zeev R, Lehavi-Regev D, Katz MN,
Pevsner-Fischer M, Gertler A, Halpern Z, Harmelin A, Aamar S, Serradas
P, Grosfeld A, Shapiro H, Geiger B, Elinav E. 2018. Hyperglycemia drives
intestinal barrier dysfunction and risk for enteric infection. Science
161. dHennezel E, Abubucker S, Murphy LO, Cullen TW. 2017. Total lipopoly-
saccharide from the human gut microbiome silences Toll-like receptor
signaling. mSystems 2:e00046-17.
162. Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R. 2018. Anti-oxidant and
anti-inammatory activity of ketogenic diet: new perspectives for neuro-
protection in Alzheimers disease. Antioxidants (Basel) 7:63. https://doi
163. Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D,
D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL,
Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. 2015. The ke-
tone metabolite
-hydroxybutyrate blocks NLRP3 inammasome-medi-
ated inammatory disease. Nat Med 21:263269.
164. Forsythe CE, Phinney SD, Fernandez ML, Quann EE, Wood RJ, Bibus DM,
Kraemer WJ, Feinman RD, Volek JS. 2008. Comparison of low fat and low
carbohydrate diets on circulating fatty acid composition and markers of
inammation. Lipids 43:6577.
165. Shen Y, Kapfhamer D, Minnella AM, Kim J-E, Won SJ, Chen Y, Huang Y,
Low LH, Massa SM, Swanson RA. 2017. Bioenergetic state regulates
innate inammatory responses through the transcriptional co-repressor
CtBP. Nat Commun 8:624.
166. Qi J, You T, Li J, Pan T, Xiang L, Han Y, Zhu L. 2018. Circulating trimethyl-
amine N-oxide and the risk of cardiovascular diseases: a systematic
review and meta-analysis of 11 prospective cohort studies. J Cell Mol
Med 22:185194.
167. Romano KA, Martinez-del Campo A, Kasahara K, Chittim CL, Vivas EI,
Amador-Noguez D, Balskus EP, Rey FE. 2017. Metabolic, epigenetic, and
transgenerational effects of gut bacterial choline consumption. Cell
Host Microbe 22:279290.e7.
168. Kivenson V, Giovannoni SJ. 2020. An expanded genetic code enables tri-
methylamine metabolism in human gut bacteria. mSystems 5:e00413-
169. Jia J, Dou P, Gao M, Kong X, Li C, Liu Z, Huang T. 2019. Assessment of
causal direction between gut microbiota-dependent metabolites and
cardiometabolic health: a bidirectional Mendelian randomization analy-
sis. Diabetes 68:17471755.
170. Wan Y, Yuan J, Li J, Li H, Zhang J, Tang J, Ni Y, Huang T, Wang F, Zhao F,
Li D. 2020. Unconjugated and secondary bile acid proles in response to
higher-fat, lower-carbohydrate diet and associated with related gut
microbiota: a 6-month randomized controlled-feeding trial. Clin Nutr
171. Raimondi F, Santoro P, Barone MV, Pappacoda S, Barretta ML, Nanayakkara
M, Apicella C, Capasso L, Paludetto R. 2008. Bile acids modulate tight junc-
tion structure and barrier function of Caco-2 monolayers via EGFR activa-
tion. Am J Physiol Gastrointest Liver Physiol 294:G906G913. https://doi
172. Santoro P, Raimondi F, Annunziata S, Paludetto R, Annella T, Ciccimarra F.
2002. Unconjugated bile acids modulate adult and neonatal neutrophil
chemotaxis induced in vitro by N-formyl-Met-Leu-Phe-peptide. Pediatr Res
173. Keating N, Keely SJ. 2009. Bile acids in regulation of intestinal physiol-
ogy. Curr Gastroenterol Rep 11:375382.
174. D'Aldebert E, Biyeyeme Bi Mve M-J, Mergey M, Wendum D, Firrincieli D,
Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N.
2009. Bile salts control the antimicrobial peptide cathelicidin through
nuclear receptors in the human biliary epithelium. Gastroenterology
175. Lorenzo-Zúñiga V. 2003. Oral bile acids reduce bacterial overgrowth,
bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology
176. Kidd M, Modlin IM, Gustafsson BI, Drozdov I, Hauso O, Pfragner R. 2008.
Luminal regulation of normal and neoplastic human EC cell serotonin
release is mediated by bile salts, amines, tastants, and olfactants. Am J Phys-
iol Gastrointest Liver Physiol 295:G260272.
177. Liu T, Song X, Khan S, Li Y, Guo Z, Li C, Wang S, Dong W, Liu W, Wang B,
Cao H. 2020. The gut microbiota at the intersection of bile acids and in-
testinal carcinogenesis: an old story, yet mesmerizing. Int J Cancer
178. Blachier F, Beaumont M, Kim E. 2019. Cysteine-derived hydrogen sulde and
gut health: a matter of endogenous or bacterial origin. Curr Opin Clin Nutr
Metab Care 22:6875.
179. Singh S, Lin H. 2015. Hydrogen sulde in physiology and diseases of the
digestive tract. Microorganisms 3:866889.
180. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A,
Antonopoulos DA, Jabri B, Chang EB. 2012. Dietary-fat-induced tauro-
cholic acid promotes pathobiont expansion and colitis in Il10
Nature 487:104108.
181. Magee EA, Richardson CJ, Hughes R, Cummings JH. 2000. Contribution
of dietary protein to sulde production in the large intestine: an in vitro
and a controlled feeding study in humans. Am J Clin Nutr 72:14881494.
182. Kellingray L, Tapp HS, Saha S, Doleman JF, Narbad A, Mithen RF. 2017.
Consumption of a diet rich in Brassica vegetables is associated with a
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reduced abundance of sulphate-reducing bacteria: a randomised cross-
over study. Mol Nutr Food Res 61:1600992.
183. Costantini L, Molinari R, Farinon B, Merendino N. 2017. Impact of
omega-3 fatty acids on the gut microbiota. Int J Mol Sci 18:2645. https://
184. Mokkala K, Houttu N, Cansev T, Laitinen K. 2020. Interactions of dietary fat
with the gut microbiota: evaluation of mechanisms and metabolic conse-
quences. Clin Nutr 39:9941018.
185. Lichtman JS, Alsentzer E, Jaffe M, Sprockett D, Masutani E, Ikwa E,
Fragiadakis GK, Clifford D, Huang BE, Sonnenburg JL, Huang KC, Elias JE.
2016. The effect of microbial colonization on the host proteome varies by
gastrointestinal location. ISME J 10:11701181.
186. Ludwig DS, Kushi LH, Heymseld SB. 2018. Conicts of interest in nutri-
tion research. JAMA 320:93.
187. Klurfeld DM. 2018. What is the role of meat in a healthy diet? Anim Front
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... Secondary bile acids have complex and unelucidated biological functions. Studies have illustrated that secondary bile acids regulated by high fat diet has adverse metabolic effects (146). DCA tends to increase in diet-related or genetic childhood obesity (147). ...
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The prevalence of overweight and obesity in children and adolescents is an increasing public health problem. Pediatric overweight and obesity result from multiple factors, including genetic background, diet, and lifestyle. In addition, the gut microbiota and their metabolites play crucial roles in the progression of overweight and obesity of children. Therefore, we reviewed the roles of gut microbiota in overweight/obese children. The relationship between pediatric overweight/obesity and gut metabolites, such as short-chain fatty acids, medium-chain fatty acids, amino acids, amines, and bile acids, are also summarized. Targeting gut microbiota and metabolites might be a promising strategy for interventions aimed at reducing pediatric overweight/obesity.
... intestine, termed "alpha diversity," can dramatically differ among subjects, however it is typically used to compare experimental cohorts. While diet, environment, and medication usage are dominant shapers of the gut microbiome (Francisco et al., 2020;Rowan et al., 2017;Weikel et al., 2012), there are also microbe-microbe interactions through the gut Muegge et al., 2011;Rothschild et al., 2018;Sholl et al., 2021;Zhernakova et al., 2016). ...
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Age-related macular degeneration (AMD) is a complex disease with increasing numbers of individuals being afflicted and treatment modalities limited. There are strong interactions between diet, age, the metabolome, and gut microbiota, and all of these have roles in the pathogenesis of AMD. Communication axes exist between the gut microbiota and the eye, therefore, knowing how the microbiota influences the host metabolism during aging could guide a better understanding of AMD pathogenesis. While considerable experimental evidence exists for a diet-gut–eye axis from murine models of human ocular diseases, human diet-microbiome-metabolome studies are needed to elucidate changes in the gut microbiome at the taxonomic and functional levels that are functionally related to ocular pathology. Such studies will reveal new ways to diminish risk for progression of- or incidence of- AMD. Current data suggest that consuming diets rich in dark fish, fruits, vegetables, and low in glycemic index are most retina-healthful during aging.
... Adding to this heterogeneity, Kennedy et al. [70] concluded that a very-low-carbohydrate diet (with lower protein content) in mice "induces a unique metabolic state congruous with weight loss". Clearly, this research must be extrapolated to humans with caution, in view of well described limitations involving idiosyncrasies of inbred strains, confounding from uncontrolled dietary exposures and dissimilar nutrition requirements of rodents and humans [71][72][73][74]. For instance, saturated fat and sugar often comprise most calories on high-fat rodent diets, a combination that causes hypothalamic inflammation and systemic insulin resistance [75][76][77][78][79][80][81][82]. ...
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The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake (“eat less”) and increase energy expenditure (“move more”). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on “complex endocrine, metabolic, and nervous system signals” that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, “ultra-processed” foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body’s metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.
... Low fiber intake would likely result in decreased bacterially produced butyrate, but KD accelerate endogenous production of beta-hydroxybutyrate in the liver, estimated to be in the range of 100-150 grams per day during nutritional ketosis [176]. Ketones are short-chain fatty acids that can function like butyrate as a preferred energy source and a signaling molecule to promote gut health [177]. From this perspective, nutritional ketosis may promote gut health. ...
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The decades-long dietary experiment embodied in the Dietary Guidelines for Americans (DGA) focused on limiting fat, especially saturated fat, and higher carbohydrate intake has coincided with rapidly escalating epidemics of obesity and type 2 diabetes (T2D) that are contributing to the progression of cardiovascular disease (CVD) and other diet-related chronic diseases. Moreover, the lack of flexibility in the DGA as it pertains to low carbohydrate approaches does not align with the contemporary trend toward precision nutrition. We argue that personalizing the level of dietary carbohydrate should be a high priority based on evidence that Americans have a wide spectrum of metabolic variability in their tolerance to high carbohydrate loads. Obesity, metabolic syndrome, and T2D are conditions strongly associated with insulin resistance, a condition exacerbated by increased dietary carbohydrate and improved by restricting carbohydrate. Low-carbohydrate diets are grounded across the time-span of human evolution, have well-established biochemical principles, and are now supported by multiple clinical trials in humans that demonstrate consistent improvements in multiple established risk factors associated with insulin resistance and cardiovascular disease. The American Diabetes Association (ADA) recently recognized a low carbohydrate eating pattern as an effective approach for patients with diabetes. Despite this evidence base, low-carbohydrate diets are not reflected in the DGA. As the DGA Dietary Patterns have not been demonstrated to be universally effective in addressing the needs of many Americans and recognizing the lack of widely available treatments for obesity, metabolic syndrome, and T2D that are safe, effective, and sustainable, the argument for an alternative, low-carbohydrate Dietary Pattern is all the more compelling.
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Animal source foods are evolutionarily appropriate foods for humans. It is therefore remarkable that they are now presented by some as unhealthy, unsustainable, and unethical, particularly in the urban West. The benefits of consuming them are nonetheless substantial, as they offer a wide spectrum of nutrients that are needed for cell and tissue development, function, and survival. They play a role in proper physical and cognitive development of infants, children, and adolescents, and help promote maintenance of physical function with ageing. While high-red meat consumption in the West is associated with several forms of chronic disease, these associations remain uncertain in other cultural contexts or when consumption is part of wholesome diets. Besides health concerns, there is also widespread anxiety about the environmental impacts of animal source foods. Although several production methods are detrimental (intensive cropping for feed, overgrazing, deforestation, water pollution, etc.) and require substantial mitigation, damaging impacts are not intrinsic to animal husbandry. When well-managed, livestock farming contributes to ecosystem management and soil health, while delivering high-quality foodstuffs through the upcycling of resources that are otherwise non-suitable for food production, making use of marginal land and inedible materials (forage, by-products, etc.), integrating livestock and crop farming where possible has the potential to benefit plant food production through enhanced nutrient recycling, while minimising external input needs such as fertilisers and pesticides. Moreover, the impacts on land use, water wastage, and greenhouse gas emissions are highly contextual, and their estimation is often erroneous due to a reductionist use of metrics. Similarly, whether animal husbandry is ethical or not depends on practical specificities, not on the fact that animals are involved. Such discussions also need to factor in that animal husbandry plays an important role in culture, societal well-being, food security, and the provision of livelihoods. We seize this opportunity to argue for less preconceived assumptions about alleged effects of animal source foods on the health of the planet and the humans and animals involved, for less top-down planning based on isolated metrics or (Western) technocratic perspectives, and for more holistic and circumstantial approaches to the food system.
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Meat intake has been linked to increased risk of colorectal cancer (CRC) and mortality. However, diet composition may affect the risks. We aimed to estimate associations between red and processed meat and poultry intake and risk of CRC and all-cause mortality and if they are modified by dietary quality using Cox regression analyses. Baseline dietary data were obtained from three survey rounds of the Danish National Survey on Diet and Physical Activity. Data on CRC and all-cause mortality were extracted from national registers. The cohort was followed from date of survey interview—or for CRC, from age 50 years, whichever came last, until 31 December 2017. Meat intake was analysed categorically and continuously, and stratified by dietary quality for 15–75-year-old Danes at baseline, n 6282 for CRC and n 9848 for mortality analyses. We found no significant association between red and processed meat intake and CRC risk. For poultry, increased CRC risk for high versus low intake (HR 1.62; 95%CI 1.13–2.31) was found, but not when examining risk change per 100 g increased intake. We showed no association between meat intake and all-cause mortality. The association between meat intake and CRC or mortality risk was not modified by dietary quality.
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Background We have previously reported that in patients with type 2 diabetes (T2D) consumption of a very low carbohydrate diet capable of inducing nutritional ketosis over 2 years (continuous care intervention, CCI) resulted in improved body weight, glycemic control, and multiple risk factors for cardiovascular disease (CVD) with the exception of an increase in low density lipoprotein cholesterol (LDL-C). In the present study, we report the impact of this intervention on markers of risk for atherosclerotic cardiovascular disease (CVD), with a focus on lipoprotein subfraction particle concentrations as well as carotid-artery intima-media thickness (CIMT). Methods Analyses were performed in patients with T2D who completed 2 years of this study (CCI; n = 194; usual care (UC): n = 68). Lipoprotein subfraction particle concentrations were measured by ion mobility at baseline, 1, and 2 years and CIMT was measured at baseline and 2 years. Principal component analysis (PCA) was used to assess changes in independent clusters of lipoprotein particles. Results At 2 years, CCI resulted in a 23% decrease of small LDL IIIb and a 29% increase of large LDL I with no change in total LDL particle concentration or ApoB. The change in proportion of smaller and larger LDL was reflected by reversal of the small LDL subclass phenotype B in a high proportion of CCI participants (48.1%) and a shift in the principal component (PC) representing the atherogenic lipoprotein phenotype characteristic of T2D from a major to a secondary component of the total variance. The increase in LDL-C in the CCI group was mainly attributed to larger cholesterol-enriched LDL particles. CIMT showed no change in either the CCI or UC group. Conclusion Consumption of a very low carbohydrate diet with nutritional ketosis for 2 years in patients with type 2 diabetes lowered levels of small LDL particles that are commonly increased in diabetic dyslipidemia and are a marker for heightened CVD risk. A corresponding increase in concentrations of larger LDL particles was responsible for higher levels of plasma LDL-C. The lack of increase in total LDL particles, ApoB, and in progression of CIMT, provide supporting evidence that this dietary intervention did not adversely affect risk of CVD.
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Links between trimethylamine- N -oxide (TMAO) and cardiovascular disease (CVD) have focused attention on mechanisms by which animal-based diets have negative health consequences. In a meta-analysis of data from foundational gut microbiome studies, we found evidence that specialized bacteria have and express a metabolic pathway that circumvents TMAO production and is often misannotated because it relies on genetic code expansion. This naturally occurring mechanism for TMAO attenuation is negatively correlated with CVD. Ultimately, these findings point to new avenues of research that could increase microbiome-informed understanding of human health and hint at potential biomedical applications in which specialized bacteria are used to curtail CVD development.
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The higher prevalence of inflammatory bowel disease (IBD) in Western countries points to Western diet as a possible IBD risk factor. High sugar, which is linked to many noncommunicable diseases, is a hallmark of the Western diet, but its role in IBD remains unknown. Here, we studied the effects of simple sugars such as glucose and fructose on colitis pathogenesis in wild-type and Il10 −/− mice. Wild-type mice fed 10% glucose in drinking water or high-glucose diet developed severe colitis induced by dextran sulfate sodium. High-glucose–fed Il10 −/− mice also developed a worsened colitis compared to glucose-untreated Il10 −/− mice. Short-term intake of high glucose or fructose did not trigger inflammatory responses in healthy gut but markedly altered gut microbiota composition. In particular, the abundance of the mucus-degrading bacteria Akkermansia muciniphila and Bacteroides fragilis was increased. Consistently, bacteria-derived mucolytic enzymes were enriched leading to erosion of the colonic mucus layer of sugar-fed wild-type and Il10 −/− mice. Sugar-induced exacerbation of colitis was not observed when mice were treated with antibiotics or maintained in a germ-free environment, suggesting that altered microbiota played a critical role in sugar-induced colitis pathogenesis. Furthermore, germ-free mice colonized with microbiota from sugar-treated mice showed increased colitis susceptibility. Together, these data suggest that intake of simple sugars predisposes to colitis and enhances its pathogenesis via modulation of gut microbiota in mice.
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An amendment to this paper has been published and can be accessed via the original article.
Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology. The biological causes or hallmarks of health include features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration). Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system coupled to the loss of numerous stigmata of health.
Use of microbiome-based biomarkers in diagnosis, prognosis, risk profiling, and precision therapy requires definition of a healthy microbiome in different populations. To determine features of the intestinal microbiota associated with health, however, we need improved microbiome profiling technologies, with strain-level resolution. We must also learn more about how the microbiome varies among apparently healthy people, how it changes with age, and the effects of diet, medications, ethnicity, geography, and lifestyle. Furthermore, many intestinal microbes, including viruses, phage, fungi, and archaea, have not been characterized, and little is known about their contributions to health and disease.Whether a healthy microbiome can be defined is an important and seemingly simple question, but with a complex answer in continual need of refinement.
As the interface between the gut microbiota and the mucosal immune system, there has been great interest in the maintenance of colonic epithelial integrity through mitochondrial oxidation of butyrate, a short-chain fatty acid produced by the gut microbiota. Herein, we showed that the intestinal epithelium can also oxidize long-chain fatty acids, and that luminally-delivered acylcarnitines in bile can be consumed via apical absorption by the intestinal epithelium resulting in mitochondrial oxidation. Finally, intestinal inflammation led to mitochondrial dysfunction in the apical domain of the surface epithelium that may reduce the consumption of fatty acids, contributing to higher concentrations of fecal acylcarnitines in murine Citrobacter rodentium-induced colitis and human inflammatory bowel disease. These results emphasized the importance of both the gut microbiota and the liver in the delivery of energy substrates for mitochondrial metabolism by the intestinal epithelium.
Cancer is the second most prevalent disease worldwide and it presents characteristic hallmarks common to all its types. Within these, it has been described a reprogramming of its energy metabolism, characterized by the preferential use of glucose as energy source in an aerobic glycolysis process. Although this feature may provide adaptive advantages to tumoral cells, it has been described as a weakness that could make them more vulnerable. The ketogenic diet, characterized by high fat and very low carbohydrate intake, aims to eliminate glucose, the main fuel used by cancer cells. Animal studies have described promising results in terms of survival and regression of tumor size; nonetheless, these have failed to replicate in human studies. Furthermore, the ketogenic diet presents possible adverse effects when used in the long term, which should be considered in a vulnerable population such as cancer patients. To date, there is no solid evidence to demonstrate the effectiveness of the ketogenic diet in tumor progression or in overall survival of cancer patients, since most of the studies are observational, uncontrolled, and of short duration. At the moment, we only have limited data to guide us, and at the same time, to promote further study of this approach as a therapeutic opportunity.
Colorectal cancer (CRC) is a heterogeneous disease of the intestinal epithelium that is characterized by the accumulation of mutations and a dysregulated immune response. Up to 90% of disease risk is thought to be due to environmental factors such as diet, which is consistent with a growing body of literature that describes an 'oncogenic' CRC-associated microbiota. Whether this dysbiosis contributes to disease or merely represents a bystander effect remains unclear. To prove causation, it will be necessary to decipher which specific taxa or metabolites drive CRC biology and to fully characterize the underlying mechanisms. Here we discuss the host-microbiota interactions in CRC that have been reported so far, with particular focus on mechanisms that are linked to intestinal barrier disruption, genotoxicity and deleterious inflammation. We further comment on unknowns and on the outstanding challenges in the field, and how cutting-edge technological advances might help to overcome these. More detailed mechanistic insights into the complex CRC-associated microbiota would potentially reveal avenues that can be exploited for clinical benefit.