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Flashcards in Midterm 3 Deck (264):
1

Sexual reproduction

• A haploid genome from both the mother and father fuse to form the diploid zygote.
• Only one allele is passed on from each parent.
• Sexual reproduction allows for the development of new admixtures of alleles from one generation to the next.

2

Hypothesis on the benefits of sexual reproduction

• Host defenses against infections (this is the hypothesis that is most favored by evolutionary biologists).

3

Sexual reproduction & host defenses against infections

• Parasites are smaller than their hosts and have faster generation times and thus a faster rate of evolution.
• Sexual recombination can, in a single generation, create a novel combination of defense mechanisms against parasites, for example by creating new allele combinations in the genes for the transmembrane proteins called major histocompatibility complexes (MHC).
• These genetically determined major histocompatibility complexes are highly variable among individuals.
• Generally the level of change in one generation of human sexual reproduction is sufficient to compensate for the parasite’s much faster reproductive time and potential for evolution.
• This interspecific co-evolutionary competition, always ongoing and seldom with a clear winner or loser, has been referred to as the “Red Queen effect”.

4

Major Histocompatibility Complex genes (MHCs)

• HLA (human leukocyte antigen) is the name for the major histocompatibility complex (MHC) in humans.
• MHC genes encode cell surface proteins that offer a display of proteins being made inside of the cells.
• This enables the immune system to detect foreign proteins (e.g., microbes or toxins) in a cell and destroy them

5

Red Queen effect/hypothesis

• In Lewis Carroll’s Through the Looking Glass, the Red Queen said, “It takes all the running you can do to keep in the same place”.
• For an evolutionary system, continuing development is needed just in order to maintain its fitness relative to the systems it is co-evolving with.

6

Mate choice (female)

• For females, fitness strategy is maximized by selecting the mate who can contribute most to sustaining viable offspring including the capacity to assist the mother in parental care of the offspring.
• There are also other factors which contribute to biological attraction of females to a mate including his major histocompatibility complex genes (MHCs).
• Women are attracted to scents of men who are most unlike themselves in major histocompatibility complex genes (MHCs)
• Human mate pairs with similar MHCs tend to be less fertile with higher miscarriage rates
• The more dissimilar the MHCs of a human male/female pair, the better their offspring immune systems will be at detecting foreign proteins, e.g., viruses or toxins

7

Sweaty T-shirts & human mate choice: MHC genes, body odors, & odor preferences

• Sweaty T-shirt experiment by Swiss scientists demonstrated that odors influence human mate choice
• Females not on oral contraceptives sniffing the T-shirts recently worn by males favored the scent of those whose immune response genes were different from their own
• Odor preferences of women on oral contraceptives were reversed as they favored the scent of men whose immune response genes were similar to their own

8

Microbial pathogens
how many are there?

• There are over 1,200 species of recognized human pathogens.
• Many of these pathogens require the human body to allow for their survival and reproduction

9

Pathogen definition

• To be a pathogen, an organism must be able to survive and replicate in or on its host, and must be transmissible between hosts, sometimes via an intermediate vector.
• Pathogen must negatively affect the host organism by secreting a toxin, damaging cellular function, competing for nutrients, or simply by causing mechanical damage.

10

The ability of different modes of transmission to transmit infection

*BOLD*

• *Respiratory infections*: respiratory secretions
• *Diarrheal infections*: fecal-oral route
• *Skin infections:* skin-skin contact
• *Sexually transmitted infections:* sexual
contact
• *Blood borne infections:* blood-blood contact
• *Vector borne infections:* malaria, zikavirus,
Lyme disease

11

Respiratory infections

• Produce respiratory and nasal secretions.
• Transmitted hand to hand.
• Transmitted by sneezing or coughing projected
aerosols which can infect the nasal/respiratory tracts of other humans.
• Part of the human defense mechanism against respiratory infections is to try to shed the pathogen by having a running nose, coughing, and sneezing.
• Shedding of the respiratory secretions also benefits the pathogen because it helps its transmission.

12

Diarrheal diseases

• Transmitted through a fecal-oral mechanism
• Human responds to pathogen by developing diarrhea to shed infection.
• This diarrheal shedding also benefits the transmission of the pathogen.
• Diarrheal shedding is highly efficient at transmitting infection to human contacts who have hand-hand contact, use the same bathroom, or consume contaminated food or water.

13

Skin infections

• Transmitted by skin to skin contact.
• Impetigo from Staphylococcus infection.
• Fungal dermatophytes e.g., tinea
corporis (ringworm) from Trichophyton
infection.
• Papilloma virus causes skin warts.
• Wrestling mats are sites where any of these skin infections can be transmitted.

14

Sexually transmitted infections

• Transmitted by sexual contact.
• Many of the sexually transmitted infectious microbes specialize in living on moist tissue surfaces (e.g., Chlamydia, Gonococcus, and Herpes simplex).
• Other sexually transmitted diseases are transmitted when there is blood to blood contact during sex e.g., HIV, Hepatitis B, & Hepatitis C.

15

Blood borne infections

• Transmitted through blood-blood contact such as through sex, blood transfusion, or IV drug use.
• HIV • Hepatitis B • Hepatitis C

16

Vector borne diseases transmitted by mosquitoes, flies, ticks, and/or snails

• Malaria
• Schistosomiasis
• Lyme disease
• Dengue
• Zika virus

17

Human immunodeficiency virus (HIV)

• HIV is present in blood, semen, cervical & vaginal secretions, breast milk, saliva, and tears
• HIV is primarily transmitted in blood
• Caused by having blood contact with a person with HIV (human immunodeficiency virus)
• Flu-like symptoms emerge 2-4 weeks after exposure and lasts for 1-2 weeks and may include fever, rash and swollen lymph nodes
• Clinical latency then lasts for 3 to over 20 years

18

Human immunodeficiency virus
(HIV) transmission routes

Blood inoculation e.g., transfusion or injection drug use
Perinatal • Across placenta • During birth • Breastfeeding Sex • Sores on genital or anal area from another
infection make it easier to be infected with HIV

19

AIDS Aquired Immune Deficiency Syndrome

• Caused by infection with HIV (human immunodeficiency virus)
• CD4+ T cell (T helper cells) count below 200 cells per µL
• The occurrence of specific diseases in association with an HIV infection which result from immune deficiency
The most common initial conditions include: •pneumocystis pneumonia •cachexia in the form of HIV wasting syndrome
•esophageal candidiasis and •other opportunistic infections e.g. cytomegalovirus
retinitis Cancers associated with human herpes virus 8: •Kaposi’s sarcoma
•lymphoma

20

Human immunodeficiency virus (HIV) Diagnosis

• Detection of HIV antibodies in blood or saliva
• Nearly all persons infected with HIV have detectable antibodies (seroconversion) within 6 months of infection
• HIV RNA test can detect virus before antibodies emerge

21

Human immunodeficiency virus (HIV) Prevention

• Condoms both for men and women
• Circumcised men have a 50% reduction in likelihood of acquiring HIV
• Breast milk can be heated to a low temperature to eliminate the HIV
• HIV positive women who are pregnant receive AZT (an NRTI) during pregnancy, labor, and delivery and the newborn receives AZT at birth
• Truvada taken orally each day to prevent HIV infection; Truvada contains two NRTI medicines, emtricitabine & tenofovir

22

AIDS
Aquired Immune Deficiency Syndrome

-with no treatmeant half of people with HIV get AIDS

23

Human immunodeficiency virus (HIV)
treatment
*BOLD*

• *Nucleoside reverse transcriptase inhibitors (NRTIs)* e.g., AZT (zidovudine): interfere with synthesis of viral DNA
• *Nonnucleoside reverse transcriptase inhibitors (NNRTIs):* interfere with synthesis of viral DNA
• *Protease inhibitors:* interfere with correct cutting of viral proteins
• *Fusion inhibitors:* prevent passage of virus into the cell

24

HIV global morbidity & mortality as of 2015

- number of AIDS cases and death decreasing but number of people living with AIDS continues to increase
• 78 million people have become infected
• 39 million people have died

25

HIV: blood borne disease derived from African primates

• Both HIV-1 and HIV-2 are believed to have emerged in West & Central Africa in humans in the early 20th century.
• The earliest documented case of HIV in a human dates back to 1959 in the Congo in Central Africa.

26

Earliest description of AIDS in the USA

• AIDS (acquired immunodeficiency syndrome) caused by HIV was first clinically described in 1981 in the United States in Los Angeles.

27

SIV origin & in African primates

• Simian immunodeficiency virus (SIV), ancestor to the human immunodeficiency virus (HIV), is 32,000 to 75,000 years old according to genetic analysis of unique SIV strains found in monkeys on Bioko, an island off the coast of Africa.
• At least forty African non-human primate species harbor different strains of simian immunodeficiency viruses (SIV)
• Some of these strains evolved into human immunodeficiency virus (HIV)
• HIV originated in humans on at least 13 separate occasions, evolving in humans from ancestral viruses that infected monkeys, chimpanzees and gorillas.

28

HIV-1 origin

-appears to have originated in southern Cameroon through the evolution of SIV (cpz), a simian immunodeficiency virus (SIV) that infects wild chimpanzees
• Dr. Martine Peeters from the University of Montpellier in France conducts virological research in apes & Found that chimpanzees are infected with a wide diversity of SIV (simian immunodeficiency virus) viruses and probably have been for tens of thousands of years

29

Chimpanzees are source of
HIV-1 groups M & N

• HIV-1 has been divided into four groups (M, N, O, P).
• Group M — short for main — is responsible for 90 percent of HIV-1 infections
• A strain of chimpanzee SIV in Cameroon is the source of HIV-1 Group M
• Another SIV strain from the same population of chimpanzees gave rise to Group N

30

Gorillas as source of HIV-1 Groups O & P

• Gorillas in Cameroon are infected with SIV that is closely related to a strain of SIV in Cameroon chimpanzees.
• Gorillas appear to have acquired SIV from chimpanzees only one time.
• There is evidence of two occasions that HIV was acquired by humans from gorillas, in one instance, producing HIV-1 Group O, and in the other HIV-1 Group P.

31

HIV-2 origin

• derived from SIV(smm), a virus of the sooty mangabey (Cercocebus atys atys), a monkey living in West Africa from southern Senegal to western Côte d'Ivoire.
• SIV has been transmitted from sooty mangabeys into humans at least nine times, evolving into a strain of HIV-2 each time

32

SIV to HIV
BOLD

• There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV.
• SIV is a weak virus, and it is typically suppressed and cleared by the human immune system within weeks of infection.
• Several transmissions of the virus from individual to individual in quick succession are required to allow it enough time to mutate into HIV.
• Due to SIVs relatively low person-to-person transmission rate, it can only spread throughout the population in the presence of one or more of *high-risk transmission channels,* which are thought to have been absent in Africa prior to the 20th century.

33

HIV-1 origin around 1910

• Genetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to circa 1910.
• There is direct evidence of extensive diversity of HIV-1 in Kinshasa in Central Africa by 1960.

34

Emergence of HIV in Africa

-colonialism in the early 20th cent that lead to prostitution
• It has been proposed that the HIV epidemic is linked with the emergence of colonialism and growth of large colonial African cities in the early part of the 20th century, leading to a dramatic increase in prostitution along with its associated high frequency of genital ulcer diseases (such as syphilis); genital ulcers increase the risk of HIV transmission
• It has been proposed that serial human passage of SIV and HIV by unsterile syringe injections contributed to the emergence of epidemic human immunodeficiency virus in Africa.

35

Mutation at CCR5 locus based on selection caused by some prior infectious disease has been exapted for protection against HIV

-CCR5 is a human receptor protein which is a seven trans-membrane spanning protein of 332 amino acids that inserts into the cell membranes of human CD4+ T helper cells.
• The widespread occurrence of a mutation in the CCRS gene appears to provide partial resistance to HIV infection is an example of selection likely caused by some prior infectious disease.
• Hence immunological outcome of this mutation has been exapted for protection against HIV.

36

Evolution of microbes

• Microbes evolve in relationship to the hosts and vectors they rely on for their survival and fitness.
• Microbes have a much faster generation time and ability to evolve than humans.
• The rapid resistance that some bacteria evolve to antibiotics is a great example of the ability of microbes to evolve rapidly.

37

Infectious diseases

• Contracted from other humans.
• Contracted from animals.
• Many viral human infectious
diseases have their origins from domesticated animals.
• Other viruses have their origins from primates.

38

Microbial evolutionary “jump”from animal hosts to human hosts
*BOLD*

• *Measles:* from cattle.
• *1918 Influenza* pandemic: from birds.
• *Avian Influenza:* from birds.
• *Influenza:* some strains come from pigs.
• *SARS (sudden acute respiratory syndrome)*:
palm civets sold as bushmeat in local markets in Guangdong, China may have been the original source transmitting virus to humans.
• *HIV:* from primates.
• *Zikavirus:* from monkeys
• *Ebola:* from bats

39

Measles

• Measles appears to have arisen within the last 20,000 years by transmission from cattle affected by a closely related morbillivirus, rinderpest.
• Measles was restricted to Eurasia until the 1500s when it was introduced into the New World.
• Because there had been no previous exposure to this pathogen, the New World population did NOT have immunity to either measles or small pox and it is estimated that in some areas, 95% of the Native American population died from these and other introduced infectious diseases.
• People who get measles and survive the infection have lifelong immunity against the disease

40

Standing water generated by irrigation for agriculture may support vector borne diseases

• Development of irrigation and drainage systems with agriculture produce ecological conditions that support the development of vector borne infections such as malaria (mosquito vector) and schistosomiasis (snail vector).

41

Bacterial virulence factors: the ability of bacteria to cause disease is described in terms of:

• number of infecting bacteria.
• route of entry into the body.
• symptoms caused by the bacteria.
• effects of host defense mechanisms.
• intrinsic characteristics of the bacteria.

42

Virulence

• Size of infectious load.
• Ability to transmit infection to other hosts.
• Measure of an infecting organism’s ability to cause morbidity and mortality in its host which includes time of incubation.

43

Virulence may manifest as incidental damage to the host that DOES NOT enhance transmission of the infecting organism

• As person with HIV develops the debilitating symptoms of AIDS, they are less likely to engage in sexual intercourse which would reduce the likelihood that they would transmit the HIV virus.

44

Virulence may manifest as incidental damage to the host that DOES enhance transmission of the infecting organism,

• nose & throat irritation with upper respiratory infection induces coughing and sneezing which enhances transmission
• toxin induction of intestinal chloride ion secretion and diarrhea which enhances transmission
• genital herpes ulcers shed virus enhance transmission.

45

Fighting the evolutionary arms-race: Coincidental evolution hypothesis for infectious pathogens

• Forms of pathogenic virulence that did not co-evolve with the human host.
• The virulence of many pathogens in humans may not be a target of selection itself, but rather an accidental by-product of selection that operates on other traits.

46

Coincidental evolution hypothesis
for infectious pathogens

• For example, tetanus is caused by the soil bacterium
Clostridium tetani.
• After C. tetani bacteria enter a human wound, the bacteria may grow and divide rapidly, even though the human body is not their normal habitat; soil is its normal habitat.
• While dividing, C. tetani produce a neurotoxin that is lethal to humans.
• But it is selection in the bacterium's normal life cycle in the soil that leads it to produce this toxin, not any evolution with a human host.
• The bacterium finds itself inside a human instead of in the soil by mere happenstance.

47

*Ebola virus*: highly virulent organism that acts quickly and has a high mortality rate in humans

• Viral infections like Ebola are highly virulent in
humans, with short incubation rates, rapid morbidity, and high mortality.
• Since most human hosts with Ebola die quickly, this limits the ability for these human hosts to transmit the infection to a large number of humans.
• Ebola also infects certain primate species who have significant morbidity and mortality from this virus.
• Some species of bats remain asymptomatic and can be chronic carriers of Ebola virus
• It appears that Ebola evolved in bats and persists in the ecosystem in bats

48

Coincidental evolution hypothesis BOLD

• Ebola infection in humans appears to be an example of the *coincidental evolution hypothesis* since this virus appears to have co-evolved a host-pathogen relationship with bats.
• Humans appear to be a coincidental host for Ebola virus.

49

West Nile virus

• *West Nile virus (WNV)* is a Flavivirus virus in the family Flaviviridae which is a vector borne infection that originated in Africa.
• The vector is the mosquito genus, Culex.
• West Nile Virus co-evolved with birds and birds are its primary hosts.
• The vector Culex can also bite and infect many other vertebrate species.
• Humans may be a coincidental host of West Nile virus.
• Approximately 80% of human infections with West Nile virus are asymptomatic.

50

Fighting the evolutionary arms-race: Short-sighted evolution hypothesis for life history strategy for infectious pathogens

• Short-sighted evolution suggests that the traits that increase reproduction rate and transmission to a new host will rise to high frequency within the pathogen population.
• As long as transmission continues despite the virulence, virulent pathogens will have the advantage.
• However, if the *pathogen's virulence kills the host before it is able to be transmitted to a new host it is seen as an example of short-sighted evolution hypothesis.*

51

Trade-off evolution hypothesis
BOLD
and examples of each

• The evolution of virulence in pathogens is a balance between the costs and benefits of virulence to the pathogen.
• High virulence with high & rapid transmission, but may kill the host quickly (Cholera, some strains of influenza)
• Low virulence with low and slow, but prolonged transmission (oral herpes and genital herpes)

52

1918 influenza: Tradeoff Evolution Hypothesis: High virulence with high & rapid transmission, but may kill host quickly

• A microbe may have a short incubation period and cause a high mortality rate in human hosts, however, if the microbe is highly contagious with a rapid and prolific method of transmission such a coughing and sneezing which produces aerosols (like the 1918 influenza), it can quickly infect a high percentage of the population even though the host mortality rate is high.
• During 1918 pandemic, 20% of the people around the world were infected by this virus.
• High virulence with high transmission.

53

Herpes simplex 1 & 2: low virulence with low and slow, but prolonged transmission

• Herpes simplex 1 produces ulcers primarily around lips and in mouth; 90% of adults carry this virus.
• Herpes simplex 2 produces ulcers primarily around genitalia.
• Both these types of herpes virus remain dormant in nerve fibers for the entire life of the host and periodically reactivate and form ulcers which can transmit the virus.
• Neither of these viruses typically kill or even severely debilitate the host and are able to intermittently transmit virus to other hosts.
• Low virulence with relatively low transmission, but sustained over many decades.

54

Trade-off evolution hypothesis
Salmonella typhi (typhoid)

• The ancestral strain of Salmonella typhi from which all other strains derive still exists today.
• Probably arose after humans migrated from Africa before the Neolithic period and since that time other strains have arisen.
• Over the past 50 years the development of new strains has been particularly rapid because of the introduction of a variety of antibiotics.
• Some strains are highly virulent and cause extreme symptoms in an affected person causing diarrhea which rapidly spreads the bacterium, while other human carriers do not develop symptoms and can transmit the bacteria to other humans.
• Other strains are less virulent and reside chronically in the intestines and produce minor or no apparent symptoms in the human host, but can be transmitted slowly and continually through the feces to other human hosts over a long period of time such as was the case for Typhoid Mary.

55

Typhoid Mary: symptom free typhoid carrier

• A famous case is about a symptom free, otherwise healthy woman named Mary Mallon, better known as Typhoid Mary.
• Emigrated from Ireland to USA at age of 15 years in 1884.
• In 1906 she was hired as a cook by a family during their summer vacation in a rented home; shortly after the vacation, 6 of 11 of the family members were hospitalized with typhoid fever.
• It was discovered that a total of 22 additional people came down with typhoid fever at several of Mary’s previous jobs.
• Mary’s stool was tested and found to be positive for typhoid.
• Five years later, Mary was responsible for an outbreak of typhoid fever in a Manhattan hospital.
• She was then quarantined the rest of her life (23 years).

56

Virulence & antibiotics: MRSA

• If an antibiotic acts to reduce the death rate of the host, then selection might act on the pathogen to develop resistance to the antibiotic, which favors an increase in its virulence, transmission, and thus the fitness of the pathogen.
• a more virulent strain of Staphyloccocus aureus called MRSA (methicillin resistant Staph aureus) which is resistant to penicillin and its relatives and needs to be treated with other types of antibiotics.
• MRSA is more virulent and causes more severe infections than previous strains of Staphylococcus aureus.
• There is no evidence that the human MHC system is evolving in an effective way to resist MRSA.
• So an important human defense innovation is the development of exogenous antibiotics to treat this infection.

57

Trade-offs with antibiotic use: Inappropriate antibiotic use can augment pathogen development

• Collateral damage from antibiotics can result in the death of beneficial microbes which may shift the ecology to favor pathogens.
• Antibiotic use can also cause commensal bacteria to evolve to be resistant to the antibiotic and be pathogenic.

58

Transition from
commensal microbe to pathogen

• While commensals are not harmful and in fact are beneficial to humans, it is possible for a commensal microorganism to evolve into a pathogen, e.g. when exposed to antibiotics.
• The normally beneficial commensal bacteria, Escherichia coli, can acquire a virulence factor such as the bacteriophage-encoded Shiga-like toxin which gives rise to the potentially fatal pathogenic strain 0157:H7.

59

Bifidobacteria can protect from enteropathic infection through production of acetate

• The human gut is colonized with a spectrum of different beneficial microorganisms.
• Bifidobacteria produce acetate and it was demonstrated in mice that this acetate inhibited the pathogenic bacteria E. coli 0157:H7.
• It is proposed that acetate produced by protective bifidobacteria improves intestinal defense mediated by epithelial cells and thereby protects the host against lethal infection by E. coli
0157:H7.

60

Commensals

• Humans have extensive beneficial co-habitation relationships with many commensal microorganisms in our gastrointestinal tracts, respiratory tracts, genitourinary tracts, and dermatological tracts.
• These commensal relationships are beautiful examples of co-evolution between humans and microbes
• Humans have evolved and adapted to the microbes and vice versa.

61

Maternal vaginal microbiome

- a woman's vaginal microbiome changes to produce higher percentage of Lactobacillus species (that helps infant digest milk

62

Maternal commensals
transferred to children

• Strains of commensals in mothers are correlated with the strains of commensals in her offspring.
• These commensals may be transferred during birth and thus can be considered a form of non-genomic inheritance.
• Benefits to vaginal delivery which facilitates the transmission of beneficial commensals from the mother to the infant.

63

C-section birth and commensals

• Compared to infants born vaginally, infants born by caesarean section have diminished exposure to their mothers' microbiome, and are more likely to be colonized from the surrounding environment such as the air, other infants, and the nursing staff, which serve as vectors for transfer.
• The primary gut flora in infants born by caesarean delivery may be disturbed for up to six months after birth.
• Vaginally born infants take up to one month for their intestinal microflora to be well established.

64

Commensal probiotics

• In the GI tract, a number of lactobacilli bacteria act as probiotics, because they out-compete the growth of harmful bacteria.
• The time taken to recover from a bout of diarrhea is partly due to the necessity of re-colonizing the gut with our beneficial commensal bacteria flora.

65

Red meat & the gut microbiome

• Meat eaters have a different gut microbiota than vegetarians.
• The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status.
• Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism.
• Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and cardiovascular disea

66

Transgenerational passage of acquired immune characteristics in breast milk

• The first milk, colostrum, produced by the mother contains interferon which inhibits viral growth.
• IgA antibodies are rich in breast milk and confer a considerable degree of passive immunity for the baby.
• Mom produces IgA based on organisms she has encountered.
• Fortunately, this IgA mom transfers to the infant does not harm the infant’s commensal intestinal flora but rather protects infant against pathogen
-Oligosaccharides in human breast milk bind to pathogenic bacteria in the gut making them more likely to be destroyed by antibodies and macrophages.
• Lactoferrin interferes with bacterial iron metabolism.
• Bifidus factor promotes the growth of the beneficial commensal, Lactobacillus bifidus.

67

MHC ability to distinguish between self and foreign antigens

• MHC play a key role in self-recognition to avoid the development of autoimmune diseases and to recognize foreign substances.

68

Autoimmune disease evolutionary pathway: excessive and uncontrolled defense mechanisms

• Autoimmune: immune system attacking cells and tissues.
• Diseases of autoimmunity, and a variety of allergic disorders e.g., eczema and asthma can be considered as situations where the normal evolved processes of defense are inappropriately and/or excessively activated resulting in the immune system attacking its own cells.

69

Association of infectious diseases and immune related diseases between 1950-2000

• Drop in rheumatic fever (Streptococcus), measles, mumps, hepatitis A, and tuberculosis.
• Rise in autoimmune diseases including multiple sclerosis, asthma, Type 1 diabetes mellitus, and Crohn’s disease.

70

Relationship of incidence of certain infectious diseases with incidence of immune-related disorders

• There is an inverse relationship to the exposure to certain infectious diseases (decrease) over the past 100 years and the prevalence of a number of autoimmune diseases (increase).

71

Hygiene hypothesis

• Germ-free mice experience abnormal development of their immune system which can be corrected by re-introduction of intestinal commensal bacteria or the administration of purified polysaccharides from this bacteria.
• A proposed underlying mechanism for this hypothesis is that the vertebrate adaptive immune system has co-evolved with both commensal and pathogenic micro-organisms, and that appropriate exposure to this microbiota early in life is beneficial to setting up normal immuno-regulatory pathways.
• Lack of such exposure can lead to inappropriate activation of immune responses which are then manifest as allergic or autoimmune diseases.

72

Hygiene hypothesis and
intestinal helminths

-worms (intestinal helminths) can live in you
-don't have to show visible symptoms
-in $$ developed countries worms not present

73

Intestinal helminth to treat inflammatory bowel disease

• Studies show that helminthic infection is protective against a number of immune-mediated diseases including inflammatory bowel disease (Crohn’s disease and ulcerative colitis).
• The pig whip worm Trichuris suis is not pathogenic in humans.
• This worm is used as a treatment and is introduced into the intestine of patients with inflammatory bowel disease and has been shown to significantly reduce disease activity in people with ulcerative colitis and Crohn’s disease.
• Research on this topic is being done at the University of Iowa Medical Center.

74

Infectious disease: heterozygote advantage

• Heterozygote advantage e.g., sickle cell and protection against malaria.

75

Contemporary selective pressures from infectious diseases e.g. malaria

• The continued high morbidity and mortality rates from malaria and the persistence of hemoglobinopathies (sickle cell disease, thalassemia, and G6PD) which protect against malaria is a demonstration of the strength of selection caused by present day malaria.

76

Evolutionary perspectives & cancer

• Neoplasia which is uncontrolled cell replication with clonal expansion of a cell population and to its migration (metastasis) from source to elsewhere in the body.
• Neoplasia/cancer causes about 1/3rd of the deaths in the USA.
• Neoplasia is not a single disease entity.
• There are many pathways to that can lead to neoplasia.
• While some cancers can be traced to a single initiating event (e.g., asbestos induced mesothelioma), most cancers do not have a singular cause.

77

Genes and cancer

• Somatic mutations induced in the clone give a particular lineage of cells a replicative advantage.
• Cancer often requires more than one mutation.
• There is evidence that mutations that support neoplasia may accumulate over time in some cancers.
• Appear to be genes involved which enable the growing clone to be supported with increased vascularization.
• May be genes that facilitate the break down of physical barriers to allow expansion.
• May be genes which enable the cells to evade the immune surveillance of its host organism.

78

Stress and cancer

- stresses can cause mutation which lead to neoplasia

79

Pipe smoking and cancer

-can lead to lip and gum cancer

80

chewing tobacco

-associated with development of oral cancer

81

-chimney sweeps

-those exposed to high amounts of toxic tar in soot from their work was linked to their high rate of scrotal cancer

82

mismatch and cancer

-high levels of gamma radiation is associated w/ triggering a number of different cancers
- people who receive a CAT scan of the brain or the abdomen are at increased risk for developing cancer later in life
-highly salted pickled foods has been associated with higher rates of stomach cancer...reduction of this has occurred in Europe b/c marked reduction of the consumption of these types of food
-excessive intake of alcohol is associated with increased rates of esophageal, stomach, and breast cancer
• The increase in meat consumption along with the reduction in fiber is associated with increased rates of colon cancer, prostate cancer, and breast cancer.
• Some data suggests that cow’s milk consumption increases the risk of breast cancer in part because of the estrogens in the cow’s milk.
• Xenoestrogens e.g., bisphenol A and other plastics and pesticides in the environment can increase breast cancer rate.

83

Gut microbiome impact on
development of colon cance

• Diet rich in fiber from fruits and vegetables influences the gut microbiome to reduce the likelihood of developing colon cancer.
• Diet rich in plant fiber balances intestinal pH and stimulates intestinal fermentation to produce short chain fatty acids (SCFAs) that reduce risk to colon and rectal cancer.
• Diet rich in red meat influences the gut microbiome to increase the likelihood of developing colon cancer

84

Cancer and the microbiota

• Mucosal surface barriers permit host-microbial symbiosis which protects the host
• When these surface barriers and the host-microbial symbiosis is compromised, tissues can be put on a path to malignancy
• So, certain microbiota can contribute to the development of tumors on mucosal surfaces
• Ten microbes have been designated as carcinogenic to humans by the International Agency for Cancer Research (IACR)

85

what are oncomicrobes

• Oncomicrobes, e.g., certain strains of HPV (human papilloma virus) are associated with cervical and anal cancer
• Certain cancer-associated microbes appear to activate NF-kB signaling within the tumor microenvironment which can contribute to the development of colon cancer.

86

cancer & evolutionary arms race
-infectious diseases

• Karposi’s sarcoma is caused by human herpes virus 8 and is associated with the immunocompromised system in people HIV/AIDS.
• Hepatocarcinoma is associated with Hepatitis B.
• Cervical cancer is associated with certain strains of human papilloma virus

87

Cancer & the evolutionary arms race
with anticancer drugs
-Cisplatin

• Cisplatin is a common chemotherapeutic drug which is used to treat various cancers by damaging the DNA of the tumor cells.
• Resistance of tumors to cisplatin has been identified and is linked to increased DNA repair by these cells.
• Long term use of cisplatin was associated with a higher expression of genes involved with DNA repair.
• Hence, an evolutionary arms race proceeds as these cancer cells evolve to become resistant to the anticancer drug cisplatin, while humans are researching to develop new anticancer drugs to treat these tumors.

88

Cancer & demographic history

• Lung cancer in non-smokers is relatively common in some Chinese populations and has been linked to an activating mutation of the epidermal growth factor receptor.
• The threshold of smoke exposure that induces cancer in this population is much lower than the general population.
• The development of lung cancer in the population with this mutation typically requires exposure to some smoke from burning wood or coal as a trigger for cancer development.

89

Outcome of demographic history Cancer associated with genes affecting DNA repair
-p53

• Cancer may involve genes affecting DNA repair.
• For example, p53 is a cellular protein that plays a major role as an intracellular signal to initiate DNA repair or to stop proliferation when stressed.
• Familial inheritance of p53 mutations leads to a high rate of sarcoma, breast cancer and other cancers.
• p53 mutations are rare.

90

Cancer associated with gene mutation & outcome of demographic history
-BRCA1

• BRCA1 is a human gene that belongs to a class of genes known as tumor suppressors.
• Mutations of the BRCA1 gene is linked with hereditary breast cancer.
• BRCA1 mutations are quite common and increase the risk for breast cancer, however, they persist despite being harmful probably because the breast cancer typically develops after reproductive years.
• Ashkenazi Jews generally have one of two mutations not found in other populations, suggesting a founder effec

91

Cancer:
cultural evolution
women

• The more children a woman has and the longer she breast feeds, the lower her risk for breast cancer will be.
• Celibate women have higher rates of breast cancer.
• Modern women have on average many more menstrual cycles and higher cumulative estrogen exposure than hunter-gatherer females who have (and had) lower body fat and more interruption of their cycles with pregnancy and lactation.
• Additionally, human lactation leads to loss and renewal of ductal epithelial cells, thus removing cells with somatic mutations.
• In one population in China where women tend to feed only from the right breast, cancer is more common in the left breast.

92

Cancer effects of deleterious allele does not typically become apparent until after reproductive age

• Breast cancer
• Ovarian cancer
• Prostate cancer
• Colon cancer

93

• Some neoplasias are directly linked to periods of particular growth plasticity, and this can explain the age distribution of certain cancers.

• For example, tumors of tissues that primarily proliferate in early life generally present as childhood tumors such as Wilm’s tumor of the kidney or rhabdomyosarcoma of muscle.
• Osteosarcoma is a bone tumor which often emerges during periods of rapid peri-adolescent bone growth.

94

cancer and living longer

• In recent centuries, humans have longer life expectancies than in our ancestral history over the past 200,000 years.
• Some propose that simply by living longer allows for more spontaneous somatic mutations to arise as there has been greater cumulative exposure to environmental mutagens.
• This is compounded by the increased human exposure to environmental mutagens the longer we live.
• The risk of most epithelial tumors such as colon cancer increases as an individual ages because these tissues replicate through life and the risk of multiple and sequential mutations increases with age (Fig 11.2).

95

Antagonistic pleiotropy

• Genes that have been selected to have benefits in early life but then have detrimental effects later in life.
• Given the higher rates in extrinsic mortality and shorter lifespans in humans until recent centuries, the negative effects in later life of such antagonistic pleiotropic selection would have been partly hidden, further favoring selection for the beneficial early-life effects.

96

Antagonistic pleiotropy estrogen

• Estrogen is a hormone essential in females for sexual system development, sexual vitality, reproductive success, and fitness.
• However, estrogen in later life can increase the risk of developing breast and uterine cancer in some females.

97

Antagonistic pleiotropy testosterone

• Testosterone is a hormone essential in males for sexual system development, sexual vitality, reproductive success, and fitness.
• However, testosterone in later life can increase the risk of developing prostate cancer and heart disease in some males.

98

Antagonistic pleiotropy, IGF-1

• Nutritional factors acting at multiple levels regulate the secretion of insulin-like growth factor-1 (IGF-1) and IGF-1 promotes fetal growth and muscle and skeletal growth during childhood and adolescence and fitness in early reproductive life.
• However, in later life, high IGF-1 levels are associated with an increased risk of breast cancer and prostate cancer.

99

24 year old female with obesity & fatigue
GESTATIONAL & BIRTH HISTORY

• Parents left Cambodia in 1978 and migrated to USA
• She was born in the USA in 1988
• Reports that both her Mom and Dad adopted the USA diet with lots of hamburgers and hotdogs soon after their arrival to the USA in 1978.
• Reports that her Mom was well nourished during pregnancy with no reported problems.
• Born close to term with birth weight of 9 pounds.
- no medical problems reported but hasn't since for over five year
- no medication

100

24 year old female with obesity & fatigue:
DIET HISTORY

• Frequent hamburgers and hotdogs for lunch or dinner and sausage for breakfast.
• Eats refined grain chips, crackers, white bread, and white rice.
• Does not eat very many fruits, vegetables, or nuts.
• Drinks a lot of sweetened sodas.

101

24 year old female with obesity & fatigue
LAB FINDINGS & DIAGNOSIS

• Increased cholesterol, triglycerides, & LDL
• Decreased HDL
• Increased AM fasting insulin
• Increased AM fasting glucose levels
• Obesity with increased BMI
• Dyslipidemia (abnormal blood lipid levels) which increases risk for cardiovascular disease
• Insulin resistance
• Type 2 diabetes mellitus

102

Pancreas islet cells within the islets of Langerhans
BOLD
what cells produce insulin

• Alpha cells (A cells) produce glucogon
•* Beta cells (B cells) produce insulin*
• Delta cells (D cells) produce somatostatin

103

what percent of people make up type 1 diabetes mellitus in the USA
what percent of people make up type 2 diabetes mellitus in the USA?

- type 1 is 10%
- type 2 is 90%

104

Type 1 diabetes mellitus

-pancreas no longer produces insulin
- juvenile onset diabetes mellitus
-insulin dependent diabetes

105

type 2 diabetes mellitus

- pancreas produces insulin but body tissue (muscle & fat) are resistant to the action of insulin
- adult onset
-non-insulin dependent diabetes

106

Insulin sensitive tissues

• Muscle
• Adipose
• Liver

107

Muscle: Insulin sensitive tissue

-insulin enhances glucose transport across cell membrane
-store glucose as glycogen to provide energy source for muscles

108

Adipose: Insulin sensitive tissue

-insulin enhances glucose transport across cell membrane & inhibits breakdown of stored triglycerides
- stored triglycerides as major source of energy in the absence of food

109

Liver: Insulin sensitive tissue

• Insulin acts to modulate activity of bi-directional enzymatic steps to regulate substrate flow
• Carries out biosynthetic functions in response to food; only source of glucose for CNS in absence of food.

110

Insulin resistance

-associated with visceral obesity (fat around the organs)
-abnormal fatty acid metabolism that leads to lipid deposition in muscle & liver w/ reduction of insulin sensitivity in these tissues
- increased insulin resistance is compensated higher levels of insulin to overcome the insulin resistance
-individuals with insulin resistance, hyperinsulinemia and normal glucose can develop syndrome X (predisposition to diabetes)
-as population gets fatter with increase BMI than high percentage of people develop insulin resistance and type 2 diabetes

111

Syndrome X = Metabolic Syndrome

-cluster of metabolic abnormalities secondary to insulin resistance and elevated insulin even though blood glucose level remain normal
- increase triglycerides
- decrease HDL cholesterol
- increase blood clotting
- increase blood pressure
- increase coronary artery disease

112

Type 2 diabetes

-resistance to action of insulin
-when compensatory ability of pancreases to increase insulin production can no longer overcome the insulin resistance, the blood glucose levels rise and person develops types 2 diabetes mellitus
-hyperglycemia develops when the pancreas can not secrete enough insulin to compensate for the insulin resistance

113

Population category at risk for syndrome x in the USA

-insulin resistant : 75 million
-adult overweight/obese million:98.9 mill
-Child overweight/obese 9.7 mill
-postmenopausal women : 8.6
-polycystic ovary syndrome: 9-15 million
high blood pressure (hyptertentsion) 12.5 million

114

type 2 diabetes increasing throughout the world

-type 2 diabetes is increasing worldwide and taking place earlier on in lifetime (younger age)
-422 million adults have diabetes in the world
-30 million diabetes in the USA with million more in pre-diabetic conditions with insulin resistance

115

type 2 diabetes in China

-study found that 90 million people in china have T2D and 148 million are in pre-diabetic conditions
-study attributed the dramatically increased rate of type 2 diabetes in china to high caloric diet & a sedentary lifestyle

116

WHO Global Report on Diabetes

-main goals of the World Health Day 2016 are to increase awareness about rise in diabetes worldwide

117

Timescales

• Miocene epoch: 23 – 5.3 million years
• Pliocene epoch: 5.3 - 2.5 million years
• Paleolithic age (stone age): 2.5 million to 10,000
years ago.
• Neolithic age (late stone age with emergence of plant and animal domestication): 10,000 - 4,000 years ago.
• Bronze age (metal tools widely used): 5,300 -2,400 years ago.
• Iron age: 3,300 - 1,600 years ago.
• Silicon age: 1971 - present

118

Hominid diets

-Ardipithecus & Australopithecus both mainly vegetarian

119

Paleolithic diet

• Humans were foragers, gatherers, hunters, and fishermen/women.
• Scientific studies indicate that during these times, humans consumed predominantly plant foods.

120

Human diet: an evolutionary history

-earlist members of Homo genus emerged about 2.5 mill yrs ago
-selecetion has driven our biology and metabolism to be better matched to the physical activity and diet that characterized the foraging way of life

121

Neolithic diet

-domestication of plants with increase grain consumption
-in some areas domestication of animals for milk and eggs & not really meat

122

Hominid Skull, jaw, & teeth

• Muzzle juts out less than chimps.
• Lack the dagger-like upper canines which are present in male chimpanzees.
• Base of skull is short from front to back as in upright walkers rather than elongated like in quadripedal apes.

123

Teeth

• Homo species have teeth suited for a primarily plant-based diet rather than a meat based diet.
• The large molars are designed to grind fibrous food to prepare for swallowing.
• Grinding of the molars to grind food in children also has the affect of lining up the upper and lower teeth properly.
• It is widely recognized that prior to modern times, humans seldom had malocclusion (imperfect position of teeth) of their teeth.

124

Foraging diet on Kung San of Southwestern Africa

-kung san are viewed by many as a model of how our distant ancestors may have lived and eaten
-spent 3 hours a day exercising as they obtain and processed food, leaving much of the day for leisure, crafts, childcare, naps and relaxation

125

Kung San of southwestern africa diet

-found to be nut-based diet with mongongo nuts & provided a major source of calories & protein, also consumed diff plant species throughout year depending on availability
-men hunted by meat only accounted for a minority of calories
-nuts store well and remain edible for much of the year & have had this for the 7,000 years

126

Diets of foraging cultures

- different foraging cultures eat omnivorous diet but mainly plants

127

Nutrition constituents

• Protein
• Fats
• Carbohydrates
• Vitamins
• Minerals
• Phytochemicals

128

Nutritional requirements

• The two required fats in human diet are linolenic acid and linoleic acid which are both widely available in a broad spectrum of plant foods.
-don't need animals to get any nutrients

129

Dietary recommendations to reduce risk of insulin resistance and coronary artery disease based on meta-analysis of numerous human clinical studies

• Saturated fat <10% of calories
• Total fat ≥40% of calories, mainly from healthy plant based fats with ratio of monounsaturated: polyunstaurated fats of 2:1
• Protein 15% of calories
• Complex carbohydrates 45% of calories (non-refined whole grains, seeds, nuts, fresh fruits and vegetables)

130

Dietary components which increase risk coronary artery disease, Type 2 diabetes mellitus and/or cancer

• Red meat
• Saturated fat from meat (>10% of total calories)
• High protein
• Refined white flour products • Refined sugar beverages
• Diet low in fiber

131

Mortality in the USA based of diets

- 1/2 people in the USA die from coronary artery disease
-1/3 people in USA die from cancer

132

protein levels

• Low-protein intake < 10% of total calories
• Moderate protein intake = 10-20% of total calories
• High-protein intake > 20% of total calories

133

Low protein associated with
reduction in cancer & mortality

• Adults aged 50-65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death over the following 18 years.
• These associations were abolished or attenuated if the proteins were plant derived
• Conversely, high protein intake in humans over 65 years of age was associated with reduced cancer and overall mortality
• If high protein intake was from plants (e.g., soy beans) it is not associated with a high cancer and overall mortality rate

134

Red meat & the gut microbiome
Nature Medicine, 7 April 2013

-meat eaters have a diff gut microbiota than vegetarians
those that switch to a veggie diet change microbiome within a week
-Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine (trimethylamine present in red meat) through a microbiota-dependent mechanism.
• Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and cardiovascular disease risk.

135

Red mammal meat linked to early death (women)

-women who eat read meat are
-50% more likely to die from heart disease
-36% more likely to die for any reason
-20% more likely to die of cancer

136

Red mammal meat linked to early death (men)

-men who red meat are
-27% more likely to die form heart disease
-31% more likely to die for any reason
-22% more likely to die of cancer

137

More mammal red meat, more mortality hardvard study

-eating one serving of unprocessed read meat = 13%i increased risk of premature death
-eating one serving of processed meat = 20% increase risk of premature death

138

Reasons why the thermoregulatory
hypothesis for hair loss is not compelling

-human running after large mammals to kill them for meat so often that there was positive selection to lose hair better thermoregulate
-why haven't other big animals like lions lost hair?
-what evidence suggest that human ancestors depended on hunted large mammal meat as part of their reg. diet
-Maasai today in Kenya and Tanzania use spears to protect themselves from lions NOT to kill large mammals for food

139

Origins of domestication of animals for milk, eggs, wool, transportation, and/or meat Old World (Europe/Africa/Asia)
BOLD

• *Cows* (Bos) three species from Africa, Asia, and Europe, 12,000 years ago
• *Goats* (Capra) southwest Asia and Eastern Europe, 8-9,000 years ago
• *Pigs* (Sus) Eurasia, New Guinea, 12-13,000 years ago
• *Sheep* (Ovis) Near East, Mid East, Mediterranean, 10,000 years ago
• *Horses* (Equus ferus) Central Asia 6,000 years ago
• *Yaks* (Bos) Himalaya Mountains
• *Camel* (Camelus) West, Central, & East Asia, 4,000 years
ago
• *Chickens* (Gallus) Asia, 8,000 years ago

140

bird, fish & plant food human

- not the same negative effects that are found in eating read meats
- decreases a spectrum of diseases and increases life expectancy

141

Fat
BOLD

oily or greasy components that contain glycerol esters

142

Saturated fatty acids:

possess no double bonds and are solid at room temperature

143

Trans-fatty acids:

hydrogenated vegetable oil that is solid at room temperature

144

Unsaturated fatty acids

possess one or more double or triple bonds and are liquid at room temperature
– monounsaturated
– polyunsaturated

145

Omega-3- fatty acids

(flaxseed oil, walnut oil, hemp oil, salmon oil) polyunsaturated fatty acids with double bond three
carbons from methyl moiety

146

Essential fatty acids:

unsaturated fats from plants essential in human diet
– linoleic acid (soy oil is excellent source)
– linolenic acid (soy oil is excellent source)

147

Monounsaturated oils

-olive oil
-canola oil
-peanut oil
-avocado oil
-sesame oil
- almond oil

148

Omega-3- fatty acids: Rich sources of omega-3-fatty acids:

- flaxseed oil
- walnut oil
- hemp oil
- salmon oil
-reduce the risk of cardiovascular disease and have anti-inflammatory effects

149

Diet that emulates with ancestral diet: Mediterranean diet rich in olive oil and nuts reduces cardiovascular disease

• Over 7,000 people in Spain at high cardiovascular risk were enrolled in a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with extra mixed nuts, or a control diet with reduced dietary fat.
• These three groups were followed for 4.8 years
• A Mediterranean diet supplemented with extra virgin olive oil or extra nuts reduced the incidence of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes).

150

Evidence based recommendations for fat

• Total fat ≥ 40% of total calories
• Monounsaturated fats > 20%
• Polyunsaturated fats ≤ 10%
• Saturated fat < 8%
• Trans fatty acids (= hydrogenated vegetable
oils): none recommended

151

Saturated Fat

• Saturated fat in animal products (especially red meat) is associated with increased coronary heart disease and cancer
• Chocolate which is rich in saturated fat REDUCES coronary heart disease and cancer

152

Inverse relationship between amount of dietary saturated fat and sperm quality

• Men in the highest 3rd of saturated fat intake had a 43% lower sperm count and 38% lower sperm concentration than men in the lower 3rd of saturated fat intake.
• Men in the highest 3rd of omega-3 polyunsaturated fat intake had a higher percentage of sperm of normal morphology compared to men in lowest 3rd.

153

Chronic high-fat in fathers programs β-cell dysfunction in female rat offspring

• In rat studies, father’s high fat diets altered the development of their sperm which then prompted Type 2 diabetes mellitus in their daughters.
• The paternal rat high fat diet exposure programs β-cell dysfunction in rat F1 female offspring who as adults have normal weight and adiposity, but impaired glucose tolerance, impaired insulin sensitivity, and abnormal gene-expression profile of the insulin secreting pancreatic islet cells
• The paternal epigenetic effects appear to be on X sperm and not Y sperm.

154


Carbohydrates
BOLD

*Carbohydrate: contain carbon and hydrogen*
•* Small Molecule Carbohydrates
– monosaccharides*
• glucose
• fructose (high intakes of this can lead to risk for T2D)
• galactose
– *disaccharides*
• sucrose (glucose + fructose) is table sugar
• lactose (glucose + galactose) is milk sugar
•* Larger Molecule Carbohydrates*
– *polysaccharides* (starch, glycogen, and cellulose)
– *refined grain polysaccharides* have much of the fiber, phytochemicals and vitamins removed
– *unrefined whole grain polysaccharides* are rich in fiber, phytochemicals, and vitamins

155

Glycemic index

• The glycemic index provides a measure of how quickly blood glucose levels rise after eating a particular type of food
• Simple carbohydrates and refined grains (e.g. white flour and white rice) have a high glycemic index
• Vegetables and non-refined grains have a low glycemic index
• Both monosaccharides and disaccharides have a high glycemic index

156

Larger molecule carbohydrates
in refined wheat grain

• Refined white flour has a high glycemic index and is digested quickly in the gut which results in rapid rises in blood glucose levels which triggers fast rise of insulin which can increase appetite and triglyceride levels.

157

Unrefined Complex carbohydrates are rich in fiber

• Fruits
• Leafy greens
• Broccoli
• Carrots
• Vegetables
• Unrefined whole grains (e.g., whole wheat flour, brown rice, corn) are rich in fiber, phytochemicals, and vitamins

158

Fiber definition
BOLD

-components of plants that resist human digestive enzymes, including lignin, inulin, some oligosaccharides, some starches, and some polysaccharides.

159

• Insoluble fiber
BOLD

fiber that is metabolically inert, absorbing water as it moves through the digestive system, making the stool softer and easing defecation, however it is not fermented

160

Soluble Fiber
BOLD
Health benefits

(prebiotic, viscous) fiber absorbs water to become a gelatinous, viscous substance that is readily fermented in the colon into gases and physiologically active byproducts.
• Soluble fiber binds to bile acids in the small intestine, making them less likely to enter the body which in turn lowers cholesterol levels in the blood.
• Soluble fiber also attenuates the absorption of sugar, reduces blood sugar spikes after eating, and improves blood lipid levels.
• Soluble fiber is also fermented in the colon to produce beneficial short-chain fatty acids.

161

Health benefits of dietary fiber

• Reduces appetite by increasing food volume without increasing caloric content
• Lowers fluctuation in blood glucose levels by shielding carbohydrates from enzymes and delaying absorption of glucose
• Lowers insulin resistance and reduces type 2 diabetes
• Reduces cardiovascular risk by reducing cholesterol and LDL
• Adding fiber bulk to the stool absorbs water and softens stools and facilitates regular defecation
• Balances intestinal pH and stimulates intestinal fermentation to produce short chain fatty acids which appear to reduce risk to colon and rectal cancer

162

Inverse relationship between level of fiber in diet and risk for stroke Threapleton et al. Stroke,

• Each 7-gram (= one-quarter ounce) increase in total daily fiber intake was linked to a 7 percent decrease in stroke risk.

163

Diet rich in vegetables & fruits

• Scores of different studies have demonstrated that increased consumption of vegetables and fruits by humans lowers their risk of cardiovascular disease, Type 2 diabetes mellitus, certain types of cancers, and dementia.

164

Foods w/ Anti cancer molecules

-Brassica oleracea and its varieties kale,
-cabbage
-brussel sprouts
-broccoli
-cauliflower

165

Anti-cancer effects of Coffee
(Coffea arabica, C. robusta)

• Origin of coffee: northeastern Africa
• Seeds roasted, ground up, and brewed in hot water as a beverage.
• Active molecules: caffeine, anti-oxidant polyphenols
• Studies conducted by the Harvard School of Public Health have demonstrated the following:
• Reduces prostate cancer in men
• Reduces endometrial cancer in women
• Reduces breast cancer in women
• Reduces basal cell carcinoma of skin in men & women
• Reduces oral cancer in men and women
• 1-3 cups of coffee a day reduces risk of lethal prostate cancer by 29%
• > 5 cups of coffee a day
• Reduced risk of endometrial cancer in females
• Study found that when comparing women who drank one or less cups of caffeinated coffee/day to those drinking four or more cups a day, the latter group had a 25% reduction in development of endometrial cancer

166

Zingiber officinalis, ginger

-origin: Asia
-Use of ginger containing sauces (e.g. teriyaki sauce) on the covering of the meat as it is grilled, significantly reduces the level of carcinogen formation in the grilled meat

167

Sirtuin & SIRT1& longevity

• Sirtuin activity is positively correlated with lifespan in several species.
• SIRT1 (sirtuin 1) is an enzyme which deacetylates proteins that contribute to cellular regulation and cellular longevity.
• SIRT1 is the target of the putative life-span extending polyphenol, resveratrol from grapes &
wine (Vitis vinifera).
• Resveratrol shifts FoxO dependent responses away from cell death towards cell survival (however, very high doses are required).

168

Astragalus root tx of HIV/AIDS

• A study at UCLA AIDS Institute has found that a chemical in the Astragalus
root, frequently used in Chinese herbal therapy, can prevent or slow this progressive telomere shortening, which could make it a key weapon in the fight against HIV.

169

Reduction in development of dementia & cognitive loss from different phytochemicals

• Blueberries (Vaccinium corymbosum & Vaccinium angustifolium from eastern USA).
• Diet rich in berries.
• Leafy green vegetables.
• Folic acid (good sources include spinach and oranges).
• Caffeine from a variety of plant species works by blocking adenosine receptors.
• Omega-3 fatty acids from walnuts, hemp seeds, flax seeds, kiwi fruit, salmon.
• Vitamin E.
• Curcumin a polyphenol in Curcurma longa (tumeric) from India.
• Cannabis sativa from Asia.

170

Antioxidants from plants in
human diet

-types: carotenoids, flavonoids, tocopherols, and ascorbic acid
• Plants are such rich sources of antioxidants, and primates and hominids have evolved to eat large amounts of plant foods.
• Because the ancestral diet was so rich in plants containing large amounts of antioxidants, primates and hominids and other vertebrates have lost the ability to synthesize many of these antioxidants and instead depend on direct or indirect sources of plant foods for the supply of these compounds.

171

Vitamin C = ascorbic acid

• Humans and other primates are NOT able to manufacture vitamin C (ascorbic acid) and must obtain it from their diet.
• The reason is a makeshift mutation in the gene for the last enzyme of the Vitamin C biosynthetic pathway, which renders the enzyme non-functional.
• Vitamin C is a strong antioxidant and is also essential as a cofactor in the production of collagen.
• Humans require vitamin C in their diet, and failure to consume this results in inability to repair connective tissue which causes symptoms of scurvy.
• Scurvy was well documented in sailors who did not have fruits or vegetables to eat on their boats.
-Because the ancestral diet was rich in vitamin C containing plants, there was no ongoing positive selection to ensure a capacity for humans to synthesize it which resulted in neutral mutations that triggered a loss of an enzyme critical to vitamin C production.

172

Flavonoids

• Flavonoids are plentiful and plant foods and are strong antioxidants associated which reduce risk for cancers, cardiovascular disease, and dementia in humans.

173

B9 (folic acid and folate)

• Folate and folic acid derive their names from the Latin word folium (which means "leaf").
• This essential B vitamin must be obtained from diet.
• Important sources of folate are leafy green vegetables (e.g., kale and spinach) and some fruits e.g. oranges.
• Folates consumed in the diet is metabolized in the liver to produce bioactive metabolites.
• Water soluble vitamin
• Involved in synthesis, repair, and methylation
of DNA.
• Cofactor in numerous biological functions.
• Aids rapid cell division and growth, such as
in infancy and pregnancy.
• Bone marrow maturation.
• Red blood cell production.
• Development of neural tubes in embryos.

174

B12 (cobalamin)

• Vitamin B12 can be obtained from fermented plant foods and beverages
• B12 from non-pathogenic bacteria is on surfaces of leaves and fruits that have not been washed
• Through evolution, hominins have consumed large amounts of uncooked leaves and fruits with B12 on the surfaces

175

Plant-based carotenoids

• Beta-carotene
• Lycopene
• Lutein
• Zeaxanthin

176

Carotenoid lycopene

• Lycopene carotenoid in tomato (Solanum esculenta), pink grape fruits, and watermelons is associated with lower rates of prostate cancer in men and lower rates of cardiovascular disease in men and women.

177

Carotenoids lutein & zeaxanthin

• Lutein and zeaxanthin carotenoids in plant foods reduce the risk for the eye disease, macular degeneration in humans.

178

BIOCHEMISTRY
BOLD

-Vitamin A (retinol)
-unsaturated 20 carbon cyclic alcohol that is fat soluble and stored in liver
-Beta-carotene = pro-vitamin A
two linked retinol molecules

179

Vitamin A = retinol
BOLD

• *Rhodopsin formation* for vision
• *Glycoprotein formation* e.g., collagen & glycosaminoglycan synthesis
• *Epithelial surface growth,* differentiation & repair e.g., conjunctiva, respiratory epithelium, and intestinal mucosa
• *Maintains normal immune responses*

180

Beta carotene = provitamin A

• Beta carotene is consumed orally from fruits and vegetables.
• In the intestinal mucosa an enzyme cleaves the beta carotene molecule in half to produce two retinol molecules that can then be used by the body.
• Beta carotene in its complete form can not be used by the body; it needs to be split into two retinol molecules to be usable.
• Once retinol levels in the blood rise above a certain optimal level, the enzyme that cleaves beta-carotene in the intestinal mucosa is inhibited.
• Hence it is not possible to get vitamin A toxicity if you consume vitamin A in the form of beta carotene (pro-vitamin A) from plant foods.
• However, you can get vitamin A toxicity if you consume high enough amounts of retinol from animal sources.
• This strongly suggests that humans evolved to obtain their vitamin A from plant food derived beta-carotene and not animal food derived retinol.\• --• Humans have evolved to not only regularly eat beta carotene from plants, but to have actually consumed such high levels of beta carotene in the diet that, through selection, humans have the metabolic capability to down-regulate the enzyme that converts dietary beta carotene to retinol when retinol levels are sufficiently high in the blood.
• When the enzyme which cleaves beta carotene is blocked, humans will absorb the beta carotene whole and can actually develop carotenemia, which is a harmless and transient condition where the skin has orange yellow pigment that is visible.

181

Features in human nutrition which indicate we have evolved to consume large amounts of plant foods


• All the nutrients required in human diet can be obtained from plant foods
• Complete protein is easily obtained from plants.
• Only required fats in human diet are unsaturated linoleic acid and linolenic acid which are both contained in plant foods.
• Dietary requirement of Vitamin C and other vitamins which are plentiful in plants.
• Ability to regulate beta carotene cleavage in response to rising blood retinol levels.
• Essential role of folic acid in human metabolism which can only be obtained from plants
• Vitamin B12 obtained from fermented plant foods; B12 from non-pathogenic bacteria is on surfaces of leaves and fruits that have not been washed
• Spectrum of plant phytochemicals that reduce risk of cancer, type 2 diabetes mellitus, cardiovascular disease, and dementia in humans.
• Dietary fiber reduces the risk of death in men and women.
• Diets with elevated levels of saturated animal fats from red meats are associated with increased cardiovascular disease, insulin resistance, cancer, and early death
• Diets with elevated levels of saturated animal fats are associated with lower sperm count and abnormal sperm morphology
• Diets high in mammal protein increase risk of cancer and type 2 diabetes mellitus

182

Changes within traditional cultures in tropical countries and within newly arrived immigrants into the USA which can influence rates of obesity & insulin resistance

• Reduction in level of physical activity.
• Change in diet from traditional diet to low fiber, high saturated fat, caloric dense Western diet.
• Reduction in consumption of food plants and with beneficial phytochemicals.
• Reduction in consumption of herbs and spices with beneficial phytochemicals

183

Contemporary urban USA human diet

• The contemporary mainstream USA diet with processed foods and minimal fresh fruits and vegetables, is low in fiber, low in beneficial phytochemicals, high in saturated mammal fats which is a dramatic mismatch compared to our ancestral diet.
• The current global epidemic of metabolic diseases can be understood, in part, as a result of a mismatch between our ancestral foraging and nutrition adapted genome and our rapidly changing modern diet and sedentary lifestyle.

184

Antagonistic pleiotropy

• Traits that have been selected to have benefits in early life but then have detrimental effects later in life.

185

Antagonistic pleiotropy
Thrifty trait

• Geneticist James Neel proposed that a genetic predisposition to develop type 2 diabetes was adaptive to the feast and famine cycles of paleolithic human existence, allowing humans to fatten rapidly and profoundly during times of feast in order that they might better survive during times of famine.
• However, in environments of consistent calorie abundance, this would be disadvantageous.
• He hypothesized the presence of a‘thrifty gene’ which generated a thrifty trait for nutrient extraction and storage.
• No single thrifty gene was ever identified.
• Thrifty phenotypes and thrifty epigenotypes form the thrifty trait.
• People with a thrifty phenotype/trait are able to extract more resources (e.g., carbohydrates, proteins, and fats) from a restricted nutritional environment and store them as fat for later advantage
• While this trait may be advantageous earlier in life, it can be disadvantageous later in life by increasing risk for obesity, type 2 diabetes mellitus, and cardiovascular disease.

186

Population variation in thrifty trait

• Compared to European populations, non-European populations from around the world tend to have a lower body mass index threshold for developing insulin resistance and Type 2 diabetes mellitus i.e. they are more inclined to have the thrifty trait.

187

Relationship between obesity and risk of developing diabetes in white vs. East Indian children in UK (Fig 8.8)

When comparing children at the same level of obesity, East Indian children in UK are more likely to develop Type 2 diabetes mellitus than Anglo children in UK.

188

The thrifty epigenotype

• Most human genotypes are maladjusted for the westernized lifestyle of widely available calorie dense food and reduced physical activity
• Trait for metabolic thrift: the capacity for efficient acquisition, storage and use of energy, is an ancient and complex trait
• The environmentally responsive gene network encoding this trait is subject to genetic canalization and thereby has become robust against allelic variations and mutational perturbations
• Phenotypic variation with tendency to develop type 2 diabetes mellitus and obesity likely arises from variations in programming events during critical stages of development and epigenetic mechanisms may contribute to this type of programming
• DNA sequence polymorphisms play a minor role in the etiology of obesity and type 2 diabetes---instead disease susceptibility is predominantly determined by epigenetic variations
• Corresponding epigenotypes have the ability to be inherited across generations
• Leptin is a candidate gene for the acquisition of a thrifty epigenotype
• A thrifty epigenotype is anticipated to be present at significantly higher frequencies in populations experiencing recurrent food shortages.
• Individuals exposed to these conditions will have a characteristic epigenetic profile, which could differ markedly from individuals native to regions of the world with a history of more consistent abundant food availability.

189

An evolutionary mismatched environment case 6

• An evolutionary mismatched environment with the shift to eating more refined carbohydrates, more red meats, less fiber, fewer vegetables, and fewer phytochemicals along with reduced physical activity results in metabolic diseases including insulin resistance, types 2 diabetes mellitus, hypertension, and increased risk of coronary artery disease.

190

Outcome of demographic history case 6

• When compared to European populations, populations from Cambodia are more inclined to have the thrifty trait i.e. they have lower body mass index threshold for developing insulin resistance and Type 2 diabetes mellitus.
• Based on dietary history, she reported that both her parents adopted a USA diet high in saturated animal fats and refined carbohydrates when they arrived into the USA in 1978, which was 10 years before she was born.
• Hence, it appears that her Dad was eating a diet high in saturated animal fats for nearly 10 years before she was conceived.
• This may have contributed to her development of type 2 diabetes mellitus through epigenetic mechanisms.

191

Antagonistic pleiotropy
case 6

• This Cambodian woman likely has a thrifty phenotype/trait.
• People with a thrifty phenotype/trait are able to extract more resources (e.g., carbohydrates, proteins, and fats) from a restricted environment and store them as fat for later advantage; while this trait may be advantageous early in life during rapid growth, it can be disadvantageous later in life if there is an overabundance of unhealthy foods by increasing risk for obesity, type 2 diabetes mellitus, and cardiovascular disease.

192

Botanicals which reduce insulin resistance in Type 2 diabetes mellitus

• Certain medicinal plants, herbs, spices, and plant-based beverages and foods reduce insulin resistance in people with type 2 diabetes mellitus.
• Galega officinalis (goat’s rue) from Europe is source of popular pharmaceutical metformin (glucophage).
• Larrea tridentata (creosote bush) from southwest USA and northwest Mexico.
• Mormordica charantia (bitter melon) from Asia.
• Cinnamomum verum (= C. zeylanicum)
(cinnamon) from Asia.
• Camellia sinensis (tea) from Asia.
• Coffea arabica (coffee) from northeastern Africa.
• Vernonia amygdala (bitter leaf) from West Africa
• The most important pharmaceutical to treat Type 2 diabetes mellitus in the USA and Europe is metformin (glucophage) is derived from Galega officinalis (goat’s rue) from Europe.
• The mechanism of action of this medication is to reduce insulin resistance.

193

Red Palm Oil in Ghana

-Vit. A deficiency is low in areas where red palm is widely available

194

15 year old male presents with severe right lower quadrant abdominal pain

• History: reports that three hours ago he developed severe right lower quadrant pain that is getting progressively worse. He has vomited two times in the last hour. He does not have diarrhea.
• Ethnic history: European American • Travel History: no trips out of the USA. • Past Medical History: previously healthy. • Developmental History: normal. • Dietary history: High intake of meat, dairy
products, and refined white flour, and low intake of fruits, vegetables, and whole grains.
• Physical Exam: severe right lower quadrant abdominal pain reported even with slight palpation. Temperature 101.5 degrees.
• Ultrasound of abdomen: inflamed appendix
• Diagnosis: appendicitis
• Treatment: laparoscopic surgical removal of inflamed appendix

195

Cecum
BOLD

– Blind pouch
– Beginning of large intestine
• The cecum is the beginning of the large intestine and is basically a large pouch that receives intestinal contents from the small intestine.
• Connected to the small intestine through the ileo-cecal valve.
• Cecum in modern humans is 6 cm long and 7.5 cm wide.
• Appendix is attached to cecum.

196

Vermiform appendix
BOLD

– Opens into posteromedial wall of cecum
– Contains lymphoid tissue
– Appendicitis is caused by inflammation of the
appendix
• Appendix in humans is referred to as a vestigial organ in many evolution textbooks.
• It has been suggested to be a vestigial organ that has diminished in size over the course of primate and hominid evolution.
• The worm-like appendix is the outcome of a reduction in diameter and size of intestinal tissue which was previously part of a larger cecum.

197

Colon (large intestine)

– Divided into distinct segments
• Ascending, transverse, descending, & sigmoid colon

198

Background information on
appendicitis

-inflammation of the appendix and secondary to obstruction of the appendix lumen such as by a piece of harden stool
-hard stool is associated with low fiber diets
-if appendix brusts it can lead to infection in the peritoneal cavity which can be fatal

199

Background information on appendicitis

-In USA 6.5% of people get appendicitis and most strikes between ages 10-30
-known to be fatal in other parts of the world and can occur before reproductive age and be fatal

200

Why hasn't appendix truly become a vestigial organ?

• William Parker, Randy Bollinger, and colleagues at Duke University proposed that the appendix serves as a haven for useful commensal bacteria when diarrheal illness flushes bacteria from the rest of the intestine.
• The lymphoid tissue surrounding the appendix supports the growth of beneficial intestinal bacteria.

201

Human response to intestinal infection

-increase fluid in gut to flush out pathogenic microbes

202

Impact of diarrhea on human host

-downside of human shedding of the intestinal pathogen with watery diarrhea is loss of a dangerous amount of fluid and electrolytes which can result in life threatening dehydration and electrolyte disorders.

203

Commensal bacteria in appendix re-colonize intestine after diarrhea

• The time taken to recover from a bout of diarrhea is partly due to time required to re-colonize the gut with our commensal gut microbiota.
• During an episode of diarrhea, the commensal bacteria in the appendix are retained and not flushed out like the rest of the intestine.
• The appendix functions as a source of beneficial commensal bacteria that re-colonizes the flushed out intestine and supports the recovery from diarrhea.

204

Role of appendix in re-colonizing Intestine

• appendix does provide a valuable function in humans as a source of beneficial commensal microorganisms for re-colonizing the intestinal tract after diarrhea.
• People with an appendix appear to have a selective advantage with a faster recovery from diarrheal infections.
• Thus, acute diarrhea has been and continues to be an important infectious disease-related selection pressure on the human population.
• The appendix replenishes the gut with beneficial bacteria following diarrhea and appears to increase fitness.

205

Evolutionary pathway which has enabled appendix to persist: Exaptation

• Organ that originally was selected for digestion and absorption of nutrients proceeded to shrink in size because of negative selection.
• Instead of shrinking down to a truly vestigial size and function, the organ has persisted in its reduced form as an appendix since it provides a selective benefit by re-colonizing the intestine with a beneficial gut microbiome after diarrhea.
• So this organ which in its ancestral larger size, was selected for nutrient digestion and absorption, now in its diminished size has been exapted to function to re-colonize the intestine with beneficial microbes.
• The trade-off is that the appendix can become plugged with hard stool which results in inflammation of the appendix30

206

Evolutionary pathway: Mismatched environment
CASE 7

• Mismatched dietary environment when comparing the high fiber ancestral diet to the contemporary low fiber diet eaten by this male that has increased risk of developing appendicitis by increasing the likelihood of a piece of hard stool blocking the appendix lumen.

207

Evolutionary pathway: fighting the evolutionary arms race
CASE 7

• Ability of intact appendix to re-colonize the intestine with commensal bacteria after a course of diarrhea enables the host to better fight the evolutionary arms race by establishing a healthy microbial flora in the gut.

208

Two week old European American male infant presents to clinic with intermittent rectal prolapse

• Gestational and Birth History: normal gestation and normal spontaneous vaginal delivery.
• Birth weight: 8 pounds
• Nutritional History: exclusively breastfed
• Genetic History: both parents are European Americans

209

Rectal prolapse

• Rectal prolapse describes a condition where the walls of the rectum protrude through the anus and hence become visible outside the body.
• In infants, this can occur when intestinal mucous is unusually thick and sluggish.

210

Rectal prolapse

-cause of rectal prolapse in infants is cystic fibrosis
-people with cycstic fibrosis have abnormal chloride channels that result in increase chloride in sweat
-when an infant presents w/ rectal prolapse, sweat test is conducted to assess chloride concentrations on the skin

211

Sweat test

-involves application of pilocarpine, a medication that stimulates sweating
-resultant sweat is collected and analyzed

212

Pilocarpine

-from wet forests in South America
-Enthnomedical uses: Tupi Culture in brazil chew leave to induce salivation and sweating
-acts as an acetylcholine mimick and stimulates receptors in sweat & salivary glands
-10-15mg of pilocarpine given subcutaneously causes secretion of 2-3 liters of sweat

213

Diagnosis

• Lab result: Positive sweat test which indicates increased concentrations of chloride in sweat.
• Diagnosis: cystic fibrosis
• People with cystic fibrosis have increased amounts of sodium and chloride in their sweat and also have very thick intestinal secretions which can result in rectal prolapse.

214

Incidence of cystic fibrosis

• Typically referred to as an autosomal recessive transmission, however, this is actually a form of incomplete dominance
• People need to be homozygous for this allele to develop cystic fibrosis
-today allele most common within European-derived populations
-4-5% of european descent carry at least one copy of this allele
-1 in 2,500 babies of european descent are homozygous for this allele and have CF
-approx. 30,000 americans have CF making it one of the most common life shortening inherited disease

215

Cellular manifestations of cystic fibrosis

• In persons homozygous for the allele, there is absence of a protein CFTR that transports chloride ion across the cell membrane and also controls the regulation of other ion channels.

216

Normal physiology of chloride channels

• In the *lungs* the fluid washes away pathogenic microbes and other unwanted debris.
• In the *intestines* the fluid washes away bacteria and also facilitates bringing digestive enzymes into contact with food.
• In *sweat glands* chloride channels have an additional function; they recycle salt out of the glands and back into the skin before it can be lost to the outside world.

217

Clinical presentation of people with cystic fibrosis

• Salty sweat and salty tasting skin.
• Frequent coughing.
• Sluggish bowel movements.
• Diabetes mellitus.
• Poor weight gain.
• Thick, sticky, and relatively dry mucus clogs the lungs and gut because the cells that line these organs are not secreting adequate water.
• The thick mucus obstructs breathing and there may be increased Pseudomonas aeriginosa
infections in the lungs and sinuses.
• The thick mucus obstructs digestion.
• The thick mucus can cause meconium ileus with
intestinal blockage and rectal prolapse in infants.
• 97% of men with cystic fibrosis are infertile, and many of these men lack the vas deferens.
• Women with CF have decreased rates of fertility

218

Genetic origins of cystic fibrosis

-original founder deltaF508 mutation gave rise to CF
-mutation that causes CF has persisted for 50,000 years

219

Indels & cystic fibrosis

• Well known example of a disease-causing indel is the three base-pair deletion removing the phenylalanine residue at position 508 in the cystic fibrosis trans-membrane conductance regulator (CFTR) protein, which is the most common mutation causing cystic fibrosis (Box 3.3)

220

Potential heterozygote advantage for protection against tuberculosis

• There is reduced frequency of tuberculosis in both homozygous and heterozygous persons with CF mutation.
• Reduced arylsulfatase activity in patients with cystic fibrosis may inhibit growth of
Mycobacterium tuberculosis.
• Modeling studies have demonstrated that the European tuberculosis epidemic that began in the 17th century and spanned through the 19th century would have provided sufficient selective pressure to account for the current prevalence of cystic fibrosis.

221

Potential heterozygote advantage
for protection against diarrhea

• Big. pop. created an environment that increased the likelihood of fecal-oral transmission of diarrheal diseases.
• This may have created an environment supporting positive selection for the mutation in CFTR protein
-protection against diarrhea likely more responsible for heterozygote advantage than protection against tuberculosis
• People with one copy of the gene, half as much fluid is secreted which might be just enough to rid someone of the cholera infection without causing them to die from dehydration.
• In the European past, when cholera and other diarrheal pathogen epidemics were more common, this would have given carriers of the cystic fibrosis gene a selective advantage and would have allowed the gene to increase in frequency due to positive selection.

222

Vibrio cholera and other diarrheal
pathogens effect on intestine

Vibrio cholera and other diarrheal pathogens colonize the wall of the small intestine and produce enterotoxins
-enterotoxin binds to intestinal enterocyte
-ADL ribosylation of the a subunit of a stimulatory G protein (Gsa)
-activation of adenylate cyclase for the life of the enterocyte as it migrates up the villi
-increases cyclic AMP and/or cyclic GMP
-stimulates CFTR protein to increase chloride ion channel secretion into intestinal lumen
-increases water secretion into intestinal lumen to flush out pathogen which also increases potential transmission to other human hosts

223

Virulence in Cholera

• Strains with a high level of virulence will tend to generate a high degree of fluid secretion into the gut and the bacteria will quickly be washed out, speeding their transmission.
• One the other hand, the production of the toxin which triggers the diarrhea carries a metabolic cost to the bacteria so this has to be traded off against the fitness benefits of rapid transmission.

224

Pathophysiology of cholera

• When the bacteria that cause cholera infect the human small intestine, they release a potent toxin that attacks the cells that line the gut.
• The cells lining the gut respond by opening their chloride channels, causing the gut to secrete as much as three or four gallons of fluid a day to flush out the toxin and bacteria.
• This form of diarrhea is called secretory diarrhea.
• Unless the lost salts and fluids are quickly replaced, the response backfires and the afflicted person can die of dehydration.
• This severe volume of diarrhea increases the likelihood that cholera will be transmitted to other hosts which is a tradeoff for the morbidity and potential mortality that can happen to the host

225

Why is the CF gene in such low frequencies in people who ancestors are from tropical climates?

• The cystic fibrosis mutation may be very low outside Europe because in hot climates it entailed an additional disadvantage, one that may have outweighed its defense against diarrhea: salty sweat.
• Experiments have shown that carriers of one mutated cystic fibrosis gene lose more salt in their sweat than those who carry two normal genes.
• So carriers of one mutated cystic fibrosis gene
lose more salt in their sweat and if they live in a tropical environment they are sweating significantly more than in cooler climates.
• This increased loss in precious salts which can result in electrolyte imbalances, may have been negatively selected against resulting in the very low frequency of this gene in hot climates.

226

Cystic fibrosis: an apparently harmful allele is maintained by balancing selection through
heterozygote advantage

• Heterozygote advantage e.g., cystic fibrosis and protection against infectious disease induced secretory diarrhea.
• People homozygous for cystic fibrosis are protected from diarrhea, but will have a lower life expectancy which reduces fitness because of developing potentially fatal cystic fibrosis disease.
• People heterozygous for the cystic fibrosis mutation have protection against getting watery diarrhea and dehydration, but do not have the down-side of developing cystic fibrosis disease.

227

Cystic fibrosis:
outcome of demographic history CASE 8

• This infant was born and lives in the USA and has ancestors from northern Europe where the cystic fibrosis allele is present in the population.
• Hence, an outcome of a individual’s demographic history resulted in him being homozygous for cystic fibrosis and having cystic fibrosis disease even though he was not born in a part of the world that has high rates of diarrhea.

228

Cystic fibrosis:
fighting the evolutionary arms race CASE 8

• People who are heterozygous for the CF allele have a clever mechanism against diarrheal pathogens which is an important defense in the evolutionary arms race

229

Croton lechleri with common name of sangre de drago & sangre de grado from the Amazon rainforest

-Bark latex of tree is widely used to treat diarrhea by indigenous peoples and mestizo peoples of Ecuador, Peru, Bolivia, Columbia and other countries in South America.

230

Gastrointestinal ethnomedical uses of Croton lechleri

• Diarrhea without blood
• Cholera
• Diarrhea with blood
• Gastric & duodenal ulcers
• Gastritis

231

Crofelemer = SP 303

• Derived from bark latex of
Croton lechleri
• MW is 2100 daltons
• Oligomeric proanthocyanidin
•SP 303 demonstrated inhibition of:
- in vivo (mouse) cholera toxin induced fluid secretion
- ex-vivo cAMP-mediated Cl ion secretion in ussing chamber

232

Phase II Study in HIV-Associated Diarrhea

-A Double Blind, Randomized, Placebo-Controlled, Phase II Study to Assess the Safety and Efficacy of Orally Administered SP-303 for the Symptomatic Treatment of Diarrhea in Patients with AIDS
-Daily measures analysis of four days of 500 mg SP-303 treatment in 51 people (25 placebo//26 SP-303):
- significant reduction in stool weight (p = 0.008)
- significant reduction in stool frequency (p = 0.04)

233

Phase II Study in Traveler’s Diarrhea

-A Double Blind, Randomized, Placebo Controlled Study of SP-303 in the Symptomatic Treatment of Acute Diarrhea Among Travelers to Mexico and Jamaica
-Statistically Significant Reduction in Diarrhea with 250 mg SP-303 (44 people placebo/48 people 250mg SP-303):
- P = 0.0004 Time to Last Unformed Stool at 48 Hours
- P = 0.0002 Time to Last Unformed Stool at 72 Hours
- P = 0.003 >90% of people showed partial or complete improvement of diarrhea in first 24 hours
- Reduction in Abdominal Pain and Urgency

234

Croton lechleri in Euphorbiaceae

-FORMULATIONS: SP-303 (crofelemer), proanthocyanidin compound SB-300 = Standardized extract of bark latex
-MECHANISMS OF ACTIONS: Antidiarrhea antisecretory mechanism: through inhibition of chloride channel secretion in intestinal mucosa
-PRE-CLINICAL & HUMAN CLINICAL STUDIES: Phase I, II, & III human studies in tx of diarrhea
-MODERN MEDICAL USES: Secretory diarrhea: Travelers’diarrhea, AIDS Diarrhea, drug-induced diarrhea

235

33 year old obese female who presents with fatigue: GESTATIONAL & BIRTH HISTORY

• Reports that her Mom was pregnant with her in a village in Romania when the Soviet Union was breaking up and their village had food shortages during the entire pregnancy.
• Born close to term with birth weight of 5 pounds.
• Was given to an orphanage in Bucharest, Romania one month after birth.
• At six months of age was adopted by parents from USA and migrated to northern California to live with her adopted parents.

236

33 year old obese female with
fatigue: DIET HISTORY

• Meat and dairy daily
• Eats refined grain chips, crackers, and white bread.
• Does not eat very many fruits and vegetables.
• Drinks some sweetened sodas and cow’s milk.
• Reports that her diet growing up was similar to
the above description.
• Gets low amounts of exercise with occasional walking.

237

33 year old obese female with fatigue: LAB FINDINGS

• Increased cholesterol, triglycerides, & LDL
• Decreased HDL
• Increased AM fasting insulin
• Increased AM fasting glucose levels
• Normal hemoglobin
• Normal thyroid studies

238

33 year old obese female with fatigue: DIAGNOSES

• Insulin resistance
• Type 2 diabetes mellitus
• Dyslipidemia (abnormal blood lipid levels)
which increases risk for cardiovascular disease
• Hypertension

239

Stages in human life cycle

• Oogenesis in mom and spermatogenesis in father
• Conception of sperm & egg. • Pre-implantation embryo.
• Implanted embryo.
• 1st trimester of pregnancy as embryo through week 8.
• 2nd trimester of pregnancy as fetus with rapid height growth.
• 3rd trimester of pregnancy as fetus with rapid weight growth
and organ maturation.
• Neonatal period.
• Infant/Toddler.
• Childhood.
• Adrenarche & Juvenile stage.
• Puberty.
• Adolescence.
• Adulthood.
• Old age and senescence.

240

Age of menarche in Europe over past 200 years

• Age of menarche has decreased by 4 years over the past 200 years in Europe while the extrinsic mortality rate has fallen and the likelihood of surviving to 15 years has increased (Fig 6-10).

241

Age of menarche

• Age of menarche in females has shown a steady decline worldwide, at a rate of about 3 months per decade over the last century.
Average age of menarche in USA
• 1900 = 14.2 years.
• 1990 = 12.3 years.

242

nutrition in 7-11 years
and menarche

• Anorexia nervosa and other types of deficient caloric intake in ages 7-11 years as well as excessive exercise can lead to low body fat and delayed puberty.
• Some evidence that females must have at least 17% of body weight as fat for sexual maturation to commence and at least 22% for menarche to occur and normal menstrual cycles to continue.
• Obese females ages 7-11 years produce estrone from their adipose tissue that contributes to the estrogen load resulting in reaching puberty at an earlier age than normal weight females

243

Interplay of fetal and childhood nutrition in determining age at menarche (Fig 5.6)

• Light birth weight is associated with earlier menarche
• Heavier weight at eight years of age is associated with earlier menarche
• The group that had light birth weights and were heavy at eight years of age had the earliest menarche
• The group that had heavy birth weights and were light at eight years of age had the latest menarche

244

Stress & menarche

-stress before 7 years can cause early sexual maturation
-stress from 8-11 can delay sexual maturation

245

Adoption and menarche

• Children from tropical countries who are adopted by families in Europe tend to go into puberty significantly earlier.
-stress prior to moving and adjusting to new homes = development of early puberty
-not just because they had to move (migration stresses)

246

-Either low weight or stress in first 7 years of life is associated with
-Either low weight or stress during 8-11 years of age is associated with

- early menarche
- delayed puberty

247

Balance between menarche and psychosocial maturation

-estimated that in the Paleolithic times menarche occurred between 10-12 years of age.
-agriculture and settlement there was an increase risk of undernutrition and disease with associated reduction in skeletal size in 7-10 year olds and a likely delay in mean age of menarche
• The increased social complexity with agriculture and settlement likely required the need for additional time for psychosocial maturation.
• Hence, the increase in mean age of menarche and the need for additional time for psychosocial maturation were likely relatively matched up until around 200 years ago

248

Imbalance between menarche and psychosocial maturation

• This reduced mean age of menarche with associated increased mean age of psychosocial development has resulted in a dramatic imbalance over the past 200 years in industrialized countries (Fig 7.6).
• There is evidence that adolescents with an earlier onset of puberty have higher rates of risk taking behavior, psychological disturbance, depression, and even higher rates of suicide.

249

in-vitro fertilization increases risk of cardiovascular disease and Type 2 diabetes mellitus.

• Individuals conceived by in vitro fertilization (IVF) have an increased risk of cardiovascular disease and Type 2 diabetes mellitus.
• With in vitro fertilization, egg and sperm are placed into a petri dish and zygote is formed and remains in vitro for the next five days as a developing pre-implantation embryo; on day 6 or 7 implantation of embryo commences.
• With in vitro fertilization, the egg, sperm, zygote and pre-implantation embryo do not experience moving through the oviduct for five days where epigenetic modification occurs.

250

Dutch hunger winter of 1944/45: Female fetal exposure to nutrition deprivation from maternal undernutrition in the 1st trimester

- no effect on birth size
- increase obesity as adults
- increase risk of developing breast cancer as adults

251

Dutch hunger winter of 1944/45: Fetal exposure to nutrition deprivation from maternal undernutrition in the 1st & 2nd trimester

- no effect on birth size
- increase glucose intolerance as adults
- increase abnormal blood lipid profiles as adults
- increase abnormal blood coagulation as adults
- increase stress sensitivity as adults
- increase artery disease as adults
-metabolic programming induced by changes in the fetal environment but without a change in birth weight

252

Dutch hunger winter of 1944/45: Fetal exposure to nutrition deprivation from maternal undernutrition in the 3rd trimester

- decrease birth weight
- decrease birth height
- increase cardiovascular disease as adults
- increase hypertension as adults
- increase type 2 diabetes mellitus as adults

253

Modification of insulin resistance
risk alleles by birth weight

• The peroxisome proliferator-activated receptor g(PPAR g) Pro-12®Ala/Pro SNP is reported to be a risk for insulin resistance later in life in a Finnish cohort, but only in those of lower birth size.

254

Predisposition of obesity and type 2 diabetes can be transmitted across generations

• Exposure in utero to maternal hyperglycemia from gestational diabetes, leads to high birth weight, high fat cell number at birth, and increased susceptibility to adult obesity and type 2 diabetes.

255

Birth weight association with later obesity and type 2 diabetes mellitus

• #1: Low birth weight followed by catch-up growth.
• #2: High birth weight followed by accelerated weight gain through childhood.

256

Current Institute of Medicine guidelines
for weight gain during pregnancy

-Body mass index (BMI) is a measure of body fat based on weight and height (see NIH BMI calculator)
• BMI = kg/meters2
• Obese women (BMI 30 or above) should gain 11 to 20 pounds
• Overweight women (BMI 25 to 29.9) should gain 15 to 25 pounds
• Normal weight women (BMI 18.5 to 24.9) should gain 25 to 35 pounds
• Underweight women (BMI <18.5) should gain 28 to 40 pounds

257

Birth size and later death from coronary heart disease in the UK

- risk of heart disease is doubled in individuals born less than 5.5 pounds compared to weight of 9.5
-greater than 9.5 pounds have increase risk of heart disease

258

CASE 8
Early menarche: Life history/developmental related factors

-There was a famine with food deprivation in Romania when this female’s mom was pregnant with her resulting in a low birth weight of five pounds.
• The perception of nutritional insecurity triggered an adaptive predictive response that programmed her to go into early menarche as well obesity later in life
• At one month of age, this female was put in an orphanage in Romania and at six months of age she was adopted by a USA couple and brought to the northern California.
• The stress of being separated from her genetic mother and living in an orphanage, and the stress of adjusting to adoption by new parents and being taken to the USA generated a perception of social stress and instability that triggered an adaptive predictive response that programmed her to go into early menarche.

259

Early menarche: Mismatch with ancestral diet
CASE 8

• Her mismatch with our ancestral diet in her childhood may have contributed to her being overweight by eight years of age which may have contributed to her early menarche.

260

Immediate adaptive responses:

responses which the organism must make to survive a developmental challenge which would otherwise threaten its survival.

261

Predictive adaptive responses:

responses that are made for anticipated need or advantage later in life course.

262

Hypertension:
Life history/developmental factors
CASE 8

• Immediate adaptive responses to reduce nutrition during fetal life minimize growth reduction of the most immediately essential organs (e.g., heart, brain, placenta) by reducing the growth of less immediately critical organs such as the kidney.
• Being born with smaller kidneys and fewer nephrons increases the risk of developing renal hypertension later in life, however fitness related to hypertension may not be reduced if its affects are in post-reproductive years.

263

thrifty epigenotype
influencing a thrifty phenotype.

Fetuses under nutritional stress can have epigenetic control of expression of key genes and phenotypes that alters metabolic set points to program the individual’s physiology to predispose a person to develop an increased propensity to store fat and develop obesity, insulin resistance, and type 2 diabetes especially when living in a calorie rich, low activity environment.

264

Mismatched between predicted nutritional environment and actual nutritional environment
CASE 8

• Since food scarcity did not occur after adoption at six months of age, an incorrect predictive adaptive response was generated that resulted in mismatch between predicted nutritional caloric environment and her actual post-birth nutritional caloric environment.
• Her predictive adaptive response programmed her to be inclined toward an increased propensity to store fat which resulted in her development of obesity, insulin resistance, type 2 diabetes mellitus, and cardiovascular disease because she lives in a calorie rich environment.