and Disease FIGURE 381 Gut microbiota shape the immune system to promote microbiotahost mutualism Abbreviations IL interleukin TH Thelper cell Treg Tregulatory cell PSA polysaccharide A see text also ID: 779776
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Slide1
Chapter 38
Gut
Microbial Metabolism in Health
and Disease
Slide2FIGURE
38.1:
Gut microbiota shape the immune system to promote microbiotahost mutualism. Abbreviations: IL, interleukin; TH, T-helper cell; Treg, T-regulatory cell; PSA, polysaccharide A (see text also).
Copyright © 2016 Elsevier Inc. All rights reserved.
Slide3FIGURE
38.2:
(A) The TRP - 5-HT - Melatonin metabolic pathway. (B) The TRP - KYN metabolic pathway. Abbreviations: NAS, N-acetylserotonin; 5-HTR2B,3A, 5-HT receptor 2B,3A; β-AR, β-
adrenergic receptor; Ucp-1, uncoupling protein-1; BAT, brown adipose tissue; GPR35
, G-protein
coupled receptor-35; NAD, nicotinamide adenine dinucleotide; iNOS, inducible nitric oxide synthase; NO, nitric oxide; PLA2, phospholipase A2; AA, arachidonic acid; COX-2, cyclooxygenase-2; PGE, prostaglandin; 5-LOX, arachidonate 5-lipoxygenase; AAND, age-associated neuroendocrine disorders; IFN, interferon; TNFα, tumor necrosis factor-α.
Copyright © 2016 Elsevier Inc. All rights reserved.
Slide4FIGURE
43.4:
The pathway for inactivation of vitamin D involving conversion of either 25-hydroxyvitamin D [25(OH)D] or 1,25-dihydroxyvitamin D [1,25(OH)2D] by the enzyme CYP24. From W.L. Miller, Genetic disorders of vitamin D biosynthesis and degradation, J. Steroid Biochem. Mol. Biol. 165
(2017) 101108.
Copyright © 2016 Elsevier Inc. All rights reserved.
Slide5FIGURE
38.3:
(A) The effect of SCFAs in IEC, (B) liver, and (C) WAT (see text for details). Abbreviations: HDAC, histone deacetylase; ACC, acetyl-CoA decarboxylase.Copyright © 2016 Elsevier Inc. All rights reserved.
Slide6FIGURE 38.4 TLR4 activation. LPS binds to LPB and then to
the CD14
accessory protein. LPS is then transferred to the next TLR4 accessory molecule, MD-2. Two TLR4/MD-2/LPS complexes must then dimerize to initiate the internal cell signaling pathways. There are two
pathways for
TLR4, MyD88 dependent and MyD88 independent, which lead to
production of inflammatory cytokines/ROS and IFNs, respectively. Abbreviations: CD, cluster of differentiation; LPB, liposaccharide-binding protein; MD-2, myeloid differentiation factor; MyD88, myeloid differentiating primary response gene 88; TIRAP, toll-interleukin 1 receptor domain containing adaptor protein; TRIF, TIR-domain-containing adaptorinducinginterferon-B; TRAM, toll-like receptor adaptor molecule 2.
Copyright © 2016 Elsevier Inc. All rights reserved.
Slide7FIGURE
38.5:
(A) The gut-brain axis. (B) The antiinflammatory effect of the VN via the cholinergic pathway. ACh is released at the distal end of VN efferent
fibers
which activates the α7nAChR receptor in macrophages. The activation of α7nAChR causes inhibition of TNFR receptor
activation by TNFα thus preventing downstream activation of NF-κB signaling. Additionally, activation of α7nAChR causes activation of a JAK-STAT mediated antiinflammatory pathway [81]. Abbreviations: TNFR, tumor necrosis factor receptor; CRF, corticotrophin-releasing factor; JAK, Janus kinase;
STAT, signal transducer and activator of transcription. ACTH, adrenocorticotropic hormone; DMN, dorsal motor nucleus of the
vagus
(origin of
VN
efferents
); EN, epinephrine; LC, locus
ceruleus
(the primary brain noradrenergic nucleus located in the pons and involved in the stress response); NE
, norepinephrine
; PVN, paraventricular nucleus of the hypothalamus (source of corticotrophin-releasing factor, CRF); RVM, rostral
ventrolateral medulla
; NTS, nucleus tractus solitarii (termination point for vagus efferents).
Copyright © 2016 Elsevier Inc. All rights reserved.
Slide8FIGURE 38.6 (A) Structure of the TJ between adjacent IECs. Transmembrane proteins
occludin
, claudin, and JAM family proteins seal the paracellular space between IECs. Plaque proteins such as ZO family proteins bind to one another to form a stabilizing scaffold and a direct link to the cytoskeleton via
ZO-1 binding to F-actin. (B) The effect of PICs that have been found to be increased in healthy, normal weight seniors on the TJ
. Activated
macrophages (Fig. 38.1) produce TNFα, IL-1β, and IL-6 as well as IL-12. IL-12 goes on to stimulate production of TH1 cells that secrete IFNγ. TNFα binds to the TNFR1 receptor on IECs and causes activation of NF-κB and its subsequent translocation to the nucleus where it acts as atranscription factor for the MLCK promoter resulting in production of MLCK protein. MLCK then phosphorylates MLC to MLC-P which then acts on F-actin to cause cytoskeletal contraction and opening of the TJ. IL-1β has been shown to downregulate the expression of occludin and also acts via NF-κB
- MLC-P to cause TJ opening. IL-6 has been shown to decrease expression of ZO-1 causing disruption of the TJ stabilizing scaffold.
IFNγ
, also
via MLC-P, has been shown to increase IEC
macropinocytosis
of
occludin
and JAM proteins, thus removing them from the
paracellular
space.
The culmination of all of these effects is a “leaky” mucosal membrane. Abbreviations: MLCK, myosin light chain kinase; MLC, myosin light chain protein; TNFR1, tumor necrosis factor receptor-1.Copyright © 2016 Elsevier Inc. All rights reserved.