Metformina y Probioticos

Annual Review of Pharmacology and Toxicology
The Gut Microbiome,

Metformin, and Aging
Sri Nitya Reddy Induri,1,∗ Payalben Kansara,1,∗
Annu. Rev. Pharmacol. Toxicol. 2022.62:85-108. Downloaded from www.annualreviews.org
Scott C. Thomas,1 Fangxi Xu,1 Deepak Saxena,1,2

Access provided by Afghanistan - R4L on 04/01/22. For personal use only.
and Xin Li1

1
Department of Molecular Pathobiology, New York University College of Dentistry,
New York, NY 10010, USA; email: xl15@nyu.edu
2
Department of Surgery, New York University School of Medicine, New York, NY 10016, USA
Annu. Rev. Pharmacol. Toxicol. 2022. 62:85–108 Keywords

First published as a Review in Advance on
gut microbiome, aging, inflammaging, drug toxicity, metformin
August 24, 2021
The Annual Review of Pharmacology and Toxicology is Abstract

online at pharmtox.annualreviews.org
Metformin has been extensively used for the treatment of type 2 diabetes,
https://doi.org/10.1146/annurev-pharmtox-051920-
and it may also promote healthy aging. Despite its widespread use and
093829
versatility, metformin’s mechanisms of action remain elusive. The gut
Copyright © 2022 by Annual Reviews.
typically harbors thousands of bacterial species, and as the concentration of
All rights reserved
metformin is much higher in the gut as compared to plasma, it is plausible
∗
These authors contributed equally to this article
that microbiome-drug-host interactions may influence the functions of
metformin. Detrimental perturbations in the aging gut microbiome lead
to the activation of the innate immune response concomitant with chronic
low-grade inflammation. With the effectiveness of metformin in diabetes
and antiaging varying among individuals, there is reason to believe that the
gut microbiome plays a role in the efficacy of metformin. Metformin has
been implicated in the promotion and maintenance of a healthy gut micro-
biome and reduces many age-related degenerative pathologies. Mechanistic
understanding of metformin in the promotion of a healthy gut microbiome
and aging will require a systems-level approach.
85
We cannot fathom the marvelous complexity of an organic being; but on the hypothesis here advanced
this complexity is much increased. Each living creature must be looked at as a microcosm—a little
universe, formed of a host of self-propagating organisms, inconceivably minute and as numerous as the
stars in heaven.
—Charles Darwin
THE MICROBIOME
The human body is inhabited by trillions of microbial cells from all domains of life (1, 2). The
microbial cells supported by the human body are estimated to outnumber somatic and germ
cells in our bodies by a factor of 10 (3). The collective ensemble of all the microbes, their genes,
and the environmental conditions found in and on the human body is referred to as the human
microbiome and creates the human ecosystem. Within the human ecosystem, the localized
differences in the taxa or types of microorganisms present are referred to as microbiota (4–6).
Each individual has a unique microbiome that becomes increasingly unique with age, likely
reflecting the culmination of the interactions throughout one’s life, including demographic and
environmental influences (7–10). These diverse microbes typically coexist harmoniously with the
host and can, in some cases, contribute to maintaining host health and immune function. The
composition of the microbiome and any disruption to its integrity can potentially adversely affect
health, disease susceptibility, and disease progression (10, 11). These observations have led to
the human microbiome being considered our so-called last organ (12) and to proposals that the
human body may be better conceptualized as a human microbial superorganism (13–16).
Human microbiome research has substantially expanded its reach in preceding decades—from
understanding the diversity of host microbiota and its influential role on human health, disease,
and evolution to technological advancements in personalized microbiome-based therapies in the
omics fields (e.g., metagenomics, proteomics, metabolomics).
Microorganisms colonize nearly every surface of the human body and can thrive in several or-
gans in our gastrointestinal, genitourinary, and respiratory tracts (13, 17–19). A typical human gut
microbiome is estimated to house at least 1,800 genera and approximately 15,000–36,000 bacte-
rial species that have evolved in a symbiotic relationship with the host, exhibiting temporal and
spatial differences in their distribution from the esophagus to the distal colon (7, 14, 20–22). The
human intestine, with an estimated surface area of 200–300 m2 (23), provides a nutrient-rich envi-
ronment to approximately 100 trillion microbes that encode for 100-fold more unique genes than
encode our genome (16, 24, 25). The healthy colon alone is host to the overwhelming majority
(up to 70%) of the microbial community (1011 –1012 cells/mL) (26), whereas the small intestine is
estimated to contain 103 –109 cells/mL of microbes (27). This homeostasis is mediated by the in-
terplay of a diversity of factors, including migration, translocation, elimination, competition, and
reproduction rates of microbiota, as determined by regional growth conditions (28, 29).
The microorganisms found in the gastrointestinal tract (GIT) are often categorized into au-
tochthonous flora (indigenous flora) and allochthonous flora (transient flora) (30). Autochthonous
flora are the resident microbes that colonize specific habitats in the GIT and that are thought
to be closely associated with the intestinal mucosa, whereas allochthonous flora cannot colonize
specific habitats—barring unusual circumstances—and are usually located in the central lumen
as part of the fecal stream (30, 31). The majority of the autochthonous gut microbiome is strictly
anaerobic and predominantly composed of two bacterial phyla, Firmicutes and Bacteroidetes,
yet members of the archaea can also be found in low relative abundance (e.g., Methanobrevibacter
smithii) (32, 33). Relatively less-represented taxa include Proteobacteria, Actinobacteria, Fusobac-
teria, and Verrucomicrobia (32). Autochthonous microbiota are currently hypothesized to have
86 Induri et al.
evolved symbiotically with the host, thereby developing specialized defense mechanisms against
endogenous antimicrobial peptides while being harmless to the host (34, 35).
Gut Microbiome in the Promotion of Health

The gut microbiome plays a crucial role in maintaining the host’s local and systemic physiology
(35). The spectrum of beneficial services provided by gut microbiota includes gut homeostasis, nu-
trient metabolism, immunomodulation of the host’s gastrointestinal (GI) system (development of
intestinal mucosa and systemic immune systems), maintenance of immune homeostasis, metabolic
activities, and protection against pathogenic microbiota.
Impact on structure and integrity of the intestine. Intestinal epithelial cells (IECs) line the
gut, forming a physicochemical barrier between host tissues and the luminal content, including
the gut microbiome. The integrity of this barrier is essential to the host’s health and appears to be
positively affected by a healthy microbiome (36). The cells of the immune system underlying IECs
showed altered microvilli morphology and decreased turnover rate in germ-free (GF) animals (37).
Normal gut bacteria also showed an influence on the glycosylation patterns of surface proteins in
the small intestinal epithelium (38). These findings indicate that the integrity and structure of the
GIT are dependent on conventional intestinal bacteria, whereas GF animals have a prolonged cell
cycle duration (39), reduced apoptosis (40), reduced intestinal surface area (up to 30%) (41), and
slower intestinal motility (42).
Nutrient metabolism. The gut microbiome enhances the host’s digestive efficacy and contains
an abundance of genes coding for enzymes involved in the metabolism of glycans and amino
acids as well as in methanogenesis and the biosynthesis of vitamins, isoprenoids, and xenobiotics
(16). Plant-based foods are rich in xylan, pectin, and arabinose-containing polysaccharides that
are indigestible by host enzymes (16). Autochthonous bacteria such as Bacteroides thetaiotaomicron
release glycosyl hydrolases that metabolize plant polysaccharides into simple carbohydrates for
easier absorption by the host (43). The primary resident microbiota can also process glycans,
including nondigestible carbohydrates, and can synthesize short-chain fatty acids (SCFAs) such as
acetate, butyrate, and propionate while also producing gases (e.g., H2 , CO2 ) (16, 44).
The distal gut microbiome is also involved in the synthesis of amino acids and vitamins such
as vitamins B1 (thiamine), B6, and K (16, 45). Polyphenolic compounds such as flavonoids, an-
thocyanidins, and tannins are hydrolyzed by enzymes of Bacteroides, Eubacterium, and Clostridium
species into final products that enter the portal vein (46). Through the microbially mediated trans-
formation of nondigestible carbon and energy sources into SCFAs and other nutrients accessible
to the host, the host gains access to additional caloric and nutrimental sources.
Immunomodulation and gut-immunological homeostasis. The human gut microbiome

is crucially involved in the training and development of the host immune system (47). The
immunomodulation of gut microbiota from gnotobiotic animal studies suggests the influence of
commensal intestinal bacteria on innate and adaptive immune systems. Compared with con-
ventionally housed animals, the mucosal immune system of GF animals is underdeveloped,
with hypoplastic Peyer’s patches with a few germinal centers (48), fewer mesenteric lymph
nodes (49), impaired and hypomature isolated lymphoid follicles (50), and significantly reduced
IgA-producing plasma cells and lamina propria CD4+ T cells (48). Signaling pathways involving
pattern recognition receptors such as Toll-like receptors (TLRs), nucleotide-binding oligomer-
ization domain–containing protein 1 (NOD1)-like receptor family, β-defensin-3, and chemokine
www.annualreviews.org • Gut Microbiome, Metformin, and Aging 87

(C–C motif ) ligand 20 (CCL20) mediated through C–C chemokine receptor 6 (CCR6) are
stimulated by peptidoglycan.
Microbial products induce lymphoid follicles, which play a pivotal role in intestinal immune
responses (50). Suzuki et al. (51) reported that bacterial products and retinoic acid stimulate fol-
licular dendritic cells (FDCs) in Peyer’s patches. Microbially mediated FDC stimulation resulted
in an increase in the expression of chemokine CXCL13, the survival factor BAFF, and chemicals
associated with the activation and secretion of cytokine transforming growth factor (TGF)-β1.
Reduced production of these molecules in GF animals is associated with deficiencies in TLR-
associated pathways (51); these pathways are crucial for microbial recognition and controlling
both innate and adaptive immune responses (52). To improve the tolerance state of the GIT im-
mune system to resident bacteria, dendritic cells in intestinal mucosa induce the differentiation of
naïve T cells into regulatory T cells—referred to as Treg cells—through the production of IL-10
(Th2 cytokines) and T cell anergy or depletion (53–56). Taken together, these results suggest that
the gut microbiome can interact with host gut cells in a manner that promotes B cell migration,
survival, and production of IgA, thereby promoting gut health (51).
Protection against pathogenic strains. A major function of indigenous gut microbiota is to

protect the host against infection from colonization and overgrowth of pathogenic microbiota
(i.e., pathobionts) (57, 58). A few strategies used by resident gut microbiota to achieve this are
competitive metabolic interactions, localization to certain physical spaces (30, 31), and modulation
of immune responses (59). Probiotic organisms/commensal microbiota such as nonpathogenic
Escherichia coli produce bacteriocin, a peptidic toxin that inhibits the growth of enterohemor-
rhagic E. coli (EHEC) (60, 61). Resident nonpathogenic E. coli and other microbiota help resist
EHEC colonization by competing for nutrients such as amino acids and organic acids, ultimately
leading to the starvation of pathogenic strains (62). Commensals also keep pathogenic microbe
colonization at bay by generating SCFAs, which alter the host’s environmental conditions and
also downregulate virulence genes, for example, those that encode for type III secretion system
(T3SS) proteins in Salmonella enterica serovar Enteritidis and Typhimurium (63).
When the composition of normal gut microbiota changes, some pathobionts are able to
thrive due to the lack of competition from endogenous microbiota. Clostridioides difficile (formerly
Clostridium) infections (CDIs) are a prime example of this dynamic. CDIs result from a dysbiosis
in normal gut microbiota, frequently from antibiotic use (especially broad-spectrum antibiotics)
(64), and the proliferation of C. difficile in the absence of competition from, and the metabolic
byproducts of, the normal microbiota (e.g., secondary bile acids) (58, 65). Of note, the restoration
of a diverse microbiome through fecal transplants from healthy donors has been shown to be an
effective treatment for CDIs (66, 67), demonstrating that a healthy gut microbiota can not only
prevent the colonization of pathogenic strains but also be used as treatment against previously
established pathobionts.
Gut Dysbiosis in the Promotion of Disease

Dysbiosis is a change in the normal or healthy composition of gut microbiota and is involved
in the pathogenesis of multiple disorders (68–70). Recent evidence suggests that dysbiosis of gut
bacteria engenders a myriad of intestinal and extraintestinal disorders (68–70).
Modulation of TLR2, a receptor that normally maintains gut barrier homeostasis, may lead
to inflammation from stress-induced damage and is considered to play a role in the patho-
genesis of inflammatory bowel disease, Crohn’s disease (CD), and ulcerative colitis (UC) (52).
88 Induri et al.
Significant differences in the composition of the gut microbiome have been noted between CD
and UC patients, mainly due to the depletion of the dominant resident phyla (i.e., Firmicutes and
Bacteroidetes) (20). An association between gut dysbiosis and celiac disease has also been reported
by comparing the IgA-coated fecal immunoglobulin levels between patients with a history of celiac
disease and healthy controls (71). Adenomas that are precursors to colorectal cancer have also been
studied to evaluate their association with bacterial community changes (72).
Dysbiosis is considered to be related to metabolic disorders such as obesity and diabetes
(73–75). This is supported by studies in animal models wherein fecal microbiome transplants
from obese mice to GF lean mice or vice versa yielded the phenotype of the microbiota donor
(56). Evidence from metagenome-wide association studies demonstrates a high correlation
between the intestinal microbiome and type 2 diabetes (76). The findings indicate that the
relative abundance of butyrate-producing bacteria such as Roseburia intestinalis, Faecalibacterium
prausnitzii, and Akkermansia muciniphila is lower in type 2 diabetics (76). It has also been suggested
that biguanides such as metformin alter the gut microbiota, increasing the relative abundance of a
few genera (e.g., Escherichia/Shigella spp. and Bilophila sp.) while decreasing the relative abundance
of others (e.g., Intestinibacter spp. and Clostridium spp.) (77).

Existing data suggest that gut bacteria play a role in central nervous system–related disorders
such as anxiety, depression (78, 79), autism spectrum disorder (80), schizophrenia (81), autoim-
mune diseases (82), epilepsy (83), lung disorders and infections (68), and aging (84, 85). These
observations suggest a direct relationship between the gut microbiota and the brain, corroborat-
ing the concept of a human microbial superorganism.
The Human Gut Microbiome and Drug Metabolism

The interplay between the human gut microbiome, drugs, and related xenobiotics is ex-
tremely complex and considered bidirectional (86). The gut microbiome is capable of directly
and indirectly affecting drug metabolism, disposition, availability, efficacy, and toxicity (87).
Some drugs can alter the composition and diversity of gut microbiota (88). Gut microbially medi-
ated drug metabolism includes biotransformations such as reductive metabolism, hydrolytic reac-
tions, demethylation, deamination, dehydroxylation, deacylation, decarboxylation, deconjugation,
and oxidation (87). Other direct effects include the expression of genetic elements involved in
drug activation, sequestering drugs from the site of action, and developing bacterial transporters
to change drug efficacy (89). Indirect effects of drug metabolism include competitive inhibition
and changes in the host’s metabolic enzymes (87).
Healthy gut bacteria are essential for detoxifying and eliminating a myriad of unwanted
metabolic waste products, but they can also complicate the efficacy of drugs. Clayton et al. (90)
proposed that a microbial metabolite, p-Cresol, has a direct effect on acetaminophen efficacy
through competitive inhibition by reducing the ability of the liver to metabolize acetaminophen.
The GI toxicity of chemotherapeutic CPT-11 (irinotecan) is dramatically increased by a bac-
terial sugar-scavenging β-glucuronidase (91). Studies on nonsteroidal anti-inflammatory drug
(NSAID)-induced enteropathy indicated that gut bacteria are determinants in the development of
GI ulcers in mice treated with NSAIDs (92, 93). Furthermore, secondary gut microbiomes derived
from bile acids contribute to predicting the magnitude of statin-induced low-density lipoprotein
(94). These results indicate a relationship between gut bacterial metabolism and therapeutic out-
comes of a diversity of drugs.
Many classes of drugs are associated with alterations in the composition of the gut microbiota
and their functions (95, 96). Drug-induced dysbiosis can impact the enteric and overall health

of the host. Multidrug analysis suggested that a few classes of drugs, including antimicrobials,
proton pump inhibitors (PPIs), laxatives, and metformin, have the largest impact on the gut
microbiome (97). Metagenomic analysis of antibiotic-induced changes in gut bacteria showed
that administration of broad-spectrum antibiotics resulted in a tenfold reduction in the number
of gut bacteria, including temporal and spatial changes that cumulatively suggest a decrease in
the abundance of Firmicutes and Lactobacillus species (98). Different classes of antibiotics alter the
gut microbiome differently given their broad spectrum of activity and targets (99). Antibiotic
treatment for 7 days with clindamycin yielded a dramatic decline in the diversity of Bacteroides and
a long-lasting impact on gut microbiota composition that could last up to 2 years posttreatment
(100). A few antibiotics (e.g., vancomycin) have demonstrated eubiotic properties, for example,
in mice models given vancomycin from birth until weaning, it played a protective role against the
development of diabetes and facilitated dominant colonization by A. muciniphila, known for its
anti-inflammatory properties (101).

Clarithromycin use, which is given to patients with Helicobacter pylori infection, caused a sharp
decline in Actinobacteria, with the presence of macrolide resistance gene erm(B) being detectable
for up to 4 years after the therapeutic regimen (102). PPIs, which are also used in the treatment of
H. pylori infection, can also alter the gut microbiome by directly inhibiting certain endogenous gut
bacteria (e.g., Dorea spp., Ruminococcus spp.) and by modulating the pH of the gut by suppressing
acid production (103, 104). A meta-analysis of 23 studies showed that among 300,000 patients
using PPIs, a 65% increase was found in the incidence of C. difficile–associated diarrhea (105).
Metformin, a common antidiabetic medication used in type 2 diabetics, has been found to alter
the microbial community composition both in vivo and in vitro where it promoted the growth of
Bifidobacterium adolescentis and Bifidobacterium, respectively, whose growth has been suggested to
enhance the antidiabetic effect of metformin (106). Transfer of metformin-altered microbiota to
GF mice showed improved gluconeogenesis triggered by significant improvement in the produc-
tion of SCFAs (i.e., butyrate, propionate) (106, 107).
Microbiome and Aging

The microbiome begins to develop immediately upon birth (108). The gut microbiome is ex-
tremely diverse and complex, and it keeps changing during different stages of life (9, 84, 109–111).
The seven pillars of aging are inflammation, stem cell regeneration, macromolecular damage,
stress, proteostasis, metabolism, and epigenetics (112). Interestingly, the tightly networked aging
pillars converge on inflammation because the impairment of any one pillar stokes inflammation,
which then affects all other pillars (112). Though the precise etiology of inflammaging is not
completely understood, the involvement of the gut microbiome has been highlighted. The
composition of the gut microbiota dramatically changes during aging and is associated with host
health and life span (113–118). The stimulation of TLR4 by lipopolysaccharides from gut micro-
biota can accelerate age-dependent inflammation, a process that can impact early hematopoietic
development and terminal myeloid differentiation potential (119–121). Studies have reported that
age-related gut dysbiosis contributes to a chronic and global inflammatory state in humans (122).
In aged animal models, genera such as Parabacteroides, Mucispirillum, Clostridium, and Sarcina are
positively associated with the proinflammatory MCP-1, while Akkermansia, Oscillospira, Blautia,
and Lactobacillus are negatively correlated with MCP-1. This finding led to the conclusion that
changes in the animal gut microbiota through age are associated with inflammaging, specifically
through increased levels of pro-inflammatory molecules and cells, including IL-6, IL-10, tumor
necrosis factor α (TNF-α), TGF-β, p16, SAM domain and HD domain–containing protein 1
(SAMHD1), eotaxin, regulated upon activation, normal T cell expressed and presumably
90 Induri et al.
secreted (RANTES), T helper type (Th)1, Th2, and Treg; activation of TLR2, nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-κB), and mechanistic target of rapamycin
(mTOR); and decreased levels of cyclin E and cyclin-dependent kinase 2 (CDK2) (122). Human
studies showed that Proteobacteria positively correlated with IL-6 and IL-8, while Ruminococcus
lactaris negatively correlated with IL-8 (122). In aged populations, a reduction in the number
of intestinal commensal bacteria that maintain immune tolerance in the gut has been observed
(122–124). Additionally, opportunistic bacteria that stimulate intestinal inflammation tend to
be more numerous at older ages (125, 126), and microbiota associated with anti-inflammatory
responses decrease (e.g., Bifidobacterium spp., F. prausnitzii) (127).
The precise etiology of inflammaging is not completely understood, but the role of the gut
microbiome and myelopoiesis has been emphasized (128). Myelopoiesis is tightly regulated by
transcription factors and extrinsic signals such as infection and inflammation to ensure homeo-
stasis, and dysregulated myelopoiesis may represent the initial step in inflammatory and stress
responses to gut dysbiosis (129, 130). Studies using model organisms indicate that age-related gut
dysbiosis may contribute to unhealthy aging and reduced longevity by triggering the innate im-
mune response and chronic low-grade inflammation, leading to many age-related degenerative
pathologies and unhealthy aging (131–138).
METFORMIN
Metformin History and Pharmacology
Metformin (dimethylbiguanide) and the related drug phenformin are derived from galegine, a
natural product from the herb Galega officinalis, which has been known since the 1920s to lower
blood glucose levels; in fact, accounts of the herb being used to treat type 2 diabetes date back
as early as the seventeenth century (139, 140). Phenformin and other derivatives proved to be
more toxic and were associated with lactic acidosis, leading to the preference for metformin (140).
Metformin is currently a preferred orally administered type 2 diabetes drug and holds the title of
the most-prescribed glucose-lowering drug worldwide (139, 141). Yet, despite its historical and
modern widespread use, the detailed mechanisms of metformin action are still unclear (140, 141).
In addition, metformin has proven useful in numerous other applications, ranging from use as a
cardiovascular protective agent to an antiaging agent (141).
Metformin is not bound to any plasma protein. Following intravenous administration, the vol-
ume of distribution has been reported at 63–276 L, and after oral administration of 200 mg daily it
is approximately 600 L; this elevated value designates significant uptake of metformin in the tissue.
Metformin Toxicity
Since its introduction, metformin has been widely consumed as a first-line treatment for
type 2 diabetes that can be used either alone or in combination with sulfonylurea, thiazolidine-
diones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-
like peptide-1 receptor agonists, and insulin (142). The biguanide available in immediate-release
(IR) and extended-release formulations is begun at 500 mg/day and titrated to a maximum dose
of 2,000 mg/day (143).
The toxic markers of biguanide (metformin/phenformin) therapy are considered to be
hyperlactatemia, metabolic acidosis, an increase in the lactate:pyruvate ratio, and elevated
blood alanine concentration (144–146), which occur when metformin concentrations are over
5 μg/mL (147, 148). Metabolic acidosis associated with hyperlactatemia is due to rapid adenosine
triphosphate (ATP) turnover during mitochondrial respiratory complex I inhibition and to the

insufficient oxidative phosphorylation for ATP hydrolysis (144). Metformin does not undergo
hepatic metabolism and is excreted renally (149, 150). Accumulation of metformin due to reduced
renal clearance or acute/chronic kidney disease results in metformin-associated lactic acidosis
(MALA) (151, 152); however, metformin accumulation does not heighten the risk of acute kidney
injury (153). Although MALA is not subject to a significant accumulation of metformin, it is
associated with comorbidities that contribute to pathological changes (144). The extent of MALA
is determined by blood pH and by concentrations of plasma metformin and lactate pH (150,
151). Metformin-induced lactic acidosis refers to the accumulation of metformin that is largely
responsible for lactic acidosis, without underlying comorbidities (144, 154).
Acute reversible effects of metformin IR involve adverse GI effects that occur in 5–20% of pa-
tients, with diarrhea present in 20% of patients and with less than 5% of patients exhibiting met-
formin intolerance (155). Metformin-associated diarrhea presented with electrolytic deficiencies
indicative of hypomagnesemia, hypocalcemia, and hypokalemia (156). These effects can be mini-
mized if it is administered with food, it is used in lower doses, and the dosage is increased slowly
(155). Case reports on metformin-induced hepatotoxicity, hepatitis, and cholestasis have been re-
ported in the literature as rare idiosyncratic reactions associated with elevated serum transaminases
markers (157–159). Most of the data on metformin-induced hepatotoxicity were associated with
concomitant intake of other drugs with hepatotoxic potential. A recent case report mentioned that
metformin alone could be responsible for elevated liver enzymes and liver damage in a patient with
no history of liver disease or toxic habits (160).
Some patients (10–30%) receiving long-term metformin therapy have shown evidence of re-
duced vitamin B12 absorption, low serum total vitamin B12, and low bioavailable B12 (holo-
TC II); however, the underlying mechanisms remain unclear (161, 162). Metformin impairs
calcium-dependent membrane activity in the ileum, in turn affecting the vitamin B12 intrinsic
factor complex (162). Metformin-induced vitamin B12 malabsorption is reversible and can be
abated with regular vitamin B12 supplementation (163), with studies currently underway to assess
the efficiency of oral calcium supplementation at treating this deficiency (162).
Management of metformin toxicity consists predominantly of supportive care, including elec-
trolyte replenishment and acid-base, respiratory, renal, and hemodynamic management. Adjunct
therapies such as serum alkalinization, metabolic rescue, extracorporeal techniques (hemodialysis,
hemoperfusion, plasma exchange, continuous renal replacement therapy), and GI decontamina-
tion can be used to manage metformin toxicity in a therapeutic setting (144). In general, the side
effects of metformin are rare and manageable. The data in the literature in the past decade have
suggested metformin’s beneficial effects on conditions beyond glucose control. These conditions,
including neoplasia, cardiovascular diseases, and others, are closely related to aging, which leads
to an intriguing question: Does metformin regulate the aging process, and if so, how?
Metformin and Aging

Life expectancy has been modulated by genetic, pharmacologic, and dietary involvement in
numerous model systems. Similar to the seven pillars of aging (112), Lopez-Otin et al. (164)
recognized and categorized the cellular and molecular hallmarks of aging into nine categories:
(a) genomic instability, (b) epigenetic alterations, (c) loss of proteostasis, (d) deregulated nutrient
sensing, (e) mitochondrial dysfunction, ( f ) cellular senescence, (g) stem cell exhaustion, (h) altered
intercellular communication, and (i) telomere attrition. These hallmarks can help evaluate and
prioritize appropriate interventions. Below, we summarize how metformin directly or indirectly
influences each hallmark of aging.
92 Induri et al.
Genomic instability. One common measure of aging is the accretion of genetic mutations
throughout the life span. Exogenous physical, chemical, and biological agents and endogenous
threats include hydrolytic reactions, DNA replication errors, and reactive oxygen species (ROS),
any of which can compromise the integrity and stability of DNA (165). Studies suggest that
metformin confers genome-defensive effects via reduction of both oxidative stress and DNA im-
pairment. AMP-activated protein kinase (AMPK) is a sensor of cellular energy that is expressed
in essentially all eukaryotic cells, implying that it evolved early during eukaryotic evolution.
Activation of AMPK by metformin can inhibit ROS production and activate p53-mediated
DNA repair (166, 167). A study by Dogan Turacli et al. (168) reinforces the potential benefit of
metformin in an antioxidative capacity to protect cells from diabetic oxidative stress and in the
regulation of DNA damages in the base excision repair system.
Epigenetic alterations. Epigenetic alterations include histone modifications, DNA methylation,

and chromatin remodeling, which affect all cells and tissues throughout life. Histone methyla-
tion is the hallmark of aging since histone demethylases modulate the life span by targeting key
longevity routes such as insulin and insulin-like growth factor-1 (IGF-1) signaling pathways (169).
AMPK influences histone methylation and activation of SIRT1 (170). Metformin may impact the
epigenome indirectly by modulation of metabolite levels, which is known to alter the activity of
histone and DNA-modulating enzymes. A recent study investigated 300,000 chemical compounds
and more than 9,000 protein binding cavities, yielding up to 41 putative metformin binding tar-
gets (171). Among these potential metformin targets, the H3K27me3 demethylase KDM6A/UTX
contains an experimentally validated unique metformin direct binding motif (171). SUV39H1, a
histone methyltransferase, has been reported to be downregulated by metformin (172).
Metformin has a direct effect on infiltrating immune cells—specifically, by increasing
CD8+ T cell recruitment, protecting them from apoptosis and exhaustion, increasing
CD8+ memory T cells, and regulating age-related inflammation (135, 173–178).
Loss of proteostasis. During aging, some biological processes such as the accumulation of
oxidative damage can lead to the mostly random accumulation of damage in cellular components
(e.g., proteins, DNA). When proteins are damaged as a consequence of various exogenous
and endogenous stress factors, it can lead to the accumulation of protein aggregates, causing
proteotoxic effects if not effectively cleared or recycled, contributing to aging and age-related
diseases. Studies have shown that, via AMPK/ERK1/2 signaling pathways, metformin can restore
antioxidant status and protein homeostasis within cells (179).
Deregulated nutrient sensing. Nutrient availability and sensing are major regulators of homeo-
stasis within cells. However, with aging, the cell begins to lose the ability to maintain homeo-
stasis. Thus, nutrient-sensing systems play a considerable role in aging, longevity, and nutrient
signaling.
The somatotropic axis in mammals comprises IGF-1 and insulin signaling (IIS) pathways, the
most conserved pathways responsible for controlling aging (180). Paradoxically, growth hormone
and IGF-1 levels decline during normal aging and in premature aging, assuming decreased IIS
is a common characteristic of physiological aging (181). Multiple genetic manipulations that
attenuate signaling intensity at different levels of IIS pathways extend the life span of worms and
mice (180). However, Garinis et al. (182) suggested that organisms with a constitutively decreased
IIS can survive longer due to the lower rate of cell growth and metabolism and, hence, lower
rates of cellular damage. Metformin has been shown to decrease the concentration of insulin and
IGF-1 in cancer cells (183, 184). mTOR, AMPK, and sirtuin signaling are the best-characterized

nutrient-sensing systems, and several studies indicate that metformin is involved in regulating
these systems. Metformin is shown to directly inhibit mTORC1 via Rag-GTPase inhibition and
indirectly via REDD1 upregulation (185). Metformin was also found to be a direct activator of
sirtuins when in low nicotinamide adenine dinucleotide (NAD+) concentrations (186). Met-
formin may decrease perceived hunger and thereby induce dietary restriction (187), leading to
the regulated reduction of food, which can refine late-life health and increase life span in some
organisms (188). Metformin also induces a restriction diet–like state in Caenorhabditis elegans that
reduces brood size, delays reproductive timing, and increases life span independent of transcrip-
tion factor DAF-16/FOXO (189). Metformin’s beneficial effect on aging and energy metabolism
is likely a consequence of directly targeting key energy sensors such as mTOR and AMPK.
Mitochondrial dysfunction. The relationship between mitochondrial dysfunction and aging has
long been known. To date, two key molecular foci of metformin have been recognized, both of
which are contained in mitochondria. Having a positive charge, metformin is driven into the cell
and then into the mitochondria in concentrations up to 1,000-fold higher than are found in the
extracellular medium, due to differences in the membrane potentials across the mitochondrial
inner membrane and the plasma membrane. In the mitochondria, the most significant action of
metformin is inhibition of complex I of the respiratory chain. Two consequences associated with
suppression of the respiratory chain include inhibition of ATP production and changes in the
NAD+:NADH ratio, which contributes to the effect of metformin on gluconeogenesis. Repres-
sion of ATP production affects gluconeogenesis since ATP production is an energy-intensive pro-
cess, which increases cytoplasmic ADP:ATP and AMP:ATP ratios; these changes activate AMPK
(190, 191). After its activation, AMPK restores the cellular energy balance by activating catabolic
(i.e., ATP-generating) pathways and inhibiting anabolic (i.e., ATP-consuming) pathways. AMPK
also controls the whole-body energy equilibrium, mainly by stimulating food intake and energy
expenditure via the hypothalamus (192, 193).
Metformin also inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), which is
a key component in the glycerophosphate shuttle that increases the lactate:pyruvate ratio and
thereby inhibits endogenous glucose production in the liver (194). AMP induces allosteric regu-
lation of key enzymes in gluconeogenesis by acting synergistically with fructose 2,6-bisphosphate
to inhibit fructose 1,6-bisphosphate and stimulate phosphofructokinase, which then inhibits glu-
coneogenesis. Our team has previously found that metformin can reduce elevated glutamate and
succinate levels to baseline levels in diabetic mice, suggesting that it has the ability to alter mito-
chondrial bioenergetic pathways (195). Metformin’s effects could be partially mediated through
the multifaceted actions of succinate (196).
Cellular senescence. Senescent cells are known to display dramatic alterations in their se-
cretome, proinflammatory cytokines, and matrix metalloproteinases, collectively known as
senescence-associated secretory phenotype (SASP), a phenotype that may contribute to ag-
ing (197). Chronic low-dose metformin administration delays senescence in human diploid
fibroblasts, irrespective of the fact that metformin does not exhibit senolytic properties (176).
Metformin prevents NF-κB translocation into the nucleus, thereby mediating anti-inflammatory
effects and downregulation of SASP (198). Noren Hooten et al. (199) suggested that in human
fibroblasts, metformin lowers the protein levels of p16 and p21 and the RNA levels of IL-6 and
IL-8, all of which increase significantly throughout aging. Recently, Kuang et al. (200) found
that metformin could alleviate oxidative stress–induced senescence by stimulating autophagy and
could partially recover the osteogenic potential of human periodontal ligament cells. Metformin
94 Induri et al.
was shown to reduce SASP in head and neck carcinoma (201), and Yi et al. (202) reported that
in hepatoma, a low concentration of metformin induces p53-dependent senescence. Therefore,
metformin’s anti- or pro-senescence effect varies in cases of aging and cancer tissue, respectively.
Stem cell exhaustion. Stem cell exhaustion holds significance in multiple types of aging-
associated injuries and likely comprises one of the ultimate causes of tissue and organismal aging.
Metformin targets stem cell exhaustion pathways, more specifically activation of glutathione per-
oxidase 7 via nuclear factor erythroid 2–related factor 2, inhibition of AKT/mTOR pathway, and
via the AMPK-activated atypical protein kinase C (aPKC)-CREB binding protein (CBP) pathway,
providing zero therapeutic effect and delaying stem cell aging (176, 203, 204). Metformin induced
rejuvenation and differentiation capacity in oligodendrocyte progenitor cells, thereby improving
remyelination and neurogenesis (205).
Altered intercellular communication. A prominent aging-associated alteration in intercellular

communication is inflammaging (164). Inflammaging (206) is a significant risk factor for both mor-
bidity and mortality in the elderly given that most—if not all—age-related diseases share inflam-
matory pathogenesis (207). Bauer et al. (208) showed that treatment with metformin can restore
intestinal sodium-glucose cotransporter 1 expression and glucose sensing while shifting the com-
position of the upper small intestinal microbiota, partly by increasing the abundance of Lactobacil-
lus. In another study, metformin acted in part through a Bacteroides fragilis–glycoursodeoxycholic
acid–intestinal farnesoid X receptor (FXR) axis to alter intercellular communication to improve
metabolic dysfunction, including hyperglycemia (209).
Telomere attrition. Telomeres, the terminal regions on the chromosome, are particularly suscep-
tible to age-related deterioration given that normal aging is accompanied by telomere attrition in
mammals. In diseases like pulmonary fibrosis, dyskeratosis congenita, and aplastic anemia, there
is a loss of regenerative capacity in different tissues due to telomerase deficiency and acceler-
ated aging due to telomere shortening (210). Moreover, genetically modified animal models with
shortened or lengthened telomeres exhibit decreased or increased life span, respectively (211).
Metformin’s action on mitochondrial function and cellular aging may give rise to protective feed-
back mechanisms on telomere preservation. Studies have reported that metformin is shown to
reduce telomere shortening in the diabetic patient (212, 213).
Metformin and Gut Microbiota

Metformin regulates the gut microbiome, and the identification of processes by which metformin
modulates gut dysbiosis to reduce age-related inflammation—and its interaction with mitochon-
drial dysfunction—is important for modulating inflammaging in the elderly. It is noteworthy that
metformin levels in the gut are 100- to 300-fold higher than those in serum, making the gut the
primary reservoir for metformin in humans and when administered orally. Indeed, the microbiome
appears to be a primary source for metabolic interactions (106, 214, 215). Further, not all individ-
uals who are prescribed metformin derive the same benefit, and some develop side effects (175,
216–218). These facts raise intriguing questions about the role played by the gut microbiome in
metformin tolerance or intolerance (215) and the molecular processes by which metformin regu-
lates the gut microbiome.
Changes in the gut microbiota may affect the gut metabolome, which, in turn, affects intestinal
output of butyrate and acetate (219). Bacteria metabolize unabsorbable carbohydrates into SCFA-
stimulating goblet cells, which leads to further mucin production and a subsequent increase in

mucus layer thickness, a reduction in epithelial permeability, a decrease in inflammation, and
lowered glucose levels (214). Studies reported that participants treated with metformin exhibited
increased production of butyrate and propionate, while controls showed an increase in microbial
genes implicated in the degradation of glycine and tryptophan (219). SCFA-producing bacteria,
including Butyrivibrio (belonging to the class Clostridia) and Roseburia (belonging to the phylum
Firmicutes), produce SCFAs from the fermentation of indigestible food such as complex carbo-
hydrates (219). This is of particular interest given that glycine has been associated with insulin
sensitivity and that glycine supplementation has been reported to improve insulin sensitivity
(220). A meta-analysis of 199 individuals with type 2 diabetes and 544 healthy controls confirmed
that metformin significantly altered gut microbiota composition (132). Using a large diverse
cohort, Forslund et al. (221) suggested that metformin efficacy in the treatment of type 2 diabetes
is microbially mediated through the production of SCFAs, improving glucose control, but that
metformin can also produce adverse effects (e.g., greater relative abundance of Escherichia spp.
and associated virulence factors).
Though metformin was found to increase the relative abundance of A. muciniphila, the under-
lying mechanism is not fully understood (222). Metformin is also associated with an increase in
the density of mucin-producing cells (222). Interestingly, A. muciniphila is found predominantly
in the mucus layer of the colon, where it promotes mucus secretion and enhances intestinal in-
tegrity by reducing its epithelial permeability (223). Further supporting a microbiota-metformin
link to gut health, expression of the genes MUC2 and MUC5, two markers for analyzing mucin lev-
els, significantly increased in high-fat diet (HFD)-fed female mice treated with metformin (224).
However, Bauer et al. (208) did not find an increase of A. muciniphila with metformin. This is
probably due to the fact that the analysis was done in the upper small intestine and A. muciniphila
colonizes more in the cecum and colon. Montandon & Jornayvaz (225) summarize that metformin
enhances SCFA-producing bacterial taxa, including Allobaculum, Bacteroides, Blautia, Butyricicoccus,
Lactobacillus, Akkermansia, and Phascolarctobacterium in rats.
Bauer et al. (208) reported that a HFD reduces glucose sensing and SGLT-1 expression, both
of which are important for lowering glucose production in rodents. Metformin restores SGLT-1
expression and glucose sensing while partly modifying the composition of the upper small intesti-
nal microbiota by increasing the abundance of Lactobacillus (208). Zhou et al. (226) reported that
in mice fed a HFD, metformin restored the concentration of the tight junction protein occludin-1
in the gut, reversed the increased gut permeability, and increased the relative abundance of bene-
ficial bacteria Lactobacillus sp. and A. muciniphila. Using a metagenomic approach, Shin et al. (214)
described that metformin had a different effect on microbial composition in HFD mice and nor-
mal caloric diet mice, indicating that the effect is diet dependent. Metformin causes a decrease
in the proportions of Anaerotruncus, Lactococcus, Parabacteroides, Odoribacter, Lawsonia, Blautia, and
Lactonifactor and increases the proportions of Akkermansia and Alistipes.
Metformin reduces the concentration of B. fragilis; subsequently, the bile acid glycoursodeoxy-
cholic acid (GUDCA) is increased through a decrease in bacterial bile salt hydrolase activity.
GUDCA is known to exert anti-inflammatory effects by reducing the level of proinflammatory
cytokines and antagonizing the FXR (209, 227). The pathogenic capsular lipopolysaccharides of
B. fragilis are elevated in obese and diabetic patients and associated with dyslipidemia, increased
blood pressure, and insulin resistance (209).
Metformin, the Microbiome, and Aging

Studies have shown that the life span of C. elegans can only be extended with the use of metformin
if specific microbiota are present. Interestingly, this effect relies on the susceptibility of the
96 Induri et al.
nematode gut microbiota to metformin (when glucose is present) (228). When E. coli cells are
incapable of metabolizing metformin, nematode life span is decreased, suggesting a direct link
between the microbiota-specific metformin mode of action and host physiological benefits that
result in a prolonged life span (228).
Metformin directly affects methionine and folate metabolism in E. coli, resulting in methio-
nine restriction in the nematode host (228, 229). Disruption of microbial folate metabolism
increases host life span, although it does not affect host folate level, suggesting that other E. coli
folate-associated pathways may be involved. Inhibition of bacterial methionine synthase (MS)
irreversibly converts 5,10-methylene-THF to 5-methyl-THF and accumulates 5-methyl-THF
via the methyl trap mechanism. Metformin-induced impairment of the bacterial methionine
cycle caused an 86% increase in S-adenosylmethionine (SAMe) levels and a 33% increase in
S-adenosylhomocysteine (SAH) levels. SAMe inhibits the folate cycle, reduces methionine
production by blocking methylene THF reductase, and increases host life span.
The life-extending effect of metformin is mediated by metformin-sensitive E. coli, and in the
absence of E. coli, the life span of C. elegans is shortened due to drug toxicity (228). Conversely,
proliferating E. coli can block the alimentary canal in older worms; however, antibiotic treatment
can prevent this proliferation and increase worm life span (230). These differences suggest that
a harmony between host and microbiota must be established in order to maximize life-extending
benefits.
Another study that employed a four-way high-throughput screening method in conjunction
with in silico human microbiota metabolic modeling strongly suggested that microbially produced
agmatine is necessary for the beneficial effects of metformin on host lipid metabolism and aging
in the model organisms C. elegans and Drosophila melanogaster (231). These findings corroborate
an interplay between host nutrient sources (e.g., sugars), specific bacterial taxa (e.g., E. coli and
other Enterobacteriales), bacterial metabolism (e.g., production of agmatine), and host health, sug-
gesting that a holistic approach is needed for a comprehensive understanding of the roles played
by metformin in the gut microbiome and in aging (231).
CONCLUSION
Metformin has been one of the most common medications worldwide for six consecutive decades.
However, the mechanisms underlying its healthy aging–associated effects remain elusive. Preclin-
ical and observational data from humans suggest that metformin has antiaging and prolongevity
properties and thus has the potential to promote healthy aging (232, 233). Beyond glucose re-
duction, metformin appears to target a number of aging-related mechanisms (Figure 1). The
bioavailability of metformin in the gut is 300 times higher than in plasma (106, 214, 215), and
metformin is known to affect the gut microbiome (106, 214, 215). Further, not all individuals who
are prescribed metformin derive identical benefits, and some develop side effects or metformin
toxicity (175, 216–218). This raises intriguing questions about the role that the gut microbiome
plays in metformin tolerance or intolerance (215) and about how metformin regulates the gut mi-
crobiome. Studies using model organisms indicate that age-related gut dysbiosis may contribute
to unhealthy aging and reduced longevity. Gut dysbiosis can trigger the innate immune response
and chronic low-grade inflammation, leading to many age-related degenerative pathologies and
unhealthy aging (131–138). Metformin treatment can suppress the growth of pathogenic bacteria
in aging to inhibit inflammaging and immunosuppression promoted by various pathobionts. How-
ever, the effects of metformin on the microbiome in the context of aging and longevity require
further research.

E AR LY LI FE
Microbiome
homeostasis
Gut-immunological
homeostasis
Dysbiosis
Leaky gut
Metabolic
disorder
Immune
dysfunction
Inflammation
A G I NG
Figure 1
The gut microbiome maintains gut homeostasis during early life; however, dysbiosis may occur later in life
and contribute to immune/metabolic disorders. Metformin has the potential to attenuate this dysfunction at
multiple stages. Figure adapted from an image created with BioRender.com.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This research project was supported by the National Institutes of Health grant AG068857 (D.S.,
X.L.) and the NYU Mega-Grant Initiative (D.S., X.L.).
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PA62_Front_Matter ARjats.cls November 11, 2021 17:25
Annual Review of
Pharmacology and
Toxicology
Contents Volume 62, 2022
Pushing Forward the Future Tense: Perspectives of a Scientist

Lee E. Limbird p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Introduction to the Theme “New Insights, Strategies, and
Therapeutics for Common Diseases”

Paul A. Insel, Terrence F. Blaschke, Susan G. Amara, and Urs A. Meyer p p p p p p p p p p p p p p p p p p19
Experimental Models of SARS-CoV-2 Infection: Possible Platforms to
Study COVID-19 Pathogenesis and Potential Treatments
Sareh Pandamooz, Benjamin Jurek, Carl-Philipp Meinung, Zahra Baharvand,
Alireza Sahebi Shahem-abadi, Silke Haerteis, Jaleel A. Miyan, James Downing,
Mehdi Dianatpour, Afshin Borhani-Haghighi, and Mohammad Saied Salehi p p p p p p p p p25
Central Nervous System Control of Glucose Homeostasis:
A Therapeutic Target for Type 2 Diabetes?
Zaman Mirzadeh, Chelsea L. Faber, and Michael W. Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p55
The Gut Microbiome, Metformin, and Aging
Sri Nitya Reddy Induri, Payalben Kansara, Scott C. Thomas, Fangxi Xu,
Deepak Saxena, and Xin Li p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p85
Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure
Kevin S. Shah and James C. Fang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 109
Repurposing Colchicine for Heart Disease
Nadia Bouabdallaoui and Jean-Claude Tardif p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 121
A New Old Target: Androgen Receptor Signaling and Advanced
Prostate Cancer
Daniel Westaby, Maria de los Dolores Fenor de La Maza, Alec Paschalis,
Juan M. Jimenez-Vacas, Jon Welti, Johann de Bono, and Adam Sharp p p p p p p p p p p p p p p 131
Synthetic Retinoids Beyond Cancer Therapy
Lorraine J. Gudas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 155
Thioredoxin Reductase Inhibition for Cancer Therapy
Radosveta Gencheva and Elias S.J. Arnér p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 177
v
Emerging Therapeutics, Technologies, and Drug Development

Strategies to Address Patient Nonadherence and Improve
Tuberculosis Treatment
Maria Garcia-Cremades, Belen P. Solans, Natasha Strydom, Bernard Vrijens,
Goonaseelan Colin Pillai, Craig Shaffer, Bruce Thomas, and Rada M. Savic p p p p p p p p p 197
Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The
Search to Prevent or Ameliorate Neurodevelopmental and
Neurodegenerative Disorders
Renata Bartesaghi, Stefano Vicari, and William C. Mobley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 211
Noncanonical Metabotropic Glutamate Receptor 5 Signaling in
Alzheimer’s Disease
Khaled S. Abd-Elrahman and Stephen S.G. Ferguson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 235
Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a

Common Strategy for Neurodegenerative Diseases
Antonio Cuadrado p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 255
Targeting NRF2 and Its Downstream Processes: Opportunities and
Challenges
Laura Torrente and Gina M. DeNicola p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
E-Cigarette Toxicology
Terry Gordon, Emma Karey, Meghan E. Rebuli, Yael-Natalie H. Escobar,
Ilona Jaspers, and Lung Chi Chen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301
Thirty Years of Neuroscientific Investigation of Placebo and Nocebo:
The Interesting, the Good, and the Bad
Fabrizio Benedetti, Elisa Frisaldi, and Aziz Shaibani p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 323
Patient Centricity Driving Formulation Innovation: Improvements in
Patient Care Facilitated by Novel Therapeutics and Drug Delivery
Technologies
Susanne Page, Tarik Khan, Peter Kühl, Gregoire Schwach, Kirsten Storch,
and Hitesh Chokshi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 341
Fragile X Syndrome: Lessons Learned and What New Treatment
Avenues Are on the Horizon
Randi J. Hagerman and Paul J. Hagerman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 365
Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions:
An Exposome Receptor
Lucie Larigot, Louise Benoit, Meriem Koual, Céline Tomkiewicz, Robert Barouki,
and Xavier Coumoul p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 383
Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug
Disposition, Toxicity, and Development
Tatsuki Fukami, Tsuyoshi Yokoi, and Miki Nakajima p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405
vi Contents
Pharmacology of TRPC Channels and Its Potential in Cardiovascular

and Metabolic Medicine
Robin S. Bon, David J. Wright, David J. Beech, and Piruthivi Sukumar p p p p p p p p p p p p p p p 427
KCNQ Potassium Channels as Targets of Botanical Folk Medicines
Kaitlyn E. Redford and Geoffrey W. Abbott p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 447
Drug Target Identification in Tissues by Thermal Proteome Profiling
André Mateus, Nils Kurzawa, Jessica Perrin, Giovanna Bergamini,
and Mikhail M. Savitski p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
Endocannabinoid-Based Therapies
Daniele Piomelli and Alex Mabou Tagne p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 483
HLA Allele–Restricted Immune-Mediated Adverse Drug Reactions:

Framework for Genetic Prediction
Kanoot Jaruthamsophon, Paul J. Thomson, Chonlaphat Sukasem, Dean J. Naisbitt,

and Munir Pirmohamed p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 509
Measuring Pharmacogene Variant Function at Scale Using
Multiplexed Assays
Renee C. Geck, Gabriel Boyle, Clara J. Amorosi, Douglas M. Fowler,
and Maitreya J. Dunham p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 531
Chemogenetic Approaches to Probe Redox Pathways: Implications for
Cardiovascular Pharmacology and Toxicology
Benjamin Steinhorn, Emrah Eroglu, and Thomas Michel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 551
Endocrine-Disrupting Chemicals and Child Health
Akhgar Ghassabian, Laura Vandenberg, Kurunthachalam Kannan,
and Leonardo Trasande p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 573
Systems Biology of the Vasopressin V2 Receptor: New Tools for
Discovery of Molecular Actions of a GPCR
Lihe Chen, Hyun Jun Jung, Arnab Datta, Euijung Park, Brian G. Poll,
Hiroaki Kikuchi, Kirby T. Leo, Yash Mehta, Spencer Lewis, Syed J. Khundmiri,
Shaza Khan, Chung-Lin Chou, Viswanathan Raghuram, Chin-Rang Yang,
and Mark A. Knepper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 595
Oxidative Stress and Metabolism: A Mechanistic Insight for
Glyphosate Toxicology
Xiaojing Wang, Qirong Lu, Jingchao Guo, Irma Ares, Marta Martínez,
María-Rosa Martínez-Larrañaga, Xu Wang, Arturo Anadón,
and María-Aránzazu Martínez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 617
Precision Medicine Approaches for Infantile-Onset Developmental
and Epileptic Encephalopathies
Kenneth A. Myers and Ingrid E. Scheffer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 641
Contents vii

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Annual Review of Pharmacology and Toxicology

The Gut Microbiome,

Scott C. Thomas,1 Fangxi Xu,1 Deepak Saxena,1,2

and Xin Li1

Annu. Rev. Pharmacol. Toxicol. 2022. 62:85–108 Keywords

The Annual Review of Pharmacology and Toxicology is Abstract

Gut Microbiome in the Promotion of Health

Immunomodulation and gut-immunological homeostasis. The human gut microbiome

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 87

Protection against pathogenic strains. A major function of indigenous gut microbiota is to

Gut Dysbiosis in the Promotion of Disease

of others (e.g., Intestinibacter spp. and Clostridium spp.) (77).

The Human Gut Microbiome and Drug Metabolism

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 89

anti-inflammatory properties (101).

Microbiome and Aging

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 91

Metformin and Aging

Epigenetic alterations. Epigenetic alterations include histone modifications, DNA methylation,

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 93

Altered intercellular communication. A prominent aging-associated alteration in intercellular

Metformin and Gut Microbiota

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 95

Metformin, the Microbiome, and Aging

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 97

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 99

Scand. J. Gastroenterol. 29:445–51

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64. Bartlett JG. 2002. Antibiotic-associated diarrhea. N. Engl. J. Med. 346:334–39

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 101

practice. Saudi Pharm. J. 27:1146–56

102 Induri et al.

biome viewed across age and geography. Nature 486:222–27

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 103

104 Induri et al.

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 105

Annu. Rev. Biochem. 77:727–54

106 Induri et al.

Cell Metab. 32:15–30

www.annualreviews.org • Gut Microbiome, Metformin, and Aging 107

108 Induri et al.

Pushing Forward the Future Tense: Perspectives of a Scientist

Therapeutics for Common Diseases”

Emerging Therapeutics, Technologies, and Drug Development

Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a

Pharmacology of TRPC Channels and Its Potential in Cardiovascular

HLA Allele–Restricted Immune-Mediated Adverse Drug Reactions:

Kanoot Jaruthamsophon, Paul J. Thomson, Chonlaphat Sukasem, Dean J. Naisbitt,

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